EPFL School of life sciences Annual Report 15-16 by EPFL School of Life Sciences

Introduction

Photos cover: Courtesy of School of life sciences - BIOP Technology Platform - Arne Seitz 2

Introduction

Welcome to SV The School of Life Sciences has set itself the goal to teach students at the interfaces between biology, engineering, mathematics, physics and chemistry leading to quantitative, analytical and design-oriented life scientists through the acquisition of a Bachelor of Science in Life Sciences and Technology, a Master of Science in Life Sciences and Technology or Bioengineering, or a Doctor of Philosophy in Molecular Life Sciences, Neurosciences, or Biotechnology and Bioengineering. The School’s professors reflect its aims, coming from diverse backgrounds in biology, chemistry, physics, engineering and medicine. They share their passion for developing new fundamental understanding of critical questions in the life sciences and translating that understanding towards impacting human health through engineering solutions.

Gisou van der Goot - Dean of the School of life sciences

Since its launching in the early 2000’s, the Faculty of Life Sciences is continuing its ascendance, as illustrated by the numerous ERC awards at all levels (Starter, Consolidator and Advanced), the increase of our position in the various rankings of the world academic institutions and the frequent prize awards received by the various Life Science professors and other members. The School of Life Sciences also greatly benefits from the dynamism of the Lemanic region, the so-called Health Valley, leading or participating in various projects bringing together the Universities of Lausanne and Geneva, the University Hospitals of the two cities and EPFL. These include the Campus Biotech in Geneva which hosts the Wyss Center for neuroengineering and the EPFL Center for Neuro-prosthetics and the Swiss Cancer Center Lausanne.

Table Of Contents Welcome to SV............................................................................................................................................... 3 School of Life Sciences at a Glance................................................................................................................ 5 Undergraduate Studies.................................................................................................................................... 6 Doctoral Programs.......................................................................................................................................... 7 SV Doctoral Graduates 2015.......................................................................................................................... 8 SV Doctoral Graduates 2016.......................................................................................................................... 9 SV Doctoral Graduates 2016 - cont’d............................................................................................................ 10 Honors & Awards 2015 & 2016.................................................................................................................... 11 SV Master’s Graduates 2015......................................................................................................................... 12 SV Master’s Graduates 2016......................................................................................................................... 13 Blue Brain Project......................................................................................................................................... 14 Center for Biomedical Imaging Research...................................................................................................... 16 Center for Neuroprosthetics.......................................................................................................................... 18

BMI.............................................................................................................................................. 21 Aebischer Lab............................................................................................................................................... 22 Blanke Lab................................................................................................................................................... 24 Courtine Lab................................................................................................................................................. 26 Gerstner Lab................................................................................................................................................. 28 Gräff Lab...................................................................................................................................................... 30 Herzog Lab................................................................................................................................................... 32 HessBellwald Lab......................................................................................................................................... 34 Lashuel Lab.................................................................................................................................................. 36 Magistretti Lab.............................................................................................................................................. 38 Markram Lab................................................................................................................................................ 40 Petersen Lab................................................................................................................................................. 42 Sandi Lab..................................................................................................................................................... 44 Schneggenburger Lab................................................................................................................................... 46 Hill Lab........................................................................................................................................................ 48 Schürmann Lab............................................................................................................................................. 50

IBI................................................................................................................................................ 53 Auwerx Lab.................................................................................................................................................. 54 Baekkeskov Lab............................................................................................................................................ 56 Barrandon Lab.............................................................................................................................................. 58 Dal Peraro Lab.............................................................................................................................................. 60 Deplancke Lab............................................................................................................................................. 62 Hubbell Lab................................................................................................................................................. 64 Jensen Lab.................................................................................................................................................... 66 Lutolf Lab..................................................................................................................................................... 68 Naef Lab....................................................................................................................................................... 70 Naveiras Lab................................................................................................................................................. 72 Schoonjans Lab............................................................................................................................................ 74 Suter Lab...................................................................................................................................................... 76 BIOS Lab...................................................................................................................................................... 80 Aminian Lab................................................................................................................................................. 82 Fantner Lab................................................................................................................................................... 84 Ghezzi Lab................................................................................................................................................... 86 Guiducci Lab................................................................................................................................................ 88 Hatzimanikatis Lab....................................................................................................................................... 90 Ijspeert Lab................................................................................................................................................... 92 Johnsson Lab................................................................................................................................................ 94 Lacour Lab................................................................................................................................................... 96 Lasser Lab..................................................................................................................................................... 98 Maerkl Lab................................................................................................................................................. 100

Mermod Lab............................................................................................................................................... 102 Micera Lab................................................................................................................................................. 104 Millán Lab.................................................................................................................................................. 106 Pioletti Lab................................................................................................................................................. 108 Psaltis Lab.................................................................................................................................................. 110 Radenovic Lab............................................................................................................................................ 112 Roke Lab.................................................................................................................................................... 114 Stellacci Lab............................................................................................................................................... 116 Stergiopoulos Lab....................................................................................................................................... 118 Van de Ville Lab.......................................................................................................................................... 120

GHI............................................................................................................................................ 123 Ablasser Lab............................................................................................................................................... 124 Blokesch Lab.............................................................................................................................................. 126 Cole Lab..................................................................................................................................................... 128 Fellay Lab................................................................................................................................................... 130 Harris Lab................................................................................................................................................... 132 Lemaitre Lab............................................................................................................................................... 134 McKinney Lab............................................................................................................................................ 136 Salathé Lab................................................................................................................................................. 138 Trono Lab................................................................................................................................................... 140 Van der Goot Lab....................................................................................................................................... 142

ISREC......................................................................................................................................... 145 Brisken Lab................................................................................................................................................. 146 Constam Lab.............................................................................................................................................. 148 De Palma Lab............................................................................................................................................. 150 Duboule Lab.............................................................................................................................................. 152 Gönczy Lab................................................................................................................................................ 154 Hanahan Lab.............................................................................................................................................. 156 Hantschel Lab............................................................................................................................................. 158 Huelsken Lab............................................................................................................................................. 160 Lingner Lab................................................................................................................................................ 162 Meylan Lab................................................................................................................................................ 164 Oricchio Lab.............................................................................................................................................. 166 Radtke Lab................................................................................................................................................. 168 Simanis Lab................................................................................................................................................ 170 Bucher Lab................................................................................................................................................. 172

Core Facilities & Technology Platforms...................................................................................... 175 Bioelectron Microscopy - BioEM................................................................................................................ 176 BioImaging & Optics - BIOP....................................................................................................................... 177 Bioinformatics & Biostatistics - BBCF.......................................................................................................... 178 Biomolecular Screening - BSF..................................................................................................................... 179 Flow Cytometry - FCCF............................................................................................................................... 180 Gene Expression Core Facility - GECF......................................................................................................... 181 Histology - HCF & Comparative Pathology................................................................................................. 182 Proteomics - PCF-PTP................................................................................................................................. 183 Protein Crystallography - PCRYCF............................................................................................................... 184 Protein Expression Technology - PTEP......................................................................................................... 185 Centre of PhenoGenomics - Transgenic - CPG-TCF..................................................................................... 186 Center of PhenoGenomics - Phenotyping - CPG-UDP................................................................................ 187

Introduction

School of life sciences at a glance Core Facilities

DEAN G. Van der Goot

School Council

Deputy H.Hirling

School Directory Board

Doctoral Schools

BMI Brain Mind Institute

IBI Institute of Bioengineering

GHI Global Health Institute

Director: C. Sandi

Director: M. LĂźtolf (interfaculty SV-STI)

Director: S. Cole

General Services

Directors + 4 full professors

ISREC Swiss Institute for Experimental Cancer Research Director: D. Hanahan

Faculty Assembly

All professors

Teaching Section BA/MA programs

Director: J. McKinney

Undergraduate Studies The Life Sciences and Technology curriculum aims to educate a new generation of engineers who will master the technical and scientific skills needed for studying life processes and developing the biomedical technologies of tomorrow. This educational program is unique in Switzerland and Europe.

Bachelor Program (3 years)

The first two years focus on foundational courses including analysis, linear algebra, numerical analysis, probability and statistics, physics, inorganic chemistry, organic chemistry, and computer programming. Courses in engineering and life sciences begin with general biology, biochemistry, cellular and molecular biology, biothermodynamics, and fluid mechanics. In the first two years, life sciences courses make up less than 20% of the total academic workload. Students also begin to acquire hands-on skills by participating in lab-based practical courses. In the third year, engineering courses (signals and systems, electrical systems and electronics, mathematical and computational modeling) and life sciences are integrated through courses on systems physiology and physical biology. During this year, students begin to fine-tune their training by choosing specific credits from a list of optional courses in engineering and life sciences to prepare iGEMinteam medal for theirthird innovative themselves for one of the orientations 2014 offered ourreceived Mastera gold programs. The year also includes a lab-based Bachelor project in a subject area of the studentâ&#x20AC;&#x2122;s choosing, such as biocomputing, Biopad design at the MIT competion, USA. bioengineering, biomedical technologies, molecular medicine, neurosciences, etc. Photo: Bruno Liardon

Master Programs (2 years)

The Master in Life Sciences and Technology includes orientations in Neurosciences and Neuroengineering or Molecular Medicine and Systems Biology. Each orientation comprises a coherent group of optional courses providing basic as well as advanced knowledge in the chosen field. Students aiming to focus their training on specific interdisciplinary subjects may choose different minors such as Biocomputing, Computational Neurosciences, or Neuroprosthetics. Each minor requires 30 specific credits selected with the guidance of a mentor. The Master in Bioengineering is organized in collaboration with EPFLâ&#x20AC;&#x2122;s School of Engineering and includes orientations in Biomechanical Engineering, Biophotonics and Bioimaging, Nanoscale Bioengineering, Regenerative Medicine, or Systems Bioengineering. Each orientation comprises a coherent group of optional courses providing basic as well as advanced knowledge in the chosen field. Students aiming to focus their training on specific interdisciplinary subjects may choose different minors such as Biocomputing, Biomedical Technologies, Biotechnologies, or Neuroprosthetics. Each minor requires 30 specific credits selected with the guidance of a mentor. Both Master programs share a common basic curriculum that aims to provide students with a working knowledge of skills and technologies used in the life sciences such as biostatistics, bioimaging, and biocomputing. In addition, students may take courses in management, law, organization, economics, and ethics for the life sciences and may choose a minor in Management, Technology and Entrepreneurship. A large portion of the Master program (up to 60 credits) can be dedicated to lab-based work and projects. http://ssv.epfl.ch/

Bertrand Rey - photographer

Doctoral Programs

Introduction

All three graduate programs combine coursework, laboratory-based research, in-house seminars, and national or international conferences. Highly qualified applicants worldwide are chosen during our Hiring Days which occur twice a year, the end of January and the end of June. Hiring Days last two and a half days: one-half day of general information followed by two days of lab immersion and evaluation. Molecular Life Sciences (EDMS) aims at providing doctoral students with the education necessary to become leaders in biological research, implementing the latest state of the art. The combination of laboratorybased research with access to modern technological platforms, course work, in-house seminars with prominent speakers, national and international conferences, etc., forms the basis of this education. The EDMS program offers PhD positions to talented and ambitious young researchers in diverse and interdisciplinary fields that include cell & developmental biology, biochemistry & biophysics, molecular genetics, cancer research, microbiology, host-pathogen interactions, immunology, systems biology, computational biology, human genetics, stem cells and metabolism. phd.epfl.ch/edms

Biotechnology and Bioengineering (EDBB)

prepares doctoral students to become leaders in the fast-growing sectors of biotechnology and bioengineering in the academic and industrial context. Within the interdisciplinary setting of the Institute of Bioengineering (IBI) at the intersection between the School of Life Sciences and the School of Engineering, EDBB provides a depth of knowledge and competence in the following focus areas: biomolecular engineering and biomaterials; cell, tissue, and process engineering; biomechanics and mechanobiology; molecular and cellular biophysics; stem cell biotechnology; advanced biomedical imaging and image processing; microtechnology and nanotechnology; orthopaedic engineering; biomimetic robotics; computational biology; â&#x20AC;&#x2DC;omicsâ&#x20AC;&#x2122; technologies (genomics, transcriptomics, proteomics, metabolomics). phd.epfl.ch/edbb

Neuroscience (EDNE)

provides its students with training from the genetic to the behavioural level which includes the molecular, cellular, cognitive, computational neuroscience and neuro-prosthetic aspects of neuroscience research. EDNE students come from a wide variety of backgrounds including physics, engineering, biology, medicine and psychology which enhances the highly dynamic and interdisciplinary environment of the program. Currently the Doctoral Program in Neuroscience has 83 students in 30 affiliated laboratories across the EPFL campus, the Geneva Bio-campus and the EPFL satellite in Sion. The program is also further strengthened by research and training opportunities in collaboration with the Universities of Lausanne and Geneva. http://phd.epfl.ch/edne

SV Doctoral Graduates 2015 Name

Programme

Thesis Director(s)

Thesis Title

Bernet Florian Urs

EDMS

Constam Daniel

Regulation of the mRNA silencing activity of Bicaudal-C

Bürgi Jérôme

EDMS

van der Goot Gisou

Unraveling the Physiological Role of Capillary Morphogenesis Gene 2 in Health and Disease

Buric Duje

EDMS

Brisken Cathrin

Mechanisms underlying cell-fate determination in the mammary gland development

Chng Wen Bin

EDMS

Lemaitre Bruno

Redefining the metabolic landscape through TGF-beta/Activin signaling in Drosophila melanogaster

Coersmeyer Monique

EDMS

Radtke Freddy

The chromatin remodeller Chd7 and the calcium ATPase Serca2 - adding new facets to the role of Notch in Hematopoiesis and T-ALL

Lemaire Laurence Anne E

EDMS

Constam Daniel, Grapin-Botton Anne

Bicaudal C1 promotes pancreatic NEUROG3+ endocrine progenitor differentiation and ductal morphogenesis

Masin Mark Jonathan

EDMS

Meylan Etienne

GLUT1 and GLUT3 in non-small cell lung cancer

Pennese Natali

EDMS

Trono Didier, Turelli Priscilla

Evolutionally dynamic control of LINE-1 elements in embryonic stem cells

Reinmüller Viktoria

EDMS

Radtke Freddy, Zhu Jieping

Lead Optimisation of a Novel Small Molecule Notch Inhibitor

Allazetta Simone

EDBB

Matthias Lütolf

Microfluidic engineering of artificial stem cell niches

Balasubramanian Sowmya

EDBB

Florian Maria Wurm, David Hacker

Study of transposon-mediated cell pool and cell line generation in CHO cells

Becker Johannes

EDBB

Felix Naef, Sebastian Maerkl

Quantitative single-cell analysis of S. cerevisiae using a microfluidic live-cell imaging platform

Cédric Paulou

EDBB

Stéphanie Lacour

Interactions of Peripheral Nerve Cells with Soft Micropillar Interfaces

Fares Mohamed-Bila

EDBB

Hilal Lashuel

Recapitulating De Novo Alpha-Synuclein Fibrillization in a Novel Neuronal Model of Parkinson's Disease

Ferretti Anna

EDBB

Carlotta Guiducci

Quantification of low molecular weight drugs: from the selection of nucleic acid-based capture molecules to the characterization in patient samples

Gencer Akçok Emel Başak

EDBB

Oliver Hantschel

Functional Perturbation of the Gab2 Multiprotein Complex by High-affinity SH2-binding Monobodies in Chronic Myelogenous Leukemia

Girotra Mukul

EDBB

Matthias Lütolf

Deciphering Metabolic Regulation of Hematopoietic Stem Cell Fate

Höhnel Sylke

EDBB

Matthias Lütolf

Bioengineering approaches to emulate the stem cell niche

Kasten Jeffrey Adam

EDBB

Dimitri Van De Ville, François Lazeyras

Superresolution Reconstruction for Magnetic Resonance Spectroscopic Imaging Exploiting Low-Rank Spatio-Spectral Structure

Kiveliö Anna-Sofia Johanna

EDBB

Jeffrey Hubbell, Martin Ehrbar

Tissue engineering for prenatal applications

Marzetta Flavia

EDBB

Didier Trono, Priscilla Turelli

Transposable elements and their KRAB/KAP1 controllers broadly regulate transcription in adult human cells

Niederholtmeyer Henrike Marie

EDBB

Sebastian Maerkl

Implementation and Characterization of Dynamic Genetic Networks in Vitro

Pezeshgi Modarres Hasan

EDBB

Matteo Dal Peraro

Modeling and Engineering Proteins Thermostability

Shivanandan Arun

EDBB

Aleksandra Radenovic, Ivo Sbalzarini

Analytical Methods, Correlative Microscopy and Software Tools for Quantitative Single Molecule Localization Microscopy

Tymoshenko Stepan

EDBB

Vassily Hatzimanikatis, Dominique Soldati-Favre

Reconstruction and systems analysis of metabolism in apicomplexan parasites Toxoplasma gondii and Plasmodium falciparum

Vardar Elif

EDBB

Jeffrey Hubbell, Peter Frey

Bio-engineered collagen-fibrin scaffolds for enhancing urological tissue regeneration

Zhang Huaijian

EDBB

Jose Millan

Connectivity Analysis of Brain States and Applications in Brain-Computer Interfaces

Bapst Linda

EDNE

Schorderet Daniel Francis

Elucidating the role of Hmx1 during mouse development.

Chicherov Vitaly

EDNE

Herzog Michael

Vision in clutter: neural correlates of visual crowding

Forget Joachim Jean-Marie

EDNE

Blanke Olaf, Meuli Reto

Visuo-vestibular mechanisms of bodily self-consciousness

Gale Steven

EDNE

Blanke Olaf

Vestibular Processing and its Cortical Signature in Humans

Ghobril Jean-Pierre

EDNE

Markram Henry, Pavone Francesco Saverio

Large Volume Imaging of Rodent Brain Anatomy with Emphasis on Selective Plane Illumination Microscopy

Kaliuzhna Mariia

EDNE

Blanke Olaf, Mast Fred

Balancing the Self

Lozano Montes Laura

EDNE

Sandil Carmen

The impact of anxiety and reward-seeking traits on social competition and the role of the mesolimbic dopaminergic system

Pfeiffer Christian

EDNE

Blanke Olaf

Vestibular contribution to bodily self-consciousness and multisensory cortical processing

Sreenivasan Varun

EDNE

Petersen Carl

Motor Control in the Mouse Whisker System

Zenger Manuel Raphael

EDNE

Magistretti Pierre

Deciphering the astrocyte-neuron metabolic cooperation in vivo

Introduction

SV Doctoral Graduates 2016

Name

Programme

Thesis Director(s)

Thesis Title

Bou Sleiman Maroun

EDMS

Lemaitre Bruno, Deplancke Bart

The Drosophila gut response to infection: a systems approach

Cannavo Rosamaria

EDMS

Naef Felix

Circadian Rhythm and Cell Cycle: two Synchronized Processes

De Simone Alessandro

EDMS

Gönczy Pierre, Naef Felix

Mechanisms of centrosome separation in C. elegans

Ducommun Serge Thanh Son

EDMS

Sakamoto Kei, Auwerx Johan

AMP-activated protein kinase: strategies for activation and downstream target identification

Jain Chhavi

EDMS

Radtke Freddy

Identification and functional characterization of protein kinases that modulate Notch signaling under physiological conditions and in cancer

Kopparam Jawahar

EDMS

Meylan Etienne

ROLE OF RIP4 IN LUNG ADENOCARCINOMA DIFFERENTIATION

Lou Ye

EDMS

Cole Stewart

Structural and functional characterization of the mycobacterial ESX-1 secretion system

Moraru Manuela

EDMS

Simanis Viesturs

Identification of genetic interactors of ypa2 in Schizosaccharomyces pombe

Pluchinotta Matteo

EDMS

Barrandon Yann

A balancing act between stratification and EMT in cultured human thymic epithelial cells

Sandoz Sarah Elisabeth

EDMS

van der Goot Gisou

Folding and Endocytosis of Anthrax Toxin Receptors

Sobel Jonathan Aryeh

EDMS

Naef Felix

Phase specific transcriptional regulation of circadian clock and metabolism in mouse liver

Tatárová Zuzana

EDMS

Hülsken Jörg, Maerkl Sebastian

Development of microfluidic devices for chemotaxis of primary stem cells

Zaffalon Andrea

EDMS

Barrandon Yann

Capturing epidermal stemness

Asgari Samira

EDBB

Fellay Jacques

Host and pathogen genomics of severe pediatric infections

Baer Caroline Maïté

EDBB

De Palma Michele

Role of microRNAs in tumor-associated macrophages

Blackburn Matthew Christopher

EDBB

Maerkl Sebastian

Integrating Gene Synthesis and MITOMI for Rapid Protein Engineering

Bornert Alicia Carine

EDBB

Verkhovskiy Alexander

Protrusion-retraction switches and traction forces in spontaneous cell polarization

Briquez Priscilla Suhasna Maithili

EDBB

Hubbell Jeffrey

Therapeutic Proteins Engineered for Super-Affinity to the Extracellular Matrix in Regenerative Medicine

Damo Martina

EDBB

Hubbell Jeffrey

Bioengineering approaches in immunotherapy:from basic to translational applications

Delincé Matthieu Jean-Hubert

EDBB

McKinney John

Quantitative Single-Cell Analysis of Host-Pathogen Interactions

Ecco Gabriela

EDBB

Trono Didier, Turelli Priscilla

Unraveling the KRAB/KAP1 control of transposable elements in pluripotent and somatic cells

Fankhauser Manuel Andreas

EDBB

Swartz Melody

Engineering Lymphangiogenesis: Implications for Cancer Immunotherapy and Beyond

Grimm Alizée Jéléna

EDBB

Hubbell Jeffrey Alan

Mechanisms of tolerance induction by erythrocyte-targeted antigens

Hausherr Tanja Cloé

EDBB

Pioletti Dominique

In vivo mechanical loading combined with cell therapy in a bone tissue engineering scaffold

Jovaisaite Virginija

EDBB

Auwerx Johan

Mitochondrial unfolded protein response, its molecular mechanism and physiological impact

Julier Ziad

EDBB

Hubbell Jeffrey

Engineering the Extra Domain A of fibronectin as a vaccine adjuvant and study of its role in tissue regeneration

Khaliliardali Zahra

EDBB

Millán Ruiz José del Rocío

BCI based on Neural Correlates of Anticipatory Behavior during Driving

Kolb Laura

EDBB

Lütolf Matthias

Stem cell niche engineering through photopatterning and microfluidics

Lamontanara Allan Joaquim

EDBB

Hantschel Oliver

Allosteric regulation and targeting of Abl SH2-kinase interface and other cytoplasmic tyrosine kinases

Laporte Grégoire Pierre Jean

EDBB

Psaltis Demetri

Nanoscopy in nonlinear scanning fluorescence imaging systems

Lukjanenko Laura

EDBB

Feige Jérome, Auwerx Johan

Novel interventions to recover the regenerative capacity of aged skeletal muscle by targeting the interactions in the stem cell niche

Manti Pierluigi Giuseppe

EDBB

Barrandon Yann

From the early steps of whisker formation to its evolutionary disappearance: the (curious) case of Prdm1 and its regulation

Metzger Stéphanie Elisabeth

EDBB

Hubbell Jeffrey, Ehrbar Martin

Tunable and cell-responsive 3D poly(ethylene glycol) microenvironments for the development of tissue models

Moufawad El Achkar Christopher

EDBB

Aminian Kamiar

Instrumented shoes for daily activity monitoring in healthy and at risk populations

Muller Georges

EDBB

Barrandon Yann, Renaud Philippe

Microwell and impedance-based approaches to isolate single cells for life sciences

Odermatt Pascal Damian

EDBB

Fantner Georg

Mechanical and Functional Study of Cell Physiology at the Nanoscale

SV Doctoral Graduates 2016 - cont’d Name

Programme

Thesis Director(s)

Thesis Title

Panagiotou Vasiliki

EDBB

Hubbell Jeffrey

Protein engineering approaches for direct antigen targeting in CD8+ T cell inducing vaccines

Qiu Tian

EDBB

Hubbell Jeffrey, Fischer Peer

Microdevices for Locomotion in Complex Biological Fluids

Ren Yufei

EDBB

Renaud Philippe

Towards brain-on-a-chip: Microfluidic and microelectrode array platforms for morphological and electrophysiological observations on the propagation of Alzheimer's disease

Rincón-Restrepo Marcela

EDBB

Swartz Melody, Hirosue Sachiko

Engineering nanoparticle-based vaccines: Implications for the quality of humoral and cellular immunity

Vokali Efthymia

EDBB

Swartz Melody

New immunomodulatory roles of lymphatic endothelium and implications for immunotherapy

Xu Pan

EDBB

Schoonjans Kristina

Deciphering the Role of LRH-1 in Liver Intermediary Metabolism and Cancer

Zhang Hongbo

EDBB

Auwerx Johan

Metabolic control of muscle and muscle stem cell function

Bapst Linda

EDNE

Schorderet Daniel Francis

Elucidating the role of Hmx1 during mouse development

Bobela Wojceich Janusz

EDNE

Aebischer Patrick, Schneider Bernard

Modulation of AMPK's activity via genetic tools and food-derived compounds as a novel approach to Parkinson's disease treatment

Chicherov Vitaly

EDNE

Herzog Michael

Vision in clutter: neural correlates of visual crowding

Forget Joachim Jean-Marie

EDNE

Blanke Olaf, Meuli Reto

Visuo-vestibular mechanisms of bodily self-consciousness

Gale Steven

EDNE

Blanke Olaf

Vestibular Processing and its Cortical Signature in Humans

Ghobril Jean-Pierre

EDNE

Markram Henry, Pavone Francesco Saverio

Large Volume Imaging of Rodent Brain Anatomy with Emphasis on Selective Plane Illumination Microscopy

Grzeczkowski Lukasz

EDNE

Herzog Michael, Mast Fred

Hyper-specificity of perceptual learning

Kaliuzhna Mariia

EDNE

Blanke Olaf, Mast Fred

Balancing the Self

Kronander Elin Kristina

EDNE

Schneggenburger Ralf

Genetic dissection of the role of BMP signaling for the development of the auditory brainstem nuclei and the large calyx of Held synapse

Lozano Montes Laura

EDNE

Sandi Perez Maria del Carmen

The impact of anxiety and reward-seeking traits on social competition and the role of the mesolimbic dopaminergic system

Mosser Sébastien

EDNE

Fraering Patrick

Endogenous Regulators of Gamma-Secretase and Amyloid-Beta Production, and Engineering of Alzheimer's Disease Therapeutic Tools

Palczynska Magda Maria

EDNE

Fraering Patrick

Proteolytic processing of the synaptic cell adhesion molecule neurexin-3beta and the neurobiological functions of the resulting cleavage products

Pfeiffer Christian

EDNE

Blanke Olaf

Vestibular contribution to bodily self-consciousness and multisensory cortical processing

Pozeg Polona

EDNE

Blanke Olaf

Multisensory and sensorimotor origins of the sense of self

Richardet Renaud Luc

EDNE

Markram Henry, Chappelier Jean-Cédric

Agile In-Litero Experiments; How can semi-automated information extraction from neuroscientific literature help neuroscience model building?

Sreenivasan Varun

EDNE

Petersen Carl

Motor Control in the Mouse Whisker System

Walker Sophie Elizabeth

EDNE

Sandi Perez Maria del Carmen

Implication of individual differences in glucocorticoid responsiveness to stress in the development of psychopathology-like behaviour and underlying neurobiology

Zenger Manuel Raphael

EDNE

Magistretti Pierre

Deciphering the astrocyte-neuron metabolic cooperation in vivo

Zheng Lu

EDNE

Aebischer Patrick, Schneider Bernard

The effect of the functional interaction between PGC-1alpha and Parkin on mitochondrial quality control in Parkinson's disease

Introduction

Honors & Awards 2015 & 2016 Name

Programme

Michele De Palma

European Research Council’s (ERC) Consolidator Grant

Ewan Williams

EPFL Doctorate Award 2016

Melanie Blokesch

European Research Council’s (ERC) Consolidator Grant

EPFL-SV 2016 IGEM team

Gold medal at the International Genetically Engineered Machine (IGEM)

Kathryn Hess-Bellwald

Nominated Fellows of the American Mathematical Society (AMS) for 2017

Julie Scotton

Winner of EPFL’s My Thesis in 180 Seconds competition 2016

Yann Barrandon

EPFL-AGEPOLY Polysphere Award 2016 for the best professor

Etienne Meylan

EPFL-SV 2016 Teaching prize

Johan Auwerx

Marcel Benoist 2016 prize

Stewart Cole

Gardner Middlebrook Life Achievement Award

Carmen Sandi

Nominated President-elect of the Federation of European Neuroscience Societies (FENS)

Ossama Khalaf

Winner of the 2016 Swiss FameLab

Melanie Blokesch

Named School of life sciences Associate Professor

Henry Markram

Bell Labs Shannon Visionary Award 2016

Andrea Serino

Leenaards Foundation Award 2016 for translational biomedical research

Grégoire Courtine and Oliver Hantschel

European Research Council’s (ERC) Consolidator Grant

Gisou van der Goot

Lelio Orci Award 2015 for outstanding scientists

Kathryn Hess-Bellwald

Elected individual member of the Swiss Academy of Engineering Sciences (SATW)

Johannes Gräff

Winner of the 2015 Fellows Awards for Mental Health Science

Melanie Blokesch

EPFL-AGEPOLY Polysphere Award 2015 for the best professor

Joerg Huelsken

Winner of the 2015 Swiss Bridge Foundation (SBF) Award for cancer research

Pierre Magistretti

Winner of the 2016 IPSEN Foundation Neuronal Plasticity prize

Kristina Schoonjans

Named School of life sciences Associate Professor

Jacques Fellay and Anisoara Ionescu

Leenaards Foundation Award 2015 for translational biomedical research

Giulia Manina and Jan Rybniker

Swiss Foundation for Tuberculosis Research (SwissTB) 2015 Award

Stewart Cole

Elected to French National Academy of Pharmacy

SV Master’s Graduates 2015 Master’s in Life Sciences & Technology Name

Host Laboratory

Name

Host Laboratory

Name

Host Laboratory

Alter Laurent

McKinney John

Colombo Florian François

Gerstner Wulfram

Moret Bernard Fabio

Meylan Etienne

Altermatt Anna Barbara

Petersen Carl

De Jonghe Joachim

McKinney John

Petit Gaëtan

Herzog Michael

Arrigo Marcelle Isaline

Trono Didier

De Pierrefeu Amicie Marie Servane

Gruetter Rolf

Putallaz Lauréanne

Schneider Bernard

Aydarkhanov Ruslan

Millán Ruiz José del Rocío

De Tribolet-Hardy Jonas

Trono Didier

Sanz Pablo

Blanke Olaf

Barnichon Pierre-Alexandre

Blokesch Melanie

Doerig Adrien Christophe

Herzog Michael

Simonet Thomas Marie

Maerkl Sebastian

Blondiaux-Garcia Fuente Eva

Blanke Olaf

Drissi Daoudi Leila

Micera Silvestro

Spaltenstein Marc

von Gunten Urs

Bornet Alban

Gerstner Wulfram

Giesbrecht Lucie

De Palma Michele

Study Morgane

Harris Nicola

Boulet Coralie

McKinney John

Guex Jean-Guillaume

Stergiopulos Nikolaos

Sturny Mikaël Nils

Stergiopulos Nikolaos

Chassouant Marion Eva Eugénie

Harris Nicola

Läderach Linda Kathrin

Lingner Joachim

Zisis Eleftherios

Schürmann Felix

Chenais Naïg Aurelia Ludmilla

Courtine Grégoire

Levy Simon

Schneider Bernard

Cheseaux Muriel Marie Célestine

Kussmann Martin

Monney Bastien Charly Fernand

van der Goot Gisou

Master’s in Bioengineering Name

Host Laboratory

Name

Host Laboratory

Name

Host Laboratory

Al-Shemmery Zelal

Meylan Etienne

Flatt Emmanuelle Ines

Stergiopulos Nikolaos

Moënnat Corinne

Altug Hatice

Amouyal Yann

Micera Silvestro

Gaillet Vivien

Lütolf Matthias

Narasimhan Shreya

Lacour Stéphanie

Anker Rebekka

Aminian Kamiar

Gavin Florence

Renaud Philippe

Nell Christophe

Renaud Philippe

Belushkin Alexander

Altug Hatice

Gay Noémie Anne Marie

Stergiopulos Nikolaos

Philippe Fabrice

Micera Silvestro

Cambria Elena

Lütolf Matthias

Girsault Arik Max Henri

Lasser Theo

Pitteloud Isabelle

Micera Silvestro

Cavinato Alessandro

Jolles-Haeberli Brigitte

Gourri Elise Myriam Hana Michèle

Blokesch Melanie

Rivest François Réal

Lütolf Matthias

Cerra Cheraka Mouna

Lacour Stéphanie

Gouy Emilia

Courtine Grégoire

Rubattel Jasmina

Aminian Kamiar

Chakravarty Pritish

Jolles-Haeberli Brigitte

Hurni Clémence Yumie Syloun

Barrandon Yann

Schenker Audrey

Ijspeert Auke

Clouet Thaïs Cléa Laura Séverine

Pioletti Dominique

Itty Pauline Marine Alizée

Lütolf Matthias

Strässle Heinz

Lütolf Matthias

Collinet Cyrielle Caroline

Lütolf Matthias

Jones Amy

Lütolf Matthias

Theillaud Quentin Antoine Marie

Blanke Olaf

Cuttelod Carine

Renaud Philippe

Kaeppeli Ariane

Pioletti Dominique

Thurre Gaëlle Madeleine

Renaud Philippe

Dalang Laura Audrey

Micera Silvestro

Kinany Nawal Noëlle

Micera Silvestro

Vallet Axelle

Lütolf Matthias

Dayer Camille Florine

Turcatti Gerardo

Kocher Juliane

Pioletti Dominique

Van Neyghem Niklas

Renaud Philippe

De Meyer Sara Valérie

Barrandon Yann et Petersen Carl

Krishnamani Gopalan Hariharan

Auwerx Johan

Vida Martins Natacha

Aminian Kamiar

Delannoy Lucas

Lütolf Matthias

Legrand Thomas

Jolles-Haeberli Brigitte

Voumard Margaux Océane

Pulgarin César

Donati Laurène

Unser Michaël

Lemaire Théo

Micera Silvestro

Watson Craig Fraser

Maerkl Sebastian

Duthilleul Nicolas Jean Marc Antoine

Micera Silvestro

Maurissen Thomas Luc

Swartz Melody

Zbinden Aline

Lütolf Matthias

El Maleh Cédric Moïse

Stergiopulos Nikolaos

Menard Nicolas

Micera Silvestro

Finelli Christopher

Unser Michaël

Michel Fanny Edith

Courtine Grégoire

Introduction

SV Master’s Graduates 2016

Master’s in Life Sciences & Technology Name

Host Laboratory

Name

Host Laboratory

Name

Host Laboratory

Aliotta Alessandro

Martin Kussmann

Foustoukos Georgios

Carl Petersen

Motta Alessandro

Knott Graham

Ameho Maxime

Auwerx Johan

Freymond Claudia

Michele De Palma

Muhech Medrano Amira

Ionescu Mihai Adrian

Appertet Mélanie Rosaria

Elisa Oricchio

Goupil Audrey Alice Anne

Sandi Carmen

Orset Bastien

Silvestro Micera

Bachmann Alexis Maximilien

Meylan Etienne

Grandjean Harish

Grégoire Courtine

Othenin-Girard Achille

Theo Lasser

Barbey Florentine Marie Elisabeth Liliane Eugénie

Johannes Gräff

Jeanneret Fanny Alexia

Martinoli Alcherio

Palgen Jean-Louis Sylvain Laurent

Nicola Harris

Basnayake Mudiyanselage Kanishka Chathuranga Basnayake

Sean Lewis Hill

Lang Andreas

Wulfram Gerstner

Piot Numa

Gisou Van Der Goot

Baumgartner Thomas Franz Laurent

Michael Herzog

Lee Umji

Matthias Lütolf

Puginier Mathilde

Jacques Fellay

Bérard Nadia

Dimitri Van De Ville

Londono Naïk Amnon Roberto

José Millan

Ravikumar Priyanka

Bernard Schneider

Chaudron Sandra Elisabeth

Trono Didier

Luan Peiling

Johan Auwerx

Sánchez Burgos Laura

Olaia Naveiras

Cherrier Dylan Emmanuel

Nicola Harris

Majubu Norbert

Olaf Blanke

Spisak Luisa

Nicola Harris

Chiffelle Johanna Pauline

Ralf Schneggenburger

Malier Marie Ingrid

John McKinney

Träger Sylvain

Dal Peraro Matteo

Cretenoud Aline Françoise

Michael Herzog

Manet Elodie

Johannes Gräff

Zhang Yifei

Aminian Kamiar

Desmurget Caroline Rose

Gisou Van Der Goot

Meng Kévin Si-Peng

Diego Ghezzi

Master’s in Bioengineering Name

Host Laboratory

Name

Host Laboratory

Name

Host Laboratory

Aeberli Luc Gaëtan

Philippe Renaud

Descombes Tiphaine Anne

Matthias Lütolf

Pancaldi-Giubbini Lucio

Melody Swartz

Badi-Dubois Marion Aimée Geneviève

José Millan

Desvachez Arnaud

Millán Ruiz José del Rocío

Pezeu Yannick

Ludwig Christian

Bauer Aline

Matthias Lütolf

Duchamp Margaux Catherine Marie

Matthias Lütolf

Pham Thanh-An Michel

Unser Michaël

Borghini Amélie

Yann Barrandon

Fonta Charlotte Marie Catherine Delphine

Matthias Lütolf

Pham Hoang Mac

Silvestro Micera

Borse Florian

Moret Bernard

Gao Minyu

Vesin Jean-Marc

Rechenmann Julien David

Millán Ruiz José del Rocío

Boulic Tunvez

Lütolf Matthias

Gayet Raphaël Vincent

Sebastian Maerkl

Rossy Tamara

Stéphanie Lacour

Broennimann Charlotte

Lütolf Matthias

Gninenko Nicolas

Dimitri Van De Ville

Shajkofci Adrian

Deplancke Bart

Cammoun Leila

Dominique Pioletti

Haedrich Nathalie Thao

Van De Ville Dimitri

Sottas Loïc

Stéphanie Lacour

Charrez Bérénice Lucie Mechthild

Matthias Lütolf

Hasler Romy Alexandra

Kamiar Aminian

Szymczak Thibaud

Philippe Renaud

Choppe Jonas

Nikolaos Stergiopulos

Jules Etienne Cédric

Olaia Naveiras

Tabata Seiji

Renaud Philippe

Christe David

Stéphanie Lacour

Krischer Nicolas Guillaume

Philippe Renaud

Talà Lorenzo Anton-Louis

Yann Barrandon

Cochet Kilian

Gerardo Turcatti

Kuhnert Dennys

Bart Deplancke

Tartini Stefano

Jeff Jensen

Cosendey Killian

Brigitte Jolles-Haeberli

Laforest Kévin

Lütolf Matthias

Togninalli Matteo

Matthias Lütolf

De Micheli Andrea Joseph

Guiducci Carlotta

Martin Bastien

Félix Naef

Venzin Olivier François

Matthias Lütolf

Decante Suzanne Élisabeth

Grégoire Courtine

Masala Nemanja

Dimitri Van De Ville

Deschaux-Beaume Florian Jacques Patrick

Nikolaos Stergiopulos

Mussard Émilie Priscille Claire

Thiran Jean-Philippe

Blue Brain Project Prof. Henry Markram - Director

Goal

Blue Brain’s strategic goal is to build accurate, biologically detailed digital reconstructions and simulations of the mammalian brain, beginning with rodents, to use simulation experiments to probe and understand the causal chains of events responsible for the brain’s emergent behavior at different levels of organization, up to and including cognition, to develop and operate a software and hardware ecosystem supporting these aims, and to translate the findings into meaningful results for neuroscience, computing and medicine.

Keywords

Brain simulation, neocortical microcircuit, Human Brain Project, rat, mouse, high performance computing, neuroinformatics, neurorobotics, high performance computing, software ecosystem, Open Source Software, hippocampus, cerebellum, basal ganglia, visualization.

Activities and results In October 2015, Blue Brain published its first draft digital reconstruction of neocortical microcircuitry comprising about 30,000 neurons and 37 million synapses (Markram et al, 2015, Cell). The paper represents the most complete description of any neural microcircuit to date, providing a map of all the cells and synapses in a block of neural tissue. It also describes simulation experiments replicating a range of previous in vivo studies. Two accompanying papers describe the algorithm used to derive the micro-connectome (Reimann et al. 2015) and the NMC Portal (https://bbp.epfl.ch/nmc-portal/welcome), a public data resource providing access to data, models and tools used in the reconstruction (Ramaswamy et al. 2015).

bluebrain..epfl.ch

In research on other levels of brain organization, Blue Brain collaborated with Prof. R. Schneggenburger of EPFL to simulate of some of the molecular interactions involved in release control by synapses (Keller et al, 2016). We also completed a multi-year project to characterize the biophysics of the voltage-gated potassium channels, using fully automated, high throughput techniques. Work is in progress to incorporate the findings in Blue Brain neuron models. An important paper used Blue Brain simulation methods to investigate the role of gap junctions in networks of large basket cells in cortical layers 2/3. The project also continued work on methods to characterize neural morphologies and to synthesize morphologies for use in large-scale models (Van Herpe et al. 2016). A Blue Brain project to model plasticity on time scales from minutes to days was selected as one of six, “Tier 1” projects in Argonne National Laboratory’s Theta Early Science Program. Participation in the program gives the team access to one of the largest supercomputers in the world, enabling very large-scale simulations of neural plasticity. BBP research results were produced through a comprehensive software ecosystem for brain modeling and simulation, including a broad range of tools, contributing to different phases in the process. The BBP has begun systematic releases of these tools, as Open Source Software. Notably the project released BluePyOpt – a general purpose framework for multi-objective optimization, now released as Open Source Software (W. Van Geit et al, 2016). Other developments included a prototype simplification pipeline allowing automated transformation of detailed brain models into point neuron models, suitable for use in very large scale simulations (Rössert et al, 2016) and visualization methods making it possible to produce images from brain that can be compared against microscopy images (Abdellah et al. 2015).

Software development within the BBP is supported by a Core Services team and a strong infrastructure for High Performance Computing. The project’s High Performance Computing infrastructure includes Blue Brain’s BlueGene/Q supercomputer, housed at CSCS, Lugano, as well as two analytics and visualization clusters (in Geneva and Lugano), petabyte storage capabilities and a large private cloud providing virtual machines on demand for BBP developers. A major goal during 2015-16 was to accelerate dissemination and uptake of BBP methods and results. The main dissemination channel was the Human Brain Project - the 1 billion euro FET Flagship Project – initially proposed and led by Henry Markram and the Blue Brain team. Within the HBP, Blue Brain coordinated the development of the Brain Simulation Platform, and the integration of BBP tools, workflows and brain models into the platform. BBP personnel also made major contributions to the Neuroinformatics, High Performance Computing and Neurorobotics Platforms. Work by HBP science teams provides evidence for the power of the Blue Brain approach. Egidio D’Angelo (University of Pavia, Italy) used Blue Brain workflows and tools to build early models of rat cerebellum, Sten Grillner (Karolinska Institute, Sweden) is using those tools to build an early model of the basal ganglia, Idan Segev (Hebrew University, Israel) built detailed models of human cortical neurons. In parallel with this work, Blue Brain played a leading role in community efforts to model the Hippocampus (http:// neuralensemble.org/meetings/HippocampCA1/). Blue Brain collaborated with Allen Brain Institute in its own Big Neuron project (http://alleninstitute.org/bigneuron/about/) as well as to build electrical models of neurons in mouse visual cortex for the Allen Cell Types Database (http://celltypes.brain-map. org/).

Centers

Selected Publications »» »» »» »» »» »» »» »» »»

Markram, H. , Muller, E., Ramaswamy S., Reimann, M.W, DeFelipe, J., Hill, S.L., I. Segev I, F. Schürmann et al., (2015). Reconstruction and Simulation of Neocortical Microcircuitry. Cell 163: 456-492. Reimann, M.W. Muller E.B., Ramaswamy, S. and Markram H., (2015). An Algorithm to Predict the Connectome of Neural Microcircuits. Front. Computational Neuroscience Ramaswamy S., Courcol, J.-D. , DeFelipe, J., Hill, S.L. , Muller, J., Segev, I., Schürmann, F. , Muller, E.B. , and H. Markram, (2015). The neocortical microcircuit collaboration portal: a resource for rat somatosensory cortex. Front. Neural Circuits, 44. Keller, D., Babai, N., Kochubey, O., Han, Y., Markram, H., Schürmann, F., Schneggenburger, R. (2015). An Exclusion Zone for Ca2+ Channels around Docked Vesicles Explains Release Control by Multiple Channels at a CNS Synapse, PLoS Comput Biol. 11(5):e1004253. O. Amsalem, W. Van Geit, E. Muller, H. Markram, I. Segev, From neuron biophysics to orientation selectivity in electrically-coupled networks of neocortical L2/3 large basket cells,. Cereb Cortex. 2016 Aug;26(8):3655-68. doi: 10.1093/cercor/ bhw166. Epub 2016 Jun 9. L. Vanherpe, , L. Kanari, G. Atenekeng, J. Palacios, and J. Shillcock. “Framework for Efficient Synthesis of Spatially Embedded Morphologies.” Physical Review E 94, no. 2 (August 23, 2016): 023315. doi:10.1103/PhysRevE.94.023315. C. Rössert, C. Pozzorini, G. Chindemi, A. P. Davison, C. Eroe, J. King, T H. Newton, et al. “Automated Point-Neuron Simplification of Data-Driven Microcircuit Models.” arXiv:1604.00087 [q-Bio], March 31, 2016. http://arxiv.org/ abs/1604.00087. Abdellah, M., Bilgilli, A., Eilemann, S., Markram, H., Schürmann, F. (2015). Physically-based in silico light sheet microscopy for visualizing fluorescent brain models. BMC Bioinformatics;16 Suppl 11:S8 W. Van Geit, M. Gevaert G. Chindemi, C. Rössert, J. Courcol, EB Muller, F. Schürmann, I. Segev I and H. Markram, BluePyOpt: Leveraging open source software and cloud infrastructure to optimise model parameters in neuroscience. Front. Neuroinform., 2016, 10:17.

Center for Biomedical Imaging Research Prof. Rolf Gruetter - Director

www.cibm.ch

Mission

Keywords

The CIBM aims to advance our understanding of biomedical processes in health and disease, focusing on mechanisms of normal functioning, pathogenic mechanisms, characterization of disease onset prior to structural damage, metabolic and functional consequences of gene expression, and non-invasive insights into disease processes under treatment. The research will use model systems ranging from transgenic animals to human patients (“from mouse to man”) and foster multidisciplinary collaboration between basic science, biomedical science and clinical applications.

Biomedical imaging, MRI, PET, Synchrotron imaging, EEG, Metabolism, Image analysis

The overall goal of the CIBM is to foster state-of-the-art applications of biomedical imaging and in the context of biomedical applications to further advance the technological development and vice-versa. The CIBM aims to enhance biomedical research capabilities of the founding institutions and beyond, as well as within the CIBM. Its main aim to develop novel imaging capabilities in the context of questions of biomedical importance. It further aims to bring together basic scientists, engineers and biomedical researchers through research collaborations, which distinguishes it from a traditional service facility.

Research Activities • • • • • •

EEG Brain Mapping Signal Processing and Image Analysis * Phase Contrast Radiology * Positron Emission Tomography * Clinical Research (3Tesla MRI) Animal Imaging and Technology (9.4, 14 and 7 Tesla human MRI) *

* effort present at EPFL campus

The CIBM is organized on 3 sites with 7 research cores. Please see www.cibm.ch for details.

Centers

Overlap between activations in the space, time, and person domains. (A) Overall orientation-related activity in a representative subject, identified by contrasting activity between each orientation domain and the lexical control task, showing overlap between regions (P < 0.05, FDR-corrected, cluster size >20 voxels). (B) Group average of the percent of overlap between active voxels in each orientation domain, demonstrating a partial overlap between domains. M. Peer (2015) Brain system for mental orientation in space, time, and person. PNAS vol. 112, p. 11072-77.

Selected Publications »» »» »» »» »» »»

Martuzzi, R., W. van der Zwaag, S. Dieguez, A. Serino, R. Gruetter and O. Blanke (2015). “Distinct contributions of Brodmann areas 1 and 2 to body ownership.” Soc Cogn Affect Neurosci10(11): 1449-1459. Peer, M., R. Salomon, I. Goldberg, O. Blanke and S. Arzy (2015). “Brain system for mental orientation in space, time, and person.” Proc Natl Acad Sci U S A 112(35): 11072-11077. Jorge, J., F. Grouiller, O. Ipek, R. Stoermer, C. M. Michel, P. Figueiredo, W. van der Zwaag and R. Gruetter (2015). “Simultaneous EEG-fMRI at ultra-high field: artifact prevention and safety assessment.” Neuroimage 105: 132-144. Cordero, M. I., N. Just, G. L. Poirier and C. Sandi (2016). “Effects of paternal and peripubertal stress on aggression, anxiety, and metabolic alterations in the lateral septum.” Eur Neuropsychopharmacol 26(2): 357-367. McCann, M. T., M. Nilchian, M. Stampanoni and M. Unser (2016). “Fast 3D reconstruction method for differential phase contrast X-ray CT.” Opt Express 24(13): 14564-14581 Sonnay, S., J. M. Duarte, N. Just and R. Gruetter (2016). “Compartmentalised energy metabolism supporting glutamatergic neurotransmission in response to increased activity in the rat cerebral cortex: A 13C MRS study in vivo at 14.1 T.” J Cereb Blood Flow Metab 36(5): 928-940. »» Thunell, E., W. van der Zwaag, H. Ogmen, G. Plomp and M. H. Herzog (2016). “Retinotopic encoding of the Ternus-Pikler display reflected in the early visual areas.” J Vis 16(3): 26.

Center for Neuroprosthetics Prof. Olaf Blanke - Director / Dr Bruno Herbelin - Deputy Director

cnp.epfl.ch

Mission

Principal Investigators

The Center for Neuroprosthetics (CNP) capitalizes on its unique access to advanced engineering, computer science, signal analysis, and brain research at the Swiss Federal Institute of Technology (Ecole Polytechnique Fédérale de Lausanne, EPFL). We strive to translate these advances to novel treatments in neurological and psychiatric diseases by developing new technologies that support, repair, replace and enhance functions of the nervous system.

Prof Olaf Blanke Bertarelli Foundation Chair in Cognitive Neuroprosthetics lnco.epfl.ch

Prof Stéphanie P. Lacour Bertarelli Foundation Chair in Neuroprosthetic Technology lsbi.epfl.ch

Prof Grégoire Courtine International Paraplegic Foundation (IRP) Chair in Spinal Cord Repair courtine-lab.epfl.ch

Prof Silvestro Micera Bertarelli Foundation Chair in Translational Neuroengineering tne.epfl.ch/

The development of such technologies and devices, called neuroprostheses, depends on engineering advances, on medical know-how, and on the understanding of the neurobiological mechanisms for sensory perception, cognitive operations, and movement. For the restoration of motor functions, we aim to record and process the dedicated signals and to translate them into data that can ultimately drive artificial limbs, bodies and robots. For the restoration of sensory and cognitive functions, we design devices that produce signals that selectively activate and control brain circuits involved in perception and different cognitive functions. Pursuing strengths in education at EPFL with our research and clinical partners, we are shaping the next generation of researchers in neuroprosthetics and empower the technology transfer from laboratory-based neuroprosthetics to startup companies with impact in industry and society.

Prof Diego Ghezzi Medtronic Chair in Neuroengineering cnp.epfl.ch/Ghezzilab Prof Friedhelm Hummel Defitech Foundation Chair in Clinical Neuroengineering

Prof José del R. Millán Défitech Foundation Chair in Non-Invasive Brain-Machine Interface cnbi.epfl.ch Prof Dimitri Van De Ville Medical Image Processing Laboratory miplab.epfl.ch

Centers

Team Members Director

Prof. Olaf Blanke Deputy Director

Dr Bruno Herbelin Administrative Assistants

Catherine Wannier

Restoration of texture discrimination in intact subjects and amputees

Selected Publications »» Blanke, O., Slater, and M., Serino, A., (2015). Behavioral, neural, and computational principles of bodily self-consciousness. Neuron. 88(1):145-66. »» Feyen, P., Colombo, E., Endeman, D., Nova, M., Laudato, L., Martino, N., Antognazza, M.R., Lanzani, G., Benfenati, F. and Ghezzi, D. (2016). Light-evoked hyperpolarization and silencing of neurons by conjugated polymers. Nature Scientific Reports. 6:22718. »» Iturrate, I., Chavarriaga, R., Montesano, L., Minguez, J. and Millán, J.d.R. (2015). Teaching brain-machine interfaces as an alternative paradigm to neuroprosthetics control. Nature Scientific Reports, 5:13893. »» Karahanoglu, F. I., Van De Ville, D. (2015) Transient Brain Activity Disentangles fMRI Resting-date Dynamics in Terms of Spatially and Temporally Overlapping Networks. Nature Communications. 6:7751. »» Martin Moraud, E., Capogrosso, M., Formento, E., Wenger, N., DiGiovanna, J., Micera, S.* and Courtine, G*. (2016). Mechanisms underlying the neuromodulation of spinal circuits for correcting gait and balance deficits after spinal cord injury. Neuron, Volume 89, Issue 4, Pages 814–828. »» Minev, I.R., Musienko, P., Hirsch, A., Barraud, Q., Wenger, N., Moraud, E. M., Gandar, J., Capogrosso, M., Milekovic, T., Asboth, L., Torres, R.F., Vachicouras, N., Liu, Q., Pavlova, N., Duis, S., Larmagnac, A., Vörös, J., Micera, S., Suo, Z., Courtine, G. and Lacour, S. P. (2015). Biomaterials. Electronic dura mater for long-term multimodal neural interfaces. Science, 347(6218). »» Oddo, C.M., Raspopovic, S., Artoni, F., Mazzoni, A., Spigler, G., Petrini, F., Giambattistelli, F., Vecchio, F., Miraglia, F., Zollo, L., Di Pino, G., Camboni, D., Carrozza, M.C., Guglielmelli, E., Rossini, P.M., Faraguna, U., and Micera, S. (2016) Intraneural stimulation elicits discrimination of textural features by artificial fingertip in intact and amputee humans. eLlife. 8;5. »» Wenger, N., Martin Moraud, E., Gandar, J., Musienko, P., Capogrosso, M., Baud, L., Le Goff, C., Barraud, Q., Pavlova, N., Dominici, N., Minev, I.R., Asboth, L., Hirsch, A., Duis, S., Kreider, J., Mortera, A., Haverbeck, O., Kraus, S., Schmitz, F., DiGiovanna, J., van den Brand, R., Bloch, J., Detemple, P., Lacour, S.P., Bézard, E., Micera S., and Courtine G. (2016). Spatiotemporal neuromodulation therapies engaging muscle synergies to improve motor control after spinal cord injury. Nature Medicine. 22(2):138-45.

BMI

Brain Mind Institute The mission of the Brain Mind Institute (BMI) is to understand the fundamental principles of brain function in health and disease, by using and developing unique experimental, theoretical, technological and computational approaches. The scientific challenge addressed by the BMI consists of connecting different levels of analysis of brain activity, such that cognitive functions can be understood as a manifestation of specific brain processes; specific brain processes as emerging from the collective activity of thousands of cells and synapses; synaptic and neuronal activity in turn as emerging properties of the biophysical and molecular mechanisms of cellular compartments. Research at the BMI focuses on four main areas: • Mechanisms of brain function and dysfunction, with a particular focus on neurodegeneration and stress-related psychopathologies. • Molecular and cellular mechanisms of synapse and microcircuit function up to the behavioral level and including metabolic aspects. • Sensory and body perception and cognition in humans. • Designing innovative interventions to restore sensorimotor functions after neural disorders.

Sandi Carmen - Director

In all areas, the BMI strives to integrate knowledge gained by multidisciplinary approaches and across different disciplines and research laboratories. An important second mission of the BMI is to bridge scientific approaches and questions with research carried out in the EPFL campus, as well as in related institutions and companies in the area, specifically with the fields of nano- and micro-technology, computer sciences, physics, neuroprosthetics, robotics, signal and medical imaging processing, genetics, metabolism, neuroeconomics, psychiatry and neurology. Major goals of the BMI are to bridge basic science approaches with clinical applications and to merge areas of experimental work with theory and modeling. Finally, the BMI is fully engaged in the teaching mission of the School of Life Sciences at the Bachelor and Master levels –with a full Neuroscience track at the Master level– and organizes the PhD program in Neurosciences. http://sv.epfl.ch/BMI

Aebischer Lab Patrick Aebischer - Full Professor - President of EPFL

Patrick Aebischer was trained as an MD (1980, Geneva University) and a Neuroscientist (1983, Fribourg University) in Switzerland. As Faculty member at Brown University (USA), he became Chairman of the Artificial Organs, Biomaterials and Cellular Technology program in 1991. He returned to Switzerland in 1992, as Professor and Director of the Surgical Research Division and Gene Therapy Center at CHUV. President of EPFL from 2000 until 2016, he is also the founder of three biotech companies.

len.epfl.ch

Introduction

Results Obtained

Although our understanding of the molecular mechanisms leading to neurodegenerative diseases has dramatically improved, very few treatments have shown disease-modifying effects. Several factors may explain this lack of efficacy. The brain is a poorly accessible organ, which limits the access to therapeutic drugs, and the pathogenic processes that affect neurons and other cell types in the CNS are notoriously complex. Treating neurodegeneration requires therapeutic approaches carefully adapted to various factors, including the molecular causes of the disease, the type of cells affected and the stage of the disease. In this context, our group explores the possibilities to devise novel treatments using viral vectors for gene therapy, as well as innovative systems for protein delivery to the CNS.

We have further developed an innovative gene therapy using RNA interference (RNAi) for the treatment of ALS caused by SOD1 mutations (Dirren et al, 2015). We have designed an AAV vector able to downregulate SOD1 in both motoneurons and astrocytes in the spinal cord. This vector has synergistic therapeutic effects that dramatically improve the motor function of treated mice. By analyzing the therapeutic effects of silencing mutated SOD1 in astrocytes, we found an effect on the ability of surviving motoneurons to reinnervate the neuromuscular junctions left unoccupied by degenerating neurons (see Figure). We are currently exploring the molecular cause of the aberrant crosstalk between neuron and glial cells in ALS.

We mainly use AAV vectors for the delivery of genes, artificial miRNAs and the CRISPR-Cas9 gene editing technology. In particular, we are developing gene therapy for motoneuron disorders, including amyotrophic lateral sclerosis (ALS). Our lab also exploits AAV-based techniques for modeling CNS diseases. We use this approach to explore the pathogenic effects of proteins such as α-synuclein and tau, which are centrally implicated in Parkinson’s and Alzheimer’s diseases. These models of neurodegeneration are used to identify pathogenic processes and test neuroprotective treatments.

Keywords Neurodegenerative diseases, gene therapy, animal models, Parkinson’s disease, Amyotrophic lateral sclerosis, Alzheimer’s disease, viral vectors, AAV, cell encapsulation, passive immunization.

Our lab has developed a mouse model of tauopathies based on the local injection of AAV vectors to overexpress human tau. This model is used to determine why tau can be toxic to neuronal cells, with a focus on the propensity of the tau protein to misfold. Conformational changes of the tau protein control binding to microtubules and subsequent pathological effects. The same approach is used to locally express the tau protein and quantify propagation along neuronal networks. In parallel, we are developing cellular implants continuously secreting recombinant antibodies for passive immunization against Alzheimer’s disease (Lathuiliere et al, 2016). In collaboration with the Holt lab at Harvard Medical School, we have finalized a proof-of-concept study to restore the function of the TMC protein using AAV vectors in a mouse model of inherited deafness (Askew et al, Science Translational Medicine 2015). This project is currently being pursued with the aim to inactivate the dominant effect of the Beethoven TMC1 mutation using the CRISPR-Cas9 gene editing technology.

BMI - Brain Mind Institute

Team Members Research and Teaching Associate

Bernard Schneider

Postdoctoral Fellows

Julianne Bobela-Aebischer Nathalie Bernard-Marissal Paola Solanes Pamela Valdès PhD Students

Wojciech Bobela Vanessa Laversenne Sameer Nazeeruddin Cylia Rochat Lu Zheng Lab Technicians

Aline Aebi Philippe Colin Fabienne Pidoux Vivianne Padrun Christel Sadeghi Visiting Students Gene therapy for mutated SOD1 ALS: AAV-mediated delivery of artificial microRNAs for SOD1 silencing in astrocytes promotes the re-innervation of neuromuscular junctions following neurodegeneration. (a) Transduction of astrocytes in the mouse spinal cord. (b) Gene therapy prevents muscle atrophy.

Daniel Blessing (CHUV) Administrative Assistants

Marie Künzle

Selected Publications »» Ryu, D., Mouchiroud, L., Andreux, P.A., Katsyuba, E., Moullan, N., Nicolet-Dit-Félix, A.A., Williams, E.G., Jha, P., Lo Sasso, G., Huzard, D., Aebischer, P., Sandi, C., Rinsch, C. and Auwerx J. (2016) Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med 22(8): 879-888. »» Lathuilière, A., Laversenne, V., Astolfo, A., Kopetzki, E., Jacobsen, H., Stampanoni, M., Bohrmann, B., Schneider, B.L. and Aebischer, P. (2016) A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau pathologies. Brain 139 :1587-1604. »» Dirren, E., Aebischer, J., Rochat, C., Towne, C., Schneider, B.L., Aebischer, P. (2015) Silencing of SOD1 expression in motoneurons and/or astrocytes rescues neuromuscular function of G93ASOD1 mice. Ann Clin Transl Neurol 2(2):1671-84. »» Filézac de l’Etang, A., Maharjan, N., Cordeiro Braña, M., Ruegsegger, C., Roos, A., Schneider, B.L., Weis, J., Saxena, S. (2015) Marinesco-Sjögren syndrome protein SIL1 regulates motoneuron subtype-selective ER stress in ALS. Nat Neurosci 8(2): 227-238. »» Ciron, C., Knott, G., Kelly, D., Aebischer, P., and Schneider, B.L. (2015). PGC-1α activity in nigral dopaminergic neurons controls vulnerability to α-synuclein. Acta Neuropathol Comm 3:16. »» Askew, C., Rochat, C., Pan, B., Asai, Y., Ahmed, H., Child, E., Schneider, B.L., Aebischer, P., and Holt J.R. (2015). Tmc gene therapy restores auditory function in deaf mice. Sci Transl Med 7(295): 295ra108. »» Chen, J.L., Margolis, D.J., Stankov, A., Sumanovski, L.T., Schneider, B.L. and Helmchen, F. (2015) Pathway-specific reorganization of projection neurons in somatosensory cortex during learning. Nat Neurosci 18(8): 1101-1108.

Blanke Lab Olaf Blanke - Full Professor - Director of the Center for Neuroprosthetics

Olaf Blanke is founding director of the Center for Neuroprosthetics and holds the Bertarelli Foundation Chair in Cognitive Neuroprosthetics at the Ecole Polytechnique Fédérale de Lausanne (EPFL). He directs the Laboratory of Cognitive Neuroscience at EPFL and is Professor of Neurology at the University Hospital of Geneva. Blanke’s neuroscience research is dedicated to the study of consciousness and how bodily processing encodes the self. This work includes pioneering technology research in virtual reality, augmented reality, and robotics that is dedicated to control and enable complex subjective experiences (i.e. experience engineering). In his medical projects in neurorehabilitation and neuroprosthetics Blanke develops devices and procedures for diagnostics and therapeutics with a focus in robotic psychiatry and cogniceuticals.

lnco.epfl.ch

Introduction

Results Obtained

The Blanke Lab (Bertarelli Chair in Cognitive Neuroprosthetics) has two missions – the neuroscientific study of consciousness and the development of cognitive neuroprostheses. In neuroscience we investigate the brain mechanisms of body perception, body awareness and how they form consciousness, combining psychophysical and cognitive paradigms, neuroimaging techniques (high resolution fMRI, intracranial and surface EEG, TMS). We have pioneered the use of engineering techniques such as robotics, haptics, and digital technologies (virtual and augmented reality) and their full integration with behavioral and neuroscience technologies (including MRI-compatible robotics), leading to the new research field of cognetics: the field of robotics and digital technologies dedicated to neuroscience research in cognition and consciousness studies.

This year saw the continuation of our efforts to understand the interplay between interoceptive and exteroceptive signals in shaping consciousness of self and environment. In two converging lines of research we showed that the subjective experience of our visual world is modulated by interoceptive signals of cardiac (Salomon et al., Journal of Neuroscience, 2016) and proprioceptive origins (Faivre et al., Journal of Neuroscience, 2017). In the same vein, we showed that the processing of cardiac signals is altered under states of illusory self-consciousness (Park et al., Journal of Neuroscience, 2016). These three studies indicate that bodily signals (including interoceptive signals) are a key determinant for perceptual and self-consciousness (Blanke et al., Neuron 2015). Another line of work documented how the integration of signals from vision, touch, and balance shape self-consciousness and in particular our first-person perspective (Pfeiffer et al., Neuroscience of Consciousness 2016), peripersonal space, and self-identification (Salomon et al., Cognition, under review). Translating these insights into cogniceutical technologies (Rognini and Blanke, Trends in Cognitive Sciences 2016) we developed novel immersive digital therapies and successfully treated patients suffering chronic regional pain syndrome (Solcà et al., submitted), neuropathic leg pain (Pozeg et al., in revision) and phantom limb syndrome (Rognini et al., submitted) and also investigated the neural underpinnings of painful body regions (Akselrod et al., in revision; Serino et al., in revision; Givraz et al., Neuroimage 2017).

In our clinical research projects we translate our cognetic insights to the development of new diagnostic and therapeutic approaches along two main lines of exploration: robotic psychiatry and cogniceuticals. In robotic psychiatry we are designing robotic devices, including wearable robotic solutions, to develop novel diagnostic and therapeutic solutions for two major neuropsychiatric diseases (schizophrenia and Parkinson’s disease), centering on hallucinations and psychosis. In cogniceuticals we develop novel immersive digital devices and therapies for chronic pain by integrating digital technologies (i.e. virtual reality) with brain stimulation and latest research from the cognitive neurosciences. Our devices induce technology-mediated pain relief in patients suffering from complex regional pain syndrome, phantom limb pain, and neuropathic leg pain in spinal cord injury.

Keywords Multisensory, sensorimotor, cognitive neuroscience, self, robotics, haptics, virtual-augmented reality, neurology, psychiatry.

Major efforts in 2016 have been devoted to the development of the emergent field of robotic psychiatry by (1) developing and testing our new robotic and haptic devices, by (2) applied neuroscience research, and by (3) investigating the diagnostic potential of our robotic devices in patients suffering from hallucinations and psychosis caused by schizophrenia and Parkinson’s disease. In 2016, we achieved full robotic integration for high-density EEG recordings (Bernasconi et al., in preparation) using a previously designed robotic device (Blanke et al., Current Biology 2014) and developed and tested a new MRI compatible robot for fMRI studies (Hara et al., Journal of Neuroscience Methods 2014; Blondiaux et al., in preparation) at our newly installed MR scanner at Campus Biotech Geneva.

BMI - Brain Mind Institute

Team Members

We have extended our clinical robotic psychiatry network to include hospitals in Geneva, Lausanne, and Sion and made major progress in the development of establishing diagnostic procedures and devices. Several major studies using these devices have been completed in 2016 and accomplished the robotically controlled induction of mild psychotic symptoms in healthy controls (Blondiaux et al., in preparation; Faivre et al., in preparation), informing the development of robotic-based diagnostic criteria in schizophrenia and Parkinson’s disease (Serino et al., in preparation; Salomon at al., in preparation).

Postdoctoral Fellows Fosco Bernasconi Elisa Canzoneri Nathan Faivre Michael Hill Hyeongdong Park Isabella Pasqualini Giulio Rognini Roberta Ronchi Roy Salomon Andrea Serino Jevita Potheegadoo Marianne Stephan Bassolino Michela Simon Gallo

Robot-controlled induction of an apparition. Participants performed stroking hand movements via a master robot in the front, while receiving an altered sensory feedback via a slave robot on their back. By manipulating through the robotic system the spatio-temporal congruency between movements and sensory feedback, we were able to systematically induce in the participants an illusory feeling of another person standing behind them, i.e., feeling of a presence. The sensory motor conflict and the induced experience activates a network of brain areas, including the sensorymotor cortices, the temporal parietal junction and the insular cortex, as shown by converging data from highdensity EEG (shown in the picture), fMRI and lesion analysis.

Selected Publications »» Faivre , N., Doenz, J., Scandola, M., Dhanis, H., Bello Ruiz, J., Bernasconi, F., Salomon, R. and Blanke, O. (2017) Self-grounded vision: hand ownership modulates visual location through cortical beta and gamma oscillations. The Journal of Neuroscience 37: 11-22. »» Grivaz, P., Blanke, O. and Serino, A. (2017) Common and distinct brain regions processing multisensory bodily signals for peripersonal space and body ownership. NeuroImage 147: 602-618. »» Park, H.D., Bernasconi, F., Bello Ruiz, J., Pfeiffer, C., Salomon, R. and Blanke, O. (2016) Transient modulations of neural responses to heartbeats covary with bodily self-consciousness. The Journal of Neuroscience 36: 8453-8460. »» Salomon, R., Ronchi, R., Doenz, J., Bello Ruiz, J., Herbelin, B., Martet, R., Schaller, K. and Blanke, O. (2016) The insula mediates access to awareness of visual stimuli presented synchronously to the heartbeat. The Journal of Neuroscience 36: 5115-5127. »» Rognini, G. and Blanke, O. (2016) Cognetics: Robotic interfaces for the conscious mind. Trends in Cognitive Science 20:162-164. »» Canzoneri, E., Di Pellegrino, G., Herbelin, B., Blanke, O. and Serino, A. (2016) Conceptual processing is referenced to the experienced location of the self, not to the location of the physical body. Cognition 154: 182192. »» Pfeiffer, C., Grivaz, P., Herbelin, B., Serino, A. and, Blanke, O. (2016) Visual gravity contributes to subjective first-person perspective, Neuroscience of Consciousness 1-12.

PhD Students Michel Akselrod Eva Blondiaux Lucie Brechet Petr Grivaz Silvia Marchesotti Polona Pozeg Marco Solcà Quentin Theillaud Matteo Franza Hyukjun Moon Myeong Song Giedre Stripeikyte Pavo Orepic Chang Wenwen Master’s Students Herberto Camacho Giuliana Sorrentino Matteo Vissani Mattia Pinardi Anush Swaminathan Christina Shea Kai Yue Wang Julia Brügger-Baumann Caroline Peters Technical staff Javier Bello Ruiz Robin Mange Medical Doctor Pierre Progin Marco Solcà Administrative Assistant Sonia Neffati-laifi

Courtine Lab Grégoire Courtine - Associate Professor - IRP Chair in Spinal Cord Repair

Grégoire Courtine was trained in Mathematics, Physics and Neurosciences. He obtained his PhD from the INSERM Motricity and Plasticity in France. After his postdoctoral training at UCLA, he established his own laboratory at Zurich (UZH) in 2008, before becoming Associate Professor at the EPFL in 2012. He founded a startup in 2015.

Introduction

Results Obtained

The World Health Organization (WHO) estimates that as many as 500’000 people suffer from a spinal cord injury each year, with dramatic consequences for the quality of life of affected individuals. Over the past 15 years, Prof Courtine and his team have developed a multifaceted intervention that reestablished voluntary control of paralyzed legs in rodent and primate models of spinal cord injury. This intervention acts over two time windows. Immediately, electrical and chemical stimulations of the lumbar spinal cord reawaken the neuronal networks below the injury that coordinate leg movements. In the long term, will-powered training regimens enabled by the electrochemical stimulation and robotic assistance promote neuroplasticity of residual connections. The goal of the laboratory is to refine this intervention with next-generation neurotechnologies, understand the underlying mechanisms, and translate these approaches into medical devices and therapeutic practices for accelerating and improving functional recovery after spinal cord injury in humans. To this aim, we are combining preclinical and clinical studies in mice, rats, non-human primates and human patients. We are also collaborating with our start-up to develop the neurotechnologies necessary to apply these concepts in paraplegic people.

Neuromodulation therapies (Neuron 2016; Nature Medicine 2016): We have identified the mechanisms underlying the facilitation of locomotion with electrical spinal cord stimulation. This conceptual framework guided the development of hardware and software to improve our neuromodulation therapies. We collaborated with Prof. Micera to develop a control platform through which neuromodulation parameters can be adjusted in real-time, based on movement feedback. Using this hardware and software, we designed control algorithms that achieve precise adjustment of leg movements in paralyzed rats.

Keywords Spinal cord injury, neurorehabilitation, neuroprosthetics, neural interface, locomotion.

courtine-lab.epfl.ch

Brain-spine interface to restore motor function (Nature, 2016): We have designed and implemented wireless control systems in monkeys that linked online neural decoding of extension and flexion motor states with stimulation protocols promoting these movements. These systems allowed the animals to behave freely without any restrictions or constraining tethered electronics. After validation of the brain-spine interface in intact (uninjured) monkeys, we tested the brain-spine interface after an experimental spinal cord injury. The brain-spine interface restored weight-bearing locomotion of a paralyzed leg on a treadmill and overground. The implantable components integrated in the brain-spine interface have all been approved for investigational applications in similar human research, suggesting a practical translational pathway for proof-of-concept studies in people with spinal cord injury. Clinical neurorobotic platform: With the CHUV and the SUVA, we established a new neurorobotic platform that brings together innovative monitoring and robotic technologies. A clinical trial has started in 2016 to evaluate the ability of spinal cord stimulation and robot-assisted gait training to improve motor function in people with incomplete spinal cord injury.

BMI - Brain Mind Institute

Team Members Postdoctoral Fellows Nicholas James Claudia Kathe Jean-Baptiste Mignardot Karen Minassian Tomislav Milekovic Ismael Seanez-Gonzalez Fabien Wagner PhD Students Mark Anderson Selin Anil Leonie Asboth Béatrice Barra Sabry Barlatey Kay-Alexander Bartholdi Marco Bonizzato Simon Borgognon Newton Cho Emanuele Formento Jérôme Gandar Nathan Greiner Camille Le Goff Galyna Pidpruzhnykova Shiqi Sun Sophie Wurth

Conceptual and technological design of the brain–spine interface. (1) Neural signal recorded from motor cortex (2) A decoder running on the control computer identified motor states. (3) These motor states triggered electrical spinal cord stimulation protocols. (4) The stimulator was connected to a spinal implant targeting specific dorsal roots of the lumbar spinal cord. Copyright J. Ruby

Technicians /Research Assistants Laetitia Baud Soline Odouard Elodie Rey Polina Shkorbatova Scientific Coordinator Quentin Barraud Administrative Assistant Pauline Hoffmann

Selected Publications »» »» »» »» »» »» »»

Capogrosso,& M., Milekovic,& T., Borton,& D. et al. (2016) A brain-spine interface alleviating gait deficits after spinal cord injury in primates. Nature 539(7628): 284-288. Wenger,& N., Martin Moraud,& E., Gandar,& J. et al. (2016) Spatiotemporal neuromodulation therapies engaging muscle synergies to improve motor control after spinal cord injury. Nature Medicine. 22(2):138-145. Martin Moraud,& E., Capogrosso,& M. et al. (2016) Mechanisms underlying the neuromodulation of spinal circuits for correcting gait and balance deficits after spinal cord injury. Neuron 89(4):814-828. DiGiovanna,& J., Dominici,& N. et al. (2016) Engagement of the rat hindlimb motor cortex across natural locomotor behaviors. J Neurosci 36(40):10440-10455 von Zitzewitz,& J., Asboth,& L. et al. (2016) A neurorobotic platform for locomotor prosthetic development in rats and mice. J Neural Eng 13(2): 026007. Wurth, S. et al. (2017) Long-term usability and bio-integration of polyimide-based intra-neural stimulating electrodes. Biomaterials 122 :114-129. Friedli&,L., Rosenzweig,& E.S. et al. (2015) Pronounced species divergence in corticospinal tract reorganization and functional recovery after lateralized spinal cord injury favors primates. Science Translational Medicine 7: 302ra134 & Equal contribution

Gerstner Lab Wulfram Gerstner - Full Professor - Director of the Teaching Section

Wulfram Gerstner is Director of the Laboratory of Computational Neuroscience LCN at the EPFL. After studies of Physics in Tübingen and at the Ludwig-Maximilians-University Munich (Master 1989), Wulfram Gerstner spent a year as a visiting researcher in Berkeley. He received his PhD in theoretical physics from the Technical University Munich in 1993 with a thesis on associative memory and dynamics in networks of spiking neurons. After short postdoctoral stays at Brandeis University and the Technical University of Munich, he joined the EPFL in 1996 as assistant professor. Promoted to Associate Professor with tenure in February 2001, he is since August 2006 a full professor with double appointment in the School of Computer and Communication Sciences and the School of Life Sciences.

lcnl.epfl.ch

Introduction

Results Obtained

At the LCN, we use neural modeling in order to understand the role of dynamics for computation in brain-like structures. Dynamics and temporal aspects play a role on all levels of information processing in the brain. On the neuronal level, we study aspects of temporal coding by “spikes”, i.e., the short electrical pulses (action potentials) that neurons use for signal transmission. On the behavioral level we focus on the dynamics of spatial navigation in a known or unknown environment. On all levels, temporal aspects of learning play a role, e.g. spike-time dependent learning or reinforcement learning.

The major efforts of the lab (partly financed by the Swiss National Science Foundation and the Human Brain Project) were focused on algorithms of synaptic plasticity that would be biologically plausible, yet compact enough for large simulations, and - most importantly - of functional significance. We have found general rules relating Hebbian synaptic plasticity to receptive field development (Brito and Gerstner). Moreover, we summarized conceptual ideas on the need of novel synaptic learning paradigms in several reviews. In a different line of research, we worked on simplified neuron models (Mensi et al.).

Models of spiking neurons In contrast to most artificial neural networks, real neurons communicate with short pulses. How could the brain use pulse coding for information processing? What are the dynamical properties of networks of spiking neurons? What is a good description of spiking neurons. We have developed the Spike Response Model as a generalized framework to describe neuronal firing behavior. One of the advantages of this framework is that we can use systematic fitting procedure exploiting the theory of Generalized Linear Models, so as to rapidly extract parameters directly from experimental data.

Keywords Computational neuroscience, spiking neuron models, plasticity, learning

Spike-timing dependent learning rules Experimental data show that the change of a synaptic weight from a neuron i to a neuron j depends on the relative timing of the pulses of neurons i and j, as well as on the postsynaptic membrane potential. What are relevant time scales of induction and consolidation? What would be a compact computational model of the main effects? What are the computational consequences of such asymmetric learning rules? We have developed an orchestrated plasticity model that covers effects observed in various labs across various time scales. The model combines Hebbian with homeostatic effects via homosynaptic and heterosynaptic plasticity as well as aspects of neuromodulation and consolidation while remaining computationally tractable.

BMI - Brain Mind Institute

Team Members Postdoctoral Fellows

Johanni Brea Gilra Aditya Tilo Schwalger Ho Ling LI PhD Students

Florian Colombo Dane Corneil Mohammadjavad Faraji Chiara Gastaldi Olivia Gozel Bernd Illing Marco Lehmann Vasiliki Liakoni Samuel Muscinelli Alex Seeholzer Hesam Setareh Master students A model of learning novel hand movements generated by spike patterns.

Parima Ahmadipouranari Administrative Assistant

Rosa Turielle

Selected Publications »» Brea, J., Gaal, A.T., Urbanczik, R. and Senn, W. (2016) Prospective coding by spiking neurons. PLoS Computational Biology 12: e1005003. »» Brea, J.M. and Gerstner, W. (2016) Does computational neuroscience need new synaptic learning paradigms? Current Opinion in Behavioral Sciences 11:61-66. »» Mensi, S., Hagens, O., Gerstner, W. and Pozzorini, C. (2016) Enhanced sensitivity to rapid input fluctuations by nonlinear threshold dynamics in neocortical pyramidal neurons. PLoS Computational Biology 12: e1004761. »» Fremaux, N. and Gerstner, W. (2016) Neuromodulated-spike-timing-dependent plasticity, and theory of three-factor learning rules. Frontiers in Neural Circuits 9: 85. »» Brito, C.S.N. and Gerstner, W. (2016) Nonlinear Hebbian learning as a unifying principle in receptive field formation. PLoS Comput Biol 12: e1005070

Gräff Lab Johannes Gräff - Tenure-track Assistant Professor

Intrigued by how genes can influence behavior – and vice versa – Johannes Gräff conducted his PhD in the lab of Isabelle Mansuy at the ETH Zürich to specialize in neuroepigenetic processes that regulate learning and memory. Then as a postdoc at MIT with Li-Huei Tsai, he showed that epigenetic mechanisms are causally involved in neurodegeneration-associated memory loss, as well as with updating traumatic memories from the distant past. Since 2013, Dr. Gräff has been a tenure-track assistant professor at the Brain Mind Institute of the Faculty of Life Sciences, and the Nestle Chair for Neurosciences at EPFL.

graefflab.epfl.ch

Introduction

Results Obtained

Our lab is interested in three main questions. How and where are long-term memories stored in the brain? Why are memories lost during neurodegeneration such as in Alzheimer’s Disease? How can traumatic memories from the past be overcome? To answer these questions, our lab focuses on the emerging field of neuroepigenetics. “Epi-genetic” mechanisms, i.e. modifications to the chromatin that regulate gene expression without changing the DNA sequence itself, have not only been shown to react to fluctuating environmental contingencies, but also to encode the cell fate of neurons and other cell types during development. With this Janus-faced property of being at once dynamic and stable, we believe that epigenetic mechanisms harbor the potential to better explain the molecular processes that govern learning, memory and memory loss. In extension, because epigenetic mechanisms are also amenable to pharmacological intervention, they might constitute a novel angle on how to counteract memory loss and resilient traumatic memories.

Two more postdocs were hired, one of whom (BS) holds an EMBO long-term fellowship (LTF) and another one ( JSM) secured a SYNAPSIS postdoctoral fellowship. JG obtained an Alzheimer’s Association New Investigator Research Grant, became an MQ and NARSAD fellow, and was awarded an ERC Starting Grant. Several projects show promising results while others are still in the ramping-up phase.

Keywords Epigenetics, Long-term memories, Memory loss, Alzheimer’s Disease, PTSD (post-traumatic stress disorder)

BMI - Brain Mind Institute

Team Members Postdoctoral Fellows

Jose Sanchez-Mut Bianca Silva Zimbul Albo PhD Students

Ossama Khalaf Allison Burns Lucie Dixsaut Technician

Liliane Glauser Administrative Assistant

Soledad Andany

Immunohistochemical labeling of the mouse brain showing a cell that was activated when the animal remembered a traumatic event (green) and that was re-activated when the same animal successfully extinguished the traumatic memory (red).

Selected Publications »» Silva B.A., Gross, C.T. and Gräff, J. (2016) The neural circuits of innate fear: detection, integration, action, and memorization. Learning and Memory 23: 544-555. »» Anda F.C., Madabhushi, R., Rei, D., Meng, J., Gräff. J., Durak, O., Meletis, K., Richter, M., Schwanke, B., Mungenast, A., and Tsai, L.H. (2016) Cortical neurons gradually attain a post-mitotic state. Cell Research 26: 1033-1047. »» Poirazi, P., Belin, D., Gräff, J., Hanganu-Opatz, I. and Lopez-Bendito, G. (2016) Balancing family with a successful career in neuroscience. European Journal of Neuroscience 44: 1797-1803. »» Khalaf. O. and Gräff, J. (2016) Structural, synaptic, and epigenetic dynamics of enduring memories. Neural Plasticity 2016:3425908. »» Sanchez-Mut, J.V. and Gräff, J. (2015) Epigenetic alterations in Alzheimer’s disease. Frontiers in Behavioral Neuroscience 9: 347 »» Rei, D., Mason, X., Seo, J., Gräff, J., Rudenko, A., Wang, J., Rueda, R., Siegert S., Cho, S., Canter, R.G., Mungenast, A.E., Deisseroth, K. and Tsai, L.H. (2015) Basolateral amygdala bidirectionally modulates stressinduced hippocampal learning and memory deficits through a p25/Cdk5-dependent pathway. PNAS 112: 7291-7296.

Herzog Lab Michael Herzog - Full Professor - Director of the Doctoral Program in Neuroscience (EDNE)

Introduction

Results Obtained

In humans, vision is the most important sense. Surprisingly, the neural and computational mechanisms of even the simplest forms of visual processing, such as spotting a pen on a cluttered desk, are largely unknown. Our research aims to understand how and why humans can cope with visual tasks so remarkably well. In addition, we investigate vision in healthy aging and have established an endophenotype of schizophrenia based on visual masking.

To cope with the complexity of vision, most models in neuroscience and computer vision are of hierarchical and feedforward nature. Low-level vision, such as edge and motion detection, is explained by basic low-level neural circuits, whose outputs serve as building blocks for more complex circuits computing higher level features such as shape and entire objects. There is an isomorphism between states of the outer world, neural circuits, and perception, inspired by the positivistic philosophy of the mind. In a variety of publications, we have shown that although such an approach is conceptually and mathematically appealing, it fails to explain many phenomena including crowding, visual masking, and non-retinotopic processing. We have proposed instead that models of visual processing need to take into account a ‘‘flexible” grouping stage, which operates on all levels of visual processing. Grouping can depend on small spatial changes, ‘‘invisible” to low-level processes, which lead to strong changes of perception. Because of the complex grouping process, there cannot be an isomorphism between external world states, basic stereotyped circuits, and perception. Subjective terms such as grouping can, at least at the moment, not be eliminated.

Keywords Michael Herzog studied Mathematics, Biology, and Philosophy. In 1996, he earned a PhD in biology under the supervision of Prof.Fahle (Tübingen) and Prof. Poggio (MIT). Then, he joined Prof. Koch’s lab at Caltech as a post-doctoral fellow. From 1999-2004, Dr. Herzog was a senior researcher at the University of Bremen and then he held a professorship for neurobiopsychology at the University of Osnabrück for one year. Since 2004, Dr. Herzog has been a professor of psychophysics at the Brain Mind Institute at the EPFL where he has established his laboratory.

lpsy.epfl.ch

Spatio-temporal vision, perceptual & reinforcement learning, ageing & schizophrenia.

BMI - Brain Mind Institute

Team Members Postdoctoral Fellows

Vitaly Chicherov Aaron Clarke Mattew Pachai Einat Rashal Albulena Shaqiri PhD Students

Amr Abdul-Jawwad Alban Bornet Adrien Doerig Leïla Drissi Daoudi Ophélie Favrod Lukasz Grzeczkowski Maya Jastrzebowska Marc Lauffs Janir Ramos Da Cruz Evelina Thunell He Xu Engineer

Marc Repnow Visual processing and Global Gestalt. Vernier acuity is determined by the configuration of the entire stimulus of the entire visual field. (a) Observers discriminated the vernier offset direction (left vs. right). (b) Thresholds increased when the vernier was embedded in a square. (c-e) Thresholds gradually decreased when the number of flanking squares increased. From Manassi, Sayim, Herzog, 2013.

Invited Professor

Gregory Francis

Administrative Assistant

Delphine Audergon Laure Dayer

Selected Publications »» »» »» »»

Herzog, M.H., Kammer, T. and Scharnowski, F. (2016) Time slices: What Is the duration of a percept? PLoS Biology,14(4): e1002433. Pachai, M., Doerig, A. and Herzog, M.H. (2016) How best to unify crowding? Current Biology 26: R352–R353. Herzog, M. H., Thunell, E. and Ögmen H. (2016) Putting low-level vision into global context: why vision cannot be reduced to basic circuits. Vision Research 126: 9-18. Lauffs, M.M., Shaqiri, A., Brand, A., Roinishvili, M., Chkonia, E., Ögmen, H., and Herzog, M. H. (2016) Local versus global and retinotopic versus non-retinotopic motion processing in schizophrenia patients. Psychiatry Research 246: 461–465. »» Herzog, M.H. and Manassi, M. (2015) Uncorking the bottleneck of crowding: a fresh look at object recognition. Current Opinion in Behavioral Sciences 1:86–93. »» Herzog, M.H., Sayim, B., Chicherov, V. and Manassi, M. (2015) Crowding, grouping, and object recognition: A matter of appearance. Journal of Vision 15 (6): 5. »» Grzeczkowski, L., Tartaglia, E., Mast, F.W. and Herzog, M.H. (2015) Linking perceptual learning with identical stimuli to imagery perceptual learning. Journal of Vision 15(10): 13

Hess Bellwald Lab Kathryn Hess Bellwald - Associate Professor

PhD in mathematics from MIT in 1989 at the age of 21. Postdocs in Stockholm, Nice, and Toronto, and at the EPFL. Adjunct professor of mathematics at the EPFL in 1999 and associate professor of mathematics and life sciences in 2015.

hessbellwald-lab.epfl.ch

Introduction

Results Obtained

The lab focuses on algebraic topology and its applications, primarily in the life sciences (in particular neuroscience and cancer biology), but also in materials science. We apply methods from Topological Data Analysis (TDA), a new branch of mathematics developed for the study of big data. TDA has evolved rapidly and has already been shown to detect significant structure in data that is invisible to standard methods. The toolbox of TDA consists of sophisticated statistical methods based on algebraic topology, the best known of which is probably the Mapper technique, which is particularly good at detecting meaningful clustering in point cloud data sets.

1) We established a link between neural network structure and its emergent function, taking the direction of synaptic transmission into account, through topological analysis of the underlying directed graph. Analysis of the digital reconstruction of the neural microcircuit published by the Blue Brain Project revealed a remarkably intricate topology of synaptic connectivity, containing an abundance of cliques of neurons bound into cavities that guide the emergence of correlated activity, indicating that the brain processes stimuli by forming increasingly complex functional cliques and cavities.

We also develop and apply innovative topological approaches to network theory. We construct and study simplicial complexes, known as clique complexes, arising from the graphs underlying brain networks, as we have shown that certain topological invariants of these complexes encode important network information. Among such invariants are the Euler characteristic and the Betti numbers of the clique complex, as well as more subtle, topological analogues of known graph-theoretic measures. Homotopy theory and category theory are areas of expertise of lab members in pure mathematics.

Keywords Computational topology, topological data analysis, network theory, homotopy theory.

2) We developed a tool for the classification of branching structures, which are usually described qualitatively based on visual inspection and quantitatively by morphometric parameters. Neither description provides a solid foundation for categorization. We introduced a stable, generic descriptor for any branching morphology, which is computed in linear computational time by tracking the topological evolution of the tree using spheres of varying diameters, centered at the root of the morphology. We thereby established a mathematically rigorous benchmark that can be used to test different classification schemes of random and neuronal trees. 3) We developed a tool for the classification of nanoporous crystalline materials, the performance of which in applications can vary by orders of magnitude depending only on the pore structure. Our method topologically quantifies similarity of pore structures, enabling us to identify materials with similar pore geometries and to screen for materials that are similar to known top-performing structures. In the case of methane storage, we showed that materials separate into topologically distinct classes requiring different optimization strategies.

BMI - Brain Mind Institute

Team Members Postdoctoral Fellows

Magdalena Kedziorek Martina Scolamiero Gard Spreemann Katharine Turner Jean Verrette PhD Students

Martina Rovelli Kay Werndli Dimitri Zaganidis Scientific collaborator

Jérôme Scherer

Administrative Assistant

Maroussia Schafffner-Portillo

(A) Examples of the most common simplex types in the microcircuit, by dimension. (B) Schematic description of the most common simplex types. (C) Result of binning simplices according to their multiplicity in the network. In magenta: the most common type.

Selected Publications »» »» »» »» »» »» »»

Brisken, C., Hess, K. and Jeitziner, R. (2015) Progesterone and overlooked endocrine pathways in breast cancer pathogenesis. Endocrinology 156: 3442-3450.   Chacholski, W., Dror Farjoun, E., Flores, R. and Scherer, J. (2015) Cellular properties of nilpotent spaces. Geometry and Topology 19 (5): 2741–2766.   Dror Farjoun, E. and Scherer, J. (2015) Conditionally flat functors on spaces and groups. Collectanea Mathematica 66 (1): 149–160.   Chorny, B. and Scherer, J. (2015) Goodwillie calculus and Whitehead products. Forum Mathematicum 27 (1): 119–130. Hess, K. (2016) The Hochschild complex of a twisting cochain. J. Algebra 451: 302-356. Hess, K. and Shipley, B. (2016) Waldhausen K-theory of spaces via comodules. Advances in Mathematics 290: 1079-1137. Chacholski, W., Scherer, J. and Werndli, K. (2016) Homotopy excisision and cellularity. Annales Institut Fourier 66: 2641-2665

Lashuel Lab Hilal A. Lashuel - Associate Professor

B.Sc. degree in chemistry (City University of New York), PhD in bioorganic chemistry (Texas A&M University). 2000-2004: Research fellow and instructor of neurology at Harvard Medical School. 2004: Assistant Professor BMI-EPFL. 2012-2013: Visiting Associate Professor, Stanford University. 2014-2015: Executive Director Qatar Biomedical Research Institute

lashuel-lab.epfl.ch

Introduction

Results Obtained

Research in the Lashuel laboratory focuses on applying integrated chemical, biophysical, and molecular/cellular biology approaches to elucidate the molecular and structural basis of protein misfolding and aggregation and the mechanisms by which these processes contribute to the pathogenesis of neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease (AD) and Huntington’s disease (HD).

The role of post-translational modifications (PTMSs) in the pathogenesis of Parkinson’s disease (PD) and Huntington’s disease (HD): We reported, for the first time, a semisynthetic strategy for generating site-specifically nitrated proteins opens up new possibilities for investigating the role of nitration in regulating protein structure and function in health and disease (Burai et al). We completed successfully the synthesis of all known α-syn (28 proteins) and exon-1 of the Huntingtin protein (Httex1, >40 proteins) PTMs, and assessed the role of each of PTM and cross-talk between different PTMs in regulating the structure and aggregation of these proteins in vitro. Our studies demonstrated that the function of these proteins are under complex regulatory mechanisms involving cross-talk among different PTMs (Dikiy et al and Burai et al). The generation of these unique libraries of modified proteins have paved the way for new projects focusing on elucidating the role of these PTMs in regulating the spreading of pathology and the discovery of novel biomarkers, antibodies and imaging agents and assays to facilitate early detection and monitoring of disease progression and response to therapies in Parkinson’s disease and Huntington’s disease (in collaboration with industry, UCB, IRBM & Biolegend. Novel Model of Parkinson’s disease: We developed a new neuronal model that recapitulates many of the key features of Lewy body pathology in PD (Fares et al). We showed that the failure to reproduce human α-Syn (hα-Syn) fibrillization into LBs in mice could be attributed to interactions between hα-Syn and its endogenously expressed mouse α-Syn homologue. This model enable real-time assessment of inclusion formation and thus provides unique opportunities to elucidate molecular and cellular determinants that influence the mechanisms of α-Syn fibrillization in living neurons, and to identify pathways, antibodies and drugs that modulate this process and protect against neurodegeneration in PD. Mechanisms of amyloid toxicity: We demonstrated that fibril growth and seeding capacity play key roles in amyloid-beta (Eleuteri et al) and α-synuclein(Mahul-Mellier et al) mediated toxicity and showed that drugs we developed to inhibit fibril growth and seeding capacity constitutes a viable and effective strategy for protecting against neurodegeneration and disease progression in AD. Furthermore, we demonstrated that photomodulation suppresses protects against neuronal loss in a genetic Model of Parkinson’s Disease.

Current research efforts cover the following topics: 1. Elucidating the sequence, molecular and cellular determinants underlying protein aggregation, propagation and toxicity; 2. Developing novel chemical approaches and tools to investigate the role of post-translational modifications in regulating the function/dysfunction of proteins implicated in the pathogenesis of AD, PD and HD; 3. Identification of biomarkers and imaging agents for early detection and monitoring of disease progression and response to therapies; 4. Developing novel cellular to test and validate therapeutic targets, and assess disease modifying strategies based on modulating protein modification, aggregation, pathology spreading and clearance. Research in the Lashuel laboratory is funded by several funding agencies (Swiss National Science Foundation, Horizon 2020) and foundations (CHDI and Michael J Fox) and through strategic partnerships with pharmaceutical and biotech companies (AC Immune and UCB and Biolegend).

Keywords Protein aggregation, post-translational modifications, biomarkers neurodegeneration, Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

BMI - Brain Mind Institute

Team Members Postdoctoral Fellows

Anne-Laure Mahul-Mellier Bruno Fauvet Bohumil Maco Elena Tobolkina Jean-Christoph Copin Joan Romani Aumedes John Warner Juan Reyes Layane Hanna-el-Daher Mahmood Haj-Yahya Niran Maharjan Ritwik Burai Sean Deguire PhD Students

Anass Chiki Mohamed Bilal Fares Nadine Ait-Bouziad Sophie Vieweg Technicians A schematic depiction illustrating the experimental approaches used in our group to elucidate the molecular mechanisms of protein aggregation, toxicity and pathology spreading and to identify and develop novel biomarkers and therapeutic strategies for early detection and treatment of neurodegenerative diseases.

Driss Boudeffa Nathalie Jordan Céline Vocat Administrative Assistant

Marie Rodriguez

Selected Publications »» Fares, M.B., Maco, B., Oueslati, A., Rockenstein, E., Ninkina, N., Buchman, V., Masliah, E. and Lashuel, H.A. * (2016) . Induction of de novo α-Synuclein fibrillization in a novel neuronal model for Parkinson’s disease. Proc. Natl. Acad. Sci. U S A. 16;113(7):E912-21. »» Vieweg S, Ansaloni A, Wang Z, and Lashuel HA*. “An Intein-based Strategy for the Production of Tag-free Huntingtin Exon 1 Proteins Enables New Insights into the Polyglutamine Dependence of Httex1 Aggregation and Fibril Formation”, J. Biol. Chem, 2016 291(23):12074-86. »» Dikiy I, Fauvet B, Jovičić A, Mahul-Mellier A, Desorby C, El-Turk F, Gitler AD, Lashuel HA*, Eliezer D*. Semisynthetic and in vitro phosphorylation of alpha-synuclein at Y39 promotes functional partly-helical membrane-bound states resembling those induced by PD mutations. ACS Chem Biol. 2016 Jul 11. [Epub ahead of print] »» Mahul-Mellier, A., Vercruysse, F., Maco, B., Ait-Bouziad, N., De Roo, M., Muller, D. and Lashuel, H.A.* (2015) “Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death, Cell Death and Differentiation, 2015, 22(12):2107-22. »» Burai, R., Ait-Bouziad, N., Chiki, A. and Lashuel, H.A.* (2015) “Elucidating the Role of Site-Specific Nitration of α-Synuclein in the Pathogenesis of Parkinson’s Disease via Protein Semisynthesis and Mutagenesis.” J Am Chem Soc. 2015 Apr 22;137(15):5041-52. »» Eleuteri, S., Di Giovanni, S., Rockenstein, E., Mante, M., Adame, A., Trejo, M., Wrasidlo, W., Wu, F., Fraering, P.C., Masliah, E.and Lashuel, H.A*. (2015). Novel therapeutic strategy for neurodegeneration by blocking Aβ seeding mediated aggregation in models of Alzheimer’s disease. Neurobiology of Disease. 2015 Feb; 74:144-57. »» Oueslati, A., Lovisa, B., Perrin, J., Wagnières, G., van den Bergh, H., Tardy, Y. and Lashuel, H.A.* (2015). Photobiomodulation Suppresses Alpha-Synuclein-Induced Toxicity in an AAV-Based Rat Genetic Model of Parkinson’s Disease. PLoS One. 10(10):e0140880.

Magistretti Lab Pierre Magistretti - Full Professor

Pierre Magistretti is a professor at the Brain Mind Institute at EPFL and at the Center for Psychiatric Neuroscience of the University of Lausanne/CHUV and an internationally recognized leader in the field of brain energy metabolism and glia biology. His group has discovered some of the mechanisms that underlie the coupling between neuronal activity and energy consumption by the brain. Professor Magistretti received the Theodore-Ott Prize (1997), was the international Chair (20072008) at the Collège de France, Paris, was President of FENS (2002 – 2004) and IBRO Secretary General (2009-2012). Since October 2010, Dr. Magistretti is the director of NCCR SYNAPSY - “The synaptic bases of mental diseases”.

lndc.epfl.ch

Introduction

Results Obtained

Research in the LNDC is centered on the study of the cellular and molecular mechanisms of brain energy metabolism. The key question addressed is how the energy is delivered to neurons in register with synaptic activity (see Figure). We have identified a set of mechanisms demonstrating the role of astrocytes in coupling synaptic signals mediated by glutamate to the entry of glucose into the brain parenchyma and the provision of energy substrates to restore the energy budget of neurons. We have also shown that energy can be delivered to neurons in register to neuronal activity from glycogen selectively stored in astrocytes. Another dimension of the metabolic coupling between astrocytes and neurons that our group has unveiled is related to synaptic plasticity and the processes of learning and memory. We have shown that lactate transfer from astrocytes to neurons is required for these processes. We have also demonstrated the existence of “metabolic plasticity” through which transcriptionally‐regulated adaptations of certain genes of brain energy metabolism occur in relation to synaptic plasticity as observed during learning and addiction. The laboratory is also interested in microscopy imaging techniques, such as digital holographic microscopy (DHM), that allow the visualization of dynamic cellular processes, including those involved in plasticity and neurodegeneration.

The main focus of our work during the last two years was to understand the role of signaling mediated by lactate produced by astrocytes on neuronal function. In addition to its role as an energy substrate for neurons, we have discovered that lactate plays a role in learning and memory. We have previously shown that lactate is necessary for the establishment of long term memory as well as for the maintenance of long-term potentiation in vivo in rat and has a stimulatory effect on the expression of neuronal plasticity-related genes (e.g. Arc, Zif 268, BDNF) (Suzuki et al, 2011; Yang et al, 2014). In line with this, we recently demonstrated that astrocytic glycogen-derived lactate also plays an important role in appetitive learning i.e. disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine (Bourry-Jamot et al, 2015). Furthermore, we found that a set of genes involved in neuro-metabolic coupling between astrocytes and neurons, such as the lactate transporter MCT1, is induced by learning in an inhibitory avoidance task (Tadi et al, 2015). Interestingly, using a gene-to-behavior approach we were able to demonstrate that inhibitory avoidance learning was impaired in MCT1-deficient mice, further demonstrating the importance of lactate transfer in memory processes (Tadi et al, 2015). These results provide insights for the understanding of the molecular mechanisms underlying the critical role of astrocyte-derived lactate in long-term memory as well as the action of L-lactate as a signaling molecule for neuronal plasticity (see Figure). Finally, we provided an in depth characterization of the neuroprotective properties of lactate using DHM, a real-time imaging technique able to detect early signs of cell death in culture. Indeed, lactate was shown to efficiently protect neurons from an excitotoxic insult through a mechanism involving an autocrine/paracrine ATP signalling on purinergic receptors (see Figure; Jourdain et al, 2016).

Keywords Neuroenergetics, neuron-glia interaction, learning & memory, neuroprotection.

BMI - Brain Mind Institute

Team Members Senior Scientist

Gabriele Grenningloh Scientists

Igor Allaman Sophie Burlet Pascal Jourdain Sylvain Lengacher (CTI) Jean-Marie Petit Postdoctoral Fellows

Charles Finsterwald (CTI) Swananda Marathe Manuel Zenger PhD Students

Benjamin Boury-Jamot Scientific Assistants

Sara De Jesus Dias Melanie Wirth Neuron-glia metabolic coupling: Role of glia-derived lactate (produced in a neuronal activity-dependent manner via glycolysis and glycogenolysis) in neuronal plasticity and neuroprotection.

Technicians

Cendrine Barrière Elena Gasparotto Trainee

Raquel Sandoval Ortega Administrative Assistant

Selected Publications

Monica Navarro Suarez

»» Magistretti, P.J. and Allaman, I. (2015) A cellular perspective on brain energy metabolism and functional imaging. Neuron 86(4):883-901. »» Boury-Jamot, B., Carrard, A., Martin, J.L., Halfon, O., Magistretti, P.J.* and Boutrel, B*. (2015) Disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine. Mol Psychiatry 21: 1070-1076. *Co-last authors »» Jolivet, R., Coggan, J.S., Allaman, I. and Magistretti, P.J. (2015) Multi-timescale modeling of activity-dependent metabolic coupling in the neuron-glia-vasculature ensemble. PLoS Comput Biol.11(2):e1004036. »» Tadi, M., Allaman, I., Lengacher, S., Grenningloh, G. and Magistretti, P.J. (2015) Learning-induced gene expression in the hippocampus reveals a role of neuron -astrocyte metabolic coupling in long term memory. PLoS One 10(10):e0141568. »» Carrard, A., Elsayed, M., Margineanu, M., Boury-Jamot, B., Fragnière, L., Meylan, E.M., Petit, J.M., Fiumelli, H., Magistretti, P.J.*and Martin, J.L.* (2016) Peripheral administration of lactate produces antidepressantlike effects. Mol Psychiatry doi: 10.1038/mp.2016.237. *Co-last authors »» Calì, C., Baghabra, J., Boges, D.J., Holst, G.R., Kreshuk, A., Hamprecht, F.A., Srinivasan, M., Lehväslaiho, H. and Magistretti, P.J. (2016) Three-dimensional immersive virtual reality for studying cellular compartments in 3D models from EM preparations of neural tissues. J Comp Neurol 524(1):23-38. »» Mächler, P., Wyss, M.T., Elsayed, M., Stobart, J., Gutierrez, R., von Faber-Castell, A., Kaelin, V., Zuend, M., San Martín, A., Romero-Gómez, I., Baeza-Lehnert, F., Lengacher, S., Schneider, B.L., Aebischer, P., Magistretti, P.J., Barros, L.F. and Weber, B. (2016) In vivo evidence for a lactate gradient from astrocytes to neurons. Cell Metab 23(1):94-102.

Group Digital Holographic* Microscopy*

Pierre Marquet Pascal Jourdain

Professor Emeritus*

Christian Depeursinge PhD Students*

Keven Bourgeaux Kaspar Rothenfusser Manuel Zenger

Markram Lab Henry Markram - Full Professor - Director of the Blue Brain Project

Henry Markram is the Principal Investigator of the LNMC and Director of the Blue Brain Project. He began his research career in South Africa in the 1980s, moved to Israel and then to the EPFL, where he founded the BMI in 2002. He has focused on neural microcircuitry pioneering the multi-neuron patch-clamp approach. His discoveries include Spike Timing Dependent Plasticity, Redistribution of Synaptic Efficacy, and Long-Term Microcircuit Plasticity. He has also been active in autism research and co-developed the Intense World Theory of Autism.

markram-lab.epfl.ch

Introduction

Results Obtained

The Laboratory of Neural Microcircuitry (LNMC) is dedicated to understanding the structure, function and plasticity of neural microcircuitry in the neocortex. To achieve this goal, the LNMC systematically characterizes the electrophysiological, structural and molecular properties of individual neurons, local rules of connectivity, the synaptic properties of interconnected neurons and the role of neuromodulation in microcircuit dynamics. Since the functional properties of the microcircuit are ultimately defined by the dynamic repertoire of its constituent neurons and synapses, the LNMC invests considerable effort in unravelling the molecular underpinnings of these dynamic properties. This work includes the development of high throughput protocols to characterize ion channels and to derive single cell transcriptome data specific neuron types. The experimental data generated by LNMC is used by the Blue Brain Project to build realistic in silico reconstructions and simulations of neocortical microcircuitry. The LNMC has also used its expertise to characterize neurocircuitry in a rat models of autism, using the results to develop a novel theory of autism (the “Intense World Theory”) and to demonstrate the beneficial effects of rearing in a predictable, enriched environment.

During 2015 and 2016, the LNMC developed important new methods for neuroscience research, continued its longstanding work in fundamental neuroscience, and applied its expertise in applied research on autism. On the methods front, J-P Ghobril participated in the development of a new, highly versatile method to make mouse brains transparent for microscopy, and used the method to acquire whole brain single-cell resolution scans of fluorescently labelled cells, achieving major reductions in scanning time. O. Hagens worked with Christof Koch and others to develop a fast novel method to build accurate neuron models, using data from simple stimulation protocols. Both these results will contribute to brain modelling in the Blue Brain Project. Meanwhile, LNMC continued its long-standing program of basic neuroscience research, producing important new findings on the modulation of plasticity by network state. Interestingly, the same stimuli that produce longterm potentiation when the network is relatively inactive, lead to long-term depression when the network is highly active. Other fundamental research showed that intracellular spiking has a significant effect on extracellular action potentials (EAP) – casting doubt on the common belief that local field potentials are a direct proxy for synaptic activity. Finally, the lab concluded a major project on the etiology of autism, based on the “Intense World Theory of Autism”. The project, based on a rat model of autism, showed that exposure to a predictable, enriched environment in early infancy can produce improved cognitive and behavioural outcomes. This novel finding suggests the possibility of applications in the treatment of human infants at high risk for autism.

Keywords Neurons, synaptic plasticity, neural microcircuits, neuronal coding, patch clamp, signal integration, electrophysiology, single cell gene expression, ion channels, neuron morphology, modeling, autism.

BMI - Brain Mind Institute

Team Members Postdoctoral Fellows

Monica Favre Sara Gonzalez Andino Olivier Hagens Emmanuelle Logette Michela Marani Kamila Markram Rodrigo Perin Maurizio Pezzoli Jesper Ryge PhD Students

Jean-Pierre Ghobril Ayah Khubieh Yi Jane Wuzhou Yang Technical Staff

Mirjia Herzog Deborah La Mendola Julie Meystre Trainees

Confocal block imaging of triple immunohistochemical labeling. DAPI labels all cells (blue). NeuN labels all neurons (Green), GABA labels all GABAergic cells including glia (amber).

Victoria Aroworade Pierrik Chapuis Beat Geissmann Jean-Marc Comby Syed Easin Uddin Quentin Herzig Dejan Jovandic Auriane Maiza Sarah Mondoloni Nell Christophe Ramadani Faton Beatriz Rebollo Gonzalez Flavio Traversa Tahni-Ann Wilson David Wuthier Lionel Ponsonnet Cristina Radaelli Visiting Professor

Selected Publications

Giorgio Innocenti

»» FMensi, S., Hagens, O., Gerstner, W. and Pozzorini, C. (2016) Enhanced sensitivity to rapid input fluctuations by nonlinear threshold dynamics in neocortical pyramidal neurons. PLoS Computational Biology 12: e1004761. »» Raimondo, J.V., Tomes, H., Irkle, A., Kay, L., Kellaway, L. et al. (2016) Tight coupling of astrocyte pH dynamics to epileptiform activity revealed by genetically encoded pH sensors. Journal of Neuroscience 36: 7002-7013. »» Favre, M.R., La Mendola, D., Meystre, J., Christodoulou, D., Cochrane M.J. et al. (2015) Predictable enriched environment prevents development of hyper-emotionality in the VPA rat model of autism. Frontiers in Neuroscience 9:127. »» Delattre, V., Keller, D., Perich, M., Markram, H. and Muller, E.B. (2015) Network-timing-dependent plasticity. Frontiers in Cellular Neuroscience 9:220. »» Anastassiou, C., Perin, R.d.C. , Buzsaki, G., Markram, H. and Koch, C. (2015) Cell-type- and activity-dependent extracellular correlates of intracellular spiking. J. Neurophys. 114 (1): 608-623. »» Pozzorini, C. A., Mensi, S., Hagens, O., Naud, R., Koch, C. et al. (2015) Automated high-throughput characterization of single neurons by means of simplified spiking models. PLoS Comp. Biol. 11 (4): e1004275. »» Costantini, I., Ghobril, J.-P., Di Giovanna, A.P., Mascaro, A.L.A., Silvestri, L. et al. (2015) A versatile clearing agent for multi-modal brain imaging. Scientific Reports 5 (9808): 1-9

Consultant

Anthony Njoku

External Employee

Michele Giugliano Students

Laura Mekarni Caroline Violot Katya Guez Stagiaire

Axel Billaud

Administrative Assistant

Petersen Lab Carl Petersen - Full Professor

Carl Petersen studied physics as a bachelor student in Oxford (1989-1992). During his PhD supervised by Prof. Sir Michael Berridge in Cambridge (19921996) he investigated cellular and molecular mechanisms of calcium signalling. As a postdoc he joined the laboratory of Prof. Roger Nicoll at the University of California San Francisco (1996-1998) to investigate synaptic transmission and plasticity in the hippocampus. Moving to the Max Planck Institute for Medical Research in Heidelberg in the laboratory of Prof. Bert Sakmann (19992003), he began working on primary somatosensory cortex. Dr. Petersen opened his Laboratory of Sensory Processing in the Brain Mind Institute in the School of Life Sciences in the EPFL in 2003 as an Assistant Professor. In 2010 he was promoted to Associate Professor and again in 2014 to Full Professor.

lsens.epfl.ch

Introduction

Results Obtained

Neural circuits and synaptic mechanisms underlying sensory perception and associative learning

Research in the Laboratory of Sensory Processing contributed to two important areas of neuroscience in 2015-16:

Research in the Laboratory of Sensory Processing aims to define the neuronal circuits and synaptic mechanisms underlying sensory perception and associative learning in mice. To understand sensory processing at the level of individual neurons and their synaptic interactions within complex networks, we use electrophysiological and optical methods combined with molecular and genetic interventions both in vitro and in vivo. We want to know how specific neuronal networks contribute to the processing of sensory information in a learning- and context-dependent manner ultimately leading to behavioural decisions.

1. Goal-directed sensorimotor transformation drives important aspects of mammalian behavior. The striatum is thought to play a key role in reward-based learning and action selection, receiving glutamatergic sensorimotor signals and dopaminergic reward signals. In the study of Sippy et al. (2015), we obtained whole-cell membrane potential recordings from the dorsolateral striatum of mice trained to lick a reward spout after a whisker deflection. Striatal projection neurons showed strong task-related modulation, with more depolarization and action potential firing on hit trials compared to misses. Direct pathway striatonigral neurons exhibited a prominent early sensory response. Optogenetic stimulation of direct pathway striatonigral neurons readily substituted for whisker stimulation evoking a licking response. Our data are consistent with direct pathway striatonigral neurons contributing to a “go” signal for goal-directed sensorimotor transformation leading to action initiation. 2. Little is known about the properties of synaptic connectivity and synaptic transmission in vivo. In the study of Pala and Petersen (2015), we combined single-cell optogenetics with whole-cell recordings to investigate glutamatergic synaptic transmission in vivo from single identified excitatory neurons onto two genetically-defined subtypes of inhibitory GABAergic neurons in layer 2/3 mouse barrel cortex. We found that parvalbumin-expressing (PV) GABAergic neurons received unitary glutamatergic synaptic input with higher probability than somatostatin-expressing (Sst) GABAergic neurons. Unitary excitatory postsynaptic potentials onto PV neurons were also faster and more reliable than inputs onto Sst neurons. Excitatory synapses targeting Sst neurons displayed strong short-term facilitation, while those targeting PV neurons showed little short-term dynamics.

We are currently working on several complementary areas of research:    1. Measurement and perturbation of neuronal activity correlated with quantified behavior in mice, focusing on the analysis of sensory percepts informed by the C2 whisker and reported through the execution of learned motor output.    2. Basic operating principles and wiring diagrams of neocortical microcircuits, focusing on the mouse C2 barrel column.   3. Genetic analysis of the determinants of sensory perception and associative learning, through combination of viral manipulations and gene-targeted mice.

Keywords Sensory perception, Motor control, Sensorimotor integration, Learning, Neocortex, Neuronal circuits, Synaptic transmission, Whole-cell membrane potential recording, Optogenetics, Two-photon microscopy.

BMI - Brain Mind Institute

Team Members Post doctoral

Sylvain Crochet Sami El-Boustani Vahid Esmaeili Célia Gasselin Xander Houbaert Taro Kiritani Johannes Mayrhofer Tanya Sippy Keita Tamura PhD Students

Matthieu Auffret Pierre Le Merre Semihcan Sermet Angeliki Vavladeli Georgios Foustoukos Technicians

Anatomical reconstruction of connected pairs of L2/3 Exc→PV (left) and Exc→Sst (right) neurons. Example whole-cell recording of uEPSPs elicited in the PV (red) and Sst (brown) neuron by a 50 Hz train of five 1-ms light pulses. Single trial uEPSPs are shown above and average uEPSPs below (Pala and Petersen, 2015)

Eloïse Charrière Katia Galan Administrative Assistant

Severine Sudre

Selected Publications »» Sreenivasan, V., Esmaeili, V., Kiritani, T., Galan, K., Crochet, S. and Petersen, C.C.H. (2016) Movement initiation signals in mouse whisker motor cortex. Neuron 92: 1368-1382. »» Sachidhanandam, S., Sermet, B.S. and Petersen, C.C.H. (2016) Parvalbumin-expressing GABAergic neurons in mouse barrel cortex contribute to gating a goal-directed sensorimotor transformation. Cell Reports 15: 700-706. »» Yamashita, T. and Petersen, C.C.H. (2016) Target-specific membrane potential dynamics of neocortical projection neurons during goal-directed behavior. eLife 5: e15798. »» Urbain, N., Salin, P.A., Libourel, P.A., Comte, J.C., Gentet, L.J. and Petersen, C.C.H. (2015) Whisking-related changes in neuronal firing and membrane potential dynamics in the somatosensory thalamus of awake mice. Cell Reports 13: 647-656. »» Sippy, T., Lapray, D., Crochet, S. and Petersen, C.C.H. (2015) Cell-type-specific sensorimotor processing in striatal projection neurons during goal-directed behavior. Neuron 88: 298-305. »» Korogod, N., Petersen, C.C.H. and Knott, G.W. (2015) Ultrastructural analysis of adult mouse neocortex comparing aldehyde perfusion and cryo fixation. eLife 4: e05793. »» Pala, A. and Petersen, C.C.H. (2015) In vivo measurement of cell-type-specific synaptic connectivity and synaptic transmission in layer 2/3 mouse barrel cortex. Neuron 85: 68-75

Sandi Lab Carmen Sandi - Full Professor - Director of Brain Mind Institute

Introduction

Results Obtained

The Laboratory of Behavioral Genetics investigates the impact and mechanisms whereby stress and personality affect brain function and behavior, with a focus on the social domain and, particularly, on aggression and social hierarchies.

Social competition is a fundamental mechanism of evolution and the organization of individuals within dominance hierarchies an integral aspect of social groups. Little is known about the factors that affect individuals’ competitive success. Our laboratory has identified, both in humans and rodents, a key role for trait anxiety in the outcome of social competition between two conspecific individuals:

Specifically, we investigate: • Carmen Sandi was trained in Psychology and carried out her Ph.D. studies in Behavioral Neuroscience at the Cajal Institute, Madrid, in Spain. Following postdoctoral appointments at the University of Bordeaux and the Open University, UK, she was recruited by UNED in Madrid, where she headed the Stress and Memory Lab. After a sabbatical year in the University of Bern, she joined the EPFL in 2003. Her goal is to understand how stress affects brain function and behaviour and to reveal key neurobiological mechanisms that underlie individual differences in behaviour and cognition.

•

The neurobiological mechanisms involved in the formation of social hierarchies, and their modulation by stress and anxiety. Our current work focuses in the mesolimbic system and the role of mitochondrial function in motivation and social competition. The mechanisms whereby early life stress enhances risk to develop psychopathology, with a main focus on the emergence of pathological aggression. We investigate the role of glucocorticoids in determining different neurodevelopmental trajectories following exposure to early life adversity. The mechanisms linking altered neuroplasticity during development and pathological aggression. We focus on genes involved in the polysialylation of the neural cell adhesion molecule NCAM and investigate alterations in gene expression and brain connectivity linked to dysfunctional behaviors.

Experimental approaches in the lab include a combination of behavioral, neurobiological, neuroimaging, neurochemical, pharmacological, metabolic, genetic and optogenetic methods. Although traditionally, the core of our work is carried out in rodents, we are currently translating our findings to humans using behavioral economics, experimental psychology (eye-tracking, computerbased tests), virtual reality, and neuroimaging and physiological approaches.

Keywords Stress, glucocorticoids, aggression, social hierarchy, psychopathology, anxiety, personality, neural cell adhesion molecules, mitochondrial function, psychopharmacology, optogenetics, neuroeconomics, neuroimaging.

lgc.epfl.ch

Using behavioral economic approaches, we found that under stressful conditions, competitive self-confidence is regulated in opposite directions depending on trait anxiety: low-anxiety individuals become overconfident, and high-anxiety individuals become underconfident, and cortisol responses were related to these effects. We have reproduced this competitive disadvantage of high-anxiety individuals in a rat model of social competition and investigated underlying mechanisms. Our results have identified a crucial role for mitochondrial function in the nucleus accumbens for social hierarchy establishment and its involvement in the low social competitiveness associated with high anxiety. Specifically, highanxious animals exhibit reduced mitochondrial complex I and II proteins and respiratory capacity as well as decreased ATP and increased ROS production in the nucleus accumbens. Moreover, in a dyadic contest between anxietymatched animals, microinfusion of specific mitochondrial complex I or II inhibitors into the nucleus accumbens reduced social rank, mimicking the low probability to become dominant observed in high-anxious animals. Conversely, intraaccumbal infusion of nicotinamide, an amide form of vitamin B3 known to enhance brain energy metabolism, prevented the development of a subordinate status in high-anxious individuals. Our findings highlight a key role for brain energy metabolism in social behavior and point to mitochondrial function in the nucleus accumbens as a potential marker and avenue of treatment for anxiety-related social disorders.

BMI - Brain Mind Institute

Team Members Post Doctoral

Simone Astori Elias Gebara João Pedro de Matos Rodrigues Borja Rodriguez Herreros Thomas Larrieu Laia Morató Fornaguera Stephan Streuber Meltem Weger Ioannis Zalachoras PhD Students

Damien Huzard Leyla Loued-Khenissi Silvia Monari Aurélie Papilloud Alina Strasser Lab Techinicians

Jocelyn Grosse Marie-Isabelle Guillot de Suduiraut Olivia Zanoletti The establishment of a social hierarchy during a first encounter in rats is modulated by trait anxiety.

Trainee Biology Laboratory Assistants

Tanja Goodwin

Administrative Assistant

Barbara Goumaz

Selected Publications »» Tzanoulinou, S., García-Mompó, C., Riccio, O., Grosse, J., Zanoletti, O., Dedousis, P., Nacher, J. and Sandi, C. (2016) Neuroligin-2 expression in the prefrontal cortex is involved in attention deficits induced by peripubertal stress. Neuropsychopharmacology 41: 751-761. »» Bendahan, S., Goette, L., Thoresen, J., Loued-Khenissi, L., Hollis, F. and Sandi C. (2016) Acute stress alters individual risk taking in a time-dependent manner and leads to anti-social risk. Eur. J. Neurosci. doi: 10.1111/ejn.13395. »» Hollis, F., van der Kooij, M. A., Zanoletti, O., Lozano, L., Cantó, C. and Sandi, C. (2015) Mitochondrial function in the brain links anxiety with social subordination. Proc. Natl. Acad. Sci. U S A. 112: 15486-15491. »» Sandi, C. and Haller, J. (2015) Stress and the social brain: behavioral effects and neurobiological mechanisms. Nat. Rev. Neurosci. 16:290-304. »» Tzanoulinou, S., García-Mompó, C., Riccio O., Grosse, J., Zanoletti O., Panagiotis, D., Nacher, J. and Sandi, C. (2016) Neuroligin-2 expression in the prefrontal cortex is involved in attention deficits induced by peripubertal stress. Neuropsychopharmacology 41:751-761. »» Goette, L., Bendahan, S., Thoresen, J., Hollis, F., and Sandi, C. (2015) Stress pulls us apart: Anxiety leads to differences in competitive confidence under stress. Psychoneuroendocrinology 54: 115-123. »» van der Kooij, M.A. and Sandi, C. (2015) The genetics of social hierarchies. Curr. Opin. Behav. Sci. 2: 52-57

Schneggenburger Lab Ralf Schneggenburger - Full Professor

Ralf Schneggenburger obtained a PhD in Natural Sciences at the University of Göttingen in 1993, and was a post-doctoral fellow at the University of Saarland (1994) and at the Ecole Normale Supérieure (1994 - 1996). During further postdoctoral work and as a Research Group Leader at the Max-Planck Institute for biophysical Chemistry (Göttingen, 1996- 2005), he developed a research program in transmitter release mechanisms and presynaptic plasticity. In 2005, he was appointed as a Professor at EPFL and has since then been leading the Laboratory for Synaptic Mechanisms at the Brain Mind Institute.

lsym.epfl.ch

Introduction

Results Obtained

Nerve cells are embedded in complex neuronal circuits, and communicate with each other via the process of chemical synaptic transmission. The Schneggenburger lab investigates three research areas related to synaptic function in the brain:

Basic function of synapses. Together with the labs of Felix Schürmann and Henry Markram, we explored how Ca2+ channels influence the probability of vesicle fusion at the presynaptic active zone, using detailed computational modelling. The number, and distance of Ca2+ channels to docked vesicles is one important determinant of vesicle fusion probability at the synapse. However, the co-localization of vesicles and Ca2+ channels on the tens of nanometer range is difficult to study in the electron microscope. We now showed by computational modellingthat in synapses in which release is controlled by several Ca2+ channels (“domain overlap”), the channels must obey a certain minimal distance to docked vesicles to avoid saturation of the Ca2+ sensor for vesicle fusion (see Figure). The results suggest that in synapses with domain overlap release control, an ordered, but not random, arrangement of Ca2+ channels and vesicles exists (Keller et al. 2015, PLoS Comp. Biology).

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Basic function of synapses with a focus on transmitter release control.

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Molecular mechanisms of synapse development, focusing on mechanisms that determine the specific form and function of synapses.

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Synaptic plasticity, and neuronal circuits which underlie simple forms of learning in animals.

We investigate these questions in the mouse model of mammalian brain function, because of the availability of advanced genetic tools to identify and target specific neuronal populations in this mammalian species. We are especially interested in neuronal circuits which process sensory information, and focus on the auditory system, the sense of hearing. First, the auditory system has several highly specialized types of synapses, which serve as models to study the molecular mechanisms driving synapse specialization. Second, auditory stimuli, which can be easily applied in the lab environment, can elicit learning in rodents like fear conditioning, or can influence the synaptic wiring of cortical auditory circuits during critical periods of development. We are beginning to investigate the role of long-term synaptic plasticity at excitatory and inhibitory synapses in these processes.

Mechanisms of synapse development. The Ca2+ sensor proteins for vesicle fusion are encoded by Synaptotagmins (Syts), and there is a quite large number of Syt isoform genes in the mammalian genome (17). We could show that at a giant excitatory synapse in the auditory system, the calyx of Held, the Syt isoform is exchanged during brain development from Syt1 to Syt2, at a developmental period when the large calyx nerve terminal begins to grow (Kochubey et al. 2016). The results show that the hindbrain-specific Syt2 isoform is only started to be expressed, and functionally relevant, a few days after birth. The results also show that a major presynaptic protein can be exchanged during brain development. This process must involve gene expression changes in the nucleus of the presynaptic neuron, and axonal transport of the new Syt isoform to nerve terminals.

Keywords Synaptic transmission, neurotransmitter, glutamate, GABA, synaptic plasticity, synapse development, neuronal circuits, critical period plasticity.

BMI - Brain Mind Institute

Team Members Post Doctoral

Emmanuelle Berret Brice Bouhours Christopher Clark Michael Kintscher Olexiy Kochubey Evan Vickers PhD Students

Aiste Baleisyte Enida Gjoni Elin Kronander Shriya Palchaudhuri Wei Tang Techinicians

Tess Baticle Jessica Dupasquier Heather Murray Administrative Assistant

Delphine Audergon Francine Sallin The “exclusion zone” model of Ca2+ channel localization at the presynaptic active zone of synapses. The minimal distance of Ca2+ channels (red dots) to docked vesicles is indicated by the blue dashed line. Taken, with permission, from Keller et al. 2015 Plos Computational Biology 11(5).

Selected Publications »» Kochubey, O., Babai, N. and Schneggenburger R. (2016) A Synaptotagmin isoform switch during the development of an identified CNS synapse. Neuron 90: 984-999. »» Keller, D., Babai, N., Han, Y., Kochubey, O., Markram, H., Schürmann, F. and Schneggenburger R. (2015) An exclusion zone for Ca2+ channels around docked vesicles explains release control by multiple channels at a CNS synapse. PLoS Comp. Biol. 11(5): e1004253. »» Han, Y., Babai, N., Kaeser, P., Südhof, T.C. and Schneggenburger, R. (2015) RIM1 and RIM2 redundantly determine Ca2+ channel density and readily-releasable pool size at a large hindbrain synapse. J. Neurophysiology 113: 255-263. »» Schneggenburger, R. and Rosenmund, C. (2015) Molecular mechanisms governing the Ca2+ regulation of evoked and spontaneous transmitter release. Nature Neuroscience 18: 935–941 (review)

Hill Lab Sean Hill - Adjunct Professor

Sean Hill is co-Director of the Blue Brain Project and Director of Neuroinformatics in the European Union funded Human Brain Project (HBP). Dr. Hill has also served as Executive Director and Scientific Director of the International Neuroinformatics Coordinating Facility (INCF) at the Karolinska Institutet in Stockholm, Sweden. After completing his Ph.D. in computational neuroscience at the UniversitĂŠ de Lausanne, Switzerland, Dr. Hill held postdoctoral positions at The Neurosciences Institute in La Jolla, California and the University of Wisconsin, Madison, then joined the IBM T.J. Watson Research Center and served as the Project Manager for Computational Neuroscience in the Blue Brain Project until his appointment at the EPFL

hill-lab.epfl.ch

Introduction

Keywords

The Laboratory for the Neural Basis of Brain States (LNBBS) is directed by Prof. Sean Hill and based at the Campus Biotech in Geneva, Switzerland. The laboratory focuses on understanding cortical and thalamocortical structure and function and the relationship to states of the brain including wakefulness, sleep and anesthesia. The group employs biophysically-detailed computational models and large-scale simulations to investigate the cellular and synaptic mechanisms underlying brain states in health and disease.

Large-scale simulation, neuroinformatics, microcircuitry, neocortex, thalamus, connectome, sleep, wakefulness, integrated information, brain atlases, TMS, EEG.

LNBBS is part of Blue Brain, a Swiss national brain initiative that applies advanced neuroinformatics, data analytics, high-performance computing infrastructure and simulation-based approaches to the challenge of understanding the structure and function of the mammalian brain in health and disease. Professor Hill also heads the Neuroinformatics division at Blue Brain. The Neuroinformatics division developed Blue Brain Nexus, the informatics infrastucture to organize, search, access and analyze heterogeneous neuroscience data including multi-scale brain atlases, machine learning, machine vision, data and text mining, data analysis and data-driven ontologies.

Results Obtained The lab has contributed to the release of the Blue Brain digital reconstruction of a neocortical microcircuitry and the major publication in Cell. In 2015, the lab also produced several publications regarding natural language parsing and text mining for neuroinformatics. In particular, the lab demonstrated the application of text mining techniques to find statements from the neuroscience literature on the whole mouse brain connectome. In 2016, the lab led the delivery of the first release of the Neuroinformatics Platform in the Human Brain Project (nip.humanbrainproject.eu), including data federation, semantic provenance graphs, atlas viewers and the KnowledgeSpace (knowledge-space.org).

BMI - Brain Mind Institute

Team Members Post Doctoral

Christian O’Reilly Bas-Jan Zandt PhD Students

Elisabetta Iavarone Administrative Assistant

Dace Stiebrina

Example of a VPL TC cell morphology (A) and patch-clamping recording in slice for tonic (B) and burst (D) firing. Corresponding single-cell simulated tonic (C) and burst (E) firing. Reconstructed circuit (F).

Selected Publications »» Hill, S. L. (2016) How do we know what we know? Discovering neuroscience data sets through minimal metadata. Nature Reviews Neuroscience 17: 735–736. »» DeFelipe, J., Douglas, R. J., Hill, S. L., Lein, S., Martin, K. A., et al. (2016) Comments and general discussion on “The anatomical problem posed by brain complexity and size: a potential solution”. Frontiers in Neuroanatomy 10: 60. »» Leitner, F., Bielza, C., Hill, S. L., and Larrañaga, P. (2016) Data publications correlate with citation impact. Frontiers in Neuroscience.10:419. »» Vogelstein, J. T., Amunts, K., Andreou, A., Angelaki, D. and Ascoli, G., et al. (2016) Grand Challenges for Global Brain Sciences. Global Brain Workshop 2016. Johns Hopkins University, Baltimore, MD USA. »» Markram, H., et al. (2015) Reconstruction and simulation of neocortical microcircuitry. Cell 163(2): 456-492. »» Richardet, R., Chappelier, J.C., Telefont, M. and Hill, S. (2015) Large-scale extraction of brain connectivity from the neuroscientific literature. Bioinformatics 31(10):1640-1647. »» Peng, H., Hawrylycz, M., Roskams, J., Hill, S., Spruston, N., Meijering, E., & Ascoli, G. A. (2015) BigNeuron: large-scale 3D neuron reconstruction from optical microscopy images. Neuron 87(2): 252-256.

Schürmann Lab schuermann-lab.epfl.ch

Felix Schürmann - Adjunct Professor

Felix Schürmann is co-director of the Blue Brain Project and is closely involved in high performance computing research in the European Human Brain Project. Prof. Schürmann studied physics at the University of Heidelberg, Germany, supported by the German National Academic Foundation. Later, as a Fulbright Scholar, he obtained his Master’s degree (M.S.) in Physics from the State University of New York, Buffalo, USA, under the supervision of Richard Gonsalves. During these studies, he became curious about the role of different computing substrates and dedicated his masters thesis to the simulation of quantum computing. He won his Ph.D. at the University of Heidelberg, Germany, under the supervision of Karlheinz Meier. For his thesis he co-designed an efficient implementation of a neural network in hardware.

Introduction

Results Obtained

Modern in silico neuroscience leverages the computational capabilities of some of the largest computers available to science. However, it also has its own special computational characteristics and requirements and will remain a computational grand challenge for many years to come. Against this background, the Schürmann group focuses on the interface between in silico neuroscience and computer architectures. Key areas of research include techniques enabling faster and more detailed simulations of brain tissue, novel techniques for model building and visualization, and new ideas for brain-inspired computing substrates.

In 2015 and 2016, the Laboratory for Neurosimulation Technology collaborated closely with the Blue Brain Project’s HPC and visualization teams, following several different lines of research:

Keywords Neurosimulation technology, In silico neuroscience, simulation, scientific computing

1. Understanding the computational characteristics of neurosimulations: the group developed a framework allowing quantitative analysis of a selected set of brain models. The metrics, which are based on information from the model and the underlying algorithm, reveal intrinsic differences among models. Combined with detailed analyses of the underlying algorithms they make it possible to predict how specific hardware characteristics will affect simulation performance. Lately, this analysis has also been extended to deep learning models. 2. Accelerating neurosimulations: on the example of the open source NEURON simulator we investigate how these types of simulations can profit from next generation asynchronous execution models (ParalleX, HPX) to achieve better strong scaling and have implemented a first working version. For that, the group is engaged in a collaboration with Prof. Thomas Sterling from Indiana University. 3. Leveraging novel architectures: We have started to explore novel nonvolatile memory technologies in supercomputers, as a way of addressing the heavy memory requirements of detailed brain simulations as well as other data-intensive parts of brain simulation workflows such as analysis. Part of this research is performed on the existing Blue Brain BlueGene/Q supercomputer that features integrated Flash memory (Blue Gene Active Storage). Part is performed at other compute centers such as the Argonne Leadership Computing Facility.

BMI - Brain Mind Institute

Team Members Post Doctoral

Judit Planas

PhD Students

Francesco Cremonesi Bruno Magalhães Administrative Assistant

Dace Stiebrina

Visualization of the computational characteristics of different published brain models. The vertical shading denotes properties that can be associated to the single node performance, whereas the crosshatch shading denotes properties associated to network communication of the underlying computing architecture.

Selected Publications »» Masoli, S., Rizza, M.F., Sgritta, M., van Geit, W., Schürmann, F. and D’Angelo, E. (2017) Single neuron optimization as a basis for accurate biophysical modelling: the case of cerebellar granule cells. Front. Cell. Neurosci. 11: 71. »» Lytton, W.W., Seidenstein, A.H., Dura-Bernal, S., McDougal, R.A., Schürmann, F. and Hines, M.L. (2016) Simulation neurotechnologies for advancing brain research: Parallelizing large networks in neuron. Neural Comput. 28(10):2063-2090. »» Van Geit, W., Gevaert, M., Chindemi, G., Rössert, C., Courcol, J., Muller, E.B., Schürmann, F., Segev, I. and Markram, H. (2016) BluePyOpt: Leveraging open source software and cloud infrastructure to optimise model parameters in neuroscience. Front. Neuroinform. 10:17. »» Kumbhar, P., Hines, M.L., Ovcharenko, A., Mallon, D.A., King, J., Sainz, F., Schürmann, F. and Delalondre, F. (2016) Leveraging a cluster-booster architecture for brain-scale simulations. International Supercomputing Conference, Frankfurt, Germany. »» Magalhaes, B., Tauheed, F., Heinis, T., Ailamaki, A. and Schürmann, F. (2016) An efficient parallel load-balancing framework for orthogonal decomposition of geometrical data. ISC High Performance, Frankfurt, Germany. »» Eilemann, S., Delalondre, F., Bernard, J., Planas, J., Schürmann, F. et al. (2016) Key/value-enabled flash memory for complex scientific workflows with on-line analysis and visualization. Parallel and Distributed Processing Symposium, IEEE International (pp. 608-617). »» Markram, H. et al., Schürmann, F. (2015) Reconstruction and simulation of neocortical microcircuitry. Cell 163: 456-492.

IBI

Institute of Bioengineering

Mattias Lutolf - Director

The Mission of the Institute of Bioengineering (IBI) is to perform world-class quantitative, systems- and design-oriented research in and for the life sciences. By breaking down the boundaries between engineering, physics, chemistry, computer science and the life sciences, IBI labs strive to better understand basic biological principles and transform this knowledge into innovative technology platforms and clinical applications. The IBI sits at the interface of the life sciences and of engineering, being situated in both the School of Life Sciences and the School of Engineering. This dual affiliation allows great diversity in hiring faculty from different backgrounds and with different research perspectives. It also provides a rich educational environment, both at the Bachelor/Master and at the PhD levels, especially since IBI’s joint Master program in Bioengineering is shared between the two Schools. The IBI’s research agenda has evolved into six main themes: biomechanics and neuroengineering, bio-optics and bioimaging, nano- and micro-bioengineering, molecular, cell and tissue engineering, systems and computational biology, systems physiology and immunoengineering. Notable events in 2016 include the welcoming of four new IBI faculty: Andrew Oates (Full Professor) and Alexandre Persat (Tenure-Track Assistant Professor - PATT), both hired through a broad search in Bioengineering launched at the end of 2014; Li Tang (PATT), hired through a joint search in Biomaterials launched in 2014 with the Institute of Materials (IMX); Paolo De Los Rios (Associate Professor), courtesy appointed (his principal affiliation is in Physics in the School of Basic Sciences). Note that Persat is co-affiliated, having his principal affiliation in SV’s Global Health Institute (GHI). At the end of the year, the IBI bid a very heartfelt farewell to two of its former Directors, as both Jeffrey Hubbell (founding director, in office from October 2003 until September 2012) and his direct successor Melody Swartz (in office from October 2012 until April 2014) were leaving the EPFL, headed for new academic horizons. As a small token of appreciation of their priceless contributions in building the institute and leading it to remarkable stature in little more than a decade, the IBI’s annual young researcher award will from now on carry their names. Further events worth mentioning here: tenure obtained by Stéphanie Lacour (promoted to Associate Professor), and promotion of Auke Ijspeert to the academic rank of Full Professor; annual Bioengineering Day held off-campus for the first time (at Campus Biotech, Geneva), with keynote talks delivered by Donald E. Ingber (Director of the Harvard Wyss Institute for Biologically Inspired Engineering, Boston, MA, USA) and Molly Stevens (Imperial College, London, UK); annual IBI-sponsored ‘Future Leader in Bioengineering’ Award bestowed upon Jiandong Feng, graduate student in the Radenovic Lab. The move of neuroprosthetics/neuroengineering-oriented IBI labs to Campus Biotech has been completed in 2016: Stéphanie Lacour’s, Silvestro Micera’s and Diego Ghezzi’s labs are now all under one roof in Geneva, together with José del R. Millán’s and Dimitri Van De Ville’s, who had relocated there in 2015. On the EPFL campus, Li Tang was the first IBI member to open a lab in the new ME-D building, where Bruno Correia will relocate his operation in 2017. On the educational side finally, 27 new Ph.D. titles were awarded in 2016 to members of IBI-affiliated labs, under the auspices of seven distinct EPFL Doctoral Programs - a fact highlighting in itself the inherently cross-disciplinary nature of Bioengineering research. Moreover, the Life Sciences and Technologies Section (SSV) graduated 49 new EPFL Masters in Bioengineering. http://bioengineering.epfl.ch © Copyright 2004-2016 EPFL for all material published in this report - info.sv@epfl.ch

Auwerx Lab Johan Auwerx - Full Professor - NestlĂŠ Chair in Energy Metabolism

Johan Auwerx received an M.D. and Ph.D. from the Katholieke Universiteit Leuven, Belgium. He performed post-doctoral training in Medical Genetics at the University of Washington, Seattle. He is certified in Endocrinology, Metabolism and Nutrition. He was elected as a member of EMBO in 2003 and received a dozen of international scientific prizes, including the Danone Nutrition Award, the Minkowski Prize, and the Morgagni Gold Medal. Prof. Auwerx is an editorial board member of Cell Metabolism, Molecular Systems Biology, EMBO Journal, Cell, and Science and he co-founded a handful of biotech companies (most recently Mitokyne) and serves on several scientific advisory boards.

auwerx-lab.epfl.ch

Introduction

Results Obtained

Our lab has extensive research expertise and experience in cellular and molecular physiology, metabolism, and genetics applied in C. elegans, mice, and humans. We have developed and used systems approaches to map the signaling networks that coordinate the communication between the nucleus and the mitochondria and as such regulate organismal metabolism in health, aging, and disease. Although our research addressed basic biomedical questions, my medical background facilitated the translation of our discoveries into novel preventive and therapeutic strategies for common diseases, such as type 2 diabetes, obesity, and frailty, as well as for rare inherited mitochondrial diseases. The translational value of our work is testified by the fact that several drugs targeting processes and pathways, which we elucidated are currently used in the clinic (e.g. PPAR agonists, nicotinamide riboside).

Whereas the initial work of Johan Auwerx (see lab introduction) was instrumental to elucidate how transcription factors and their associated transcriptional cofactors are involved in the antegrade control of mitochondrial activity, more recently, he elucidated a novel retrograde signaling pathway that emanates from the mitochondria to influence nuclear function, i.e. mitochondriaâ&#x2020;&#x2019;nucleus. Interference with mitochondrial translation -either through genetic (mutations and variation in expression of the mitochondrial ribosomal proteins) or pharmacological strategies (doxycycline and chloramphenicol)- reduces the production of mtDNA encoded ETC components, resulting into a mitonuclear imbalance between mtDNA and nDNA encoded ETC proteins, which subsequently activates the mitochondrial stress response, such as the unfolded protein response (UPRmt). UPRmt is an adaptive response that restores mitochondrial function, which in the worm is linked with the extension of lifespan. He furthermore discovered that exposing mice, worms and cells to compounds, which activate mitochondrial biogenesis, such as well-known longevity compounds rapamycin and resveratrol, as well as compounds that boost NAD+ levels, also induce UPRmt. This work indicates that UPRmt is triggered both during mitochondrial biogenesis and mitonuclear proteostatic imbalance, and in each case has beneficial effects on mitochondrial function and organismal health. The translational value of these observations were underscored by the fact that induction of the UPRmt by administering the NAD+ booster, nicotinamide riboside, was shown to (1) protects against stem cell aging, resulting in a significant extension of mouse lifespan; (2) protects against the onset fatty liver disease; and (3) delayes the symptoms of muscular dystrophy.

Keywords Aging, C.elegans, diabetes, genetics, mitochondria, metabolism, obesity, transcription.

IBI - Institute of Bioengineering

Team Members Academic Guest

Keir Menzies ( July to November 2015) Post Doctoral Associates

Maroun Bou Sleiman (from October 2016) Davide D’Amico Pooja Jha Olli Matilainen Keir Menzies (until June 2015) Pedro Moral Quiros Laurent Mouchiroud Dongryeol Ryu (Until 31.08.2016) Vincenzo Sorrentino Xu Wang Evan Williams (March – August 2015) PhD Students

C.elegans expressing a GFP reporter gene under the control of the hsp-60 promotor lights up in the presence of mitochondrial stress

Karim Gariani Virginija Jovaisaite (until 30.11.2016) Elena Katsyuba Jun Yong Kim (from August 2016) Hao Li Peiling Luan (from September 2016) Adrienne Mottis Evan Williams (until March 2015) Hongbo Zhang Internships Students

Selected Publications »» Moullan, N., Mouchiroud, L., Wang, X., Ryu, D., Williams,E.G., Mottis, A., Jovaisaite, V., Frochaux, M.V., Quiros, P.M., Deplancke, B., Houtkooper, R.H. and Auwerx, J. (2015). Tetracyclines disturb mitochondrial function across eukaryotic models: a call for caution in biomedical research. Cell Reports 10:1681-1691. »» Gariani, K., Menzies, K.J., Ryu, D., Wegner, C.J., Wang, X., Ropelle,E.R.,. Moullan, N., Zhang, H., Perino, A., Lemos, V., Kim,B., Park, Y.K., Piersigilli, A.,, Pham, T.X., Yang, Y., Ku, C.S., Koo, S.I., Fomitchova, A., Cantó, C., Schoonjans, K., Sauve, A.A., Lee, J.Y. and Auwerx, J. (2016) Eliciting the mitochondrial unfolded protein response via NAD+ repletion reverses fatty liver disease. Hepatology 63: 1190-1204. »» Merkwirth, C., Jovaisaite, V., Durieux, J., Matilainen, O., Jordan, S.D., Quiros, P.M., Steffen, K.K., Williams, E.G., Mouchiroud, L., Uhlein, S.N., Murillo, V., Wolff, S.C., Shaw, R.J., Auwerx, J.* and Dillin, A.* (2016) Two conserved histone demethylases regulate mitochondrial stress-induced longevity. Cell 165: 1209-1223. (*co-last and co-corresponding authors) »» Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., D’Amico, D., Ropelle, E.R., Lutolf, M.P., Aebersold, R., Schoonjans, K., Menzies, K.J.* and Auwerx, J.* (2016) NAD+ repletion improves mitochondrial and stem cell function and enhances lifespan in mice. (*co-last and co-corresponding authors). Science 352: 1436-1443. (*co-last and co-corresponding authors) »» Williams, E.G., Wu, Y., Dubuis, S., Blattmann, P., Argmann, C.A.,. Houten, S.M., Amariuta, T., Wolski, W., Zamboni, N., Aebersold, R.* and, Auwerx, J.* (2016) Systems proteomics of liver mitochondria function. Science 352 doi: 10.1126/science.aad0189. (*co-last and co-corresponding authors) »» Ryu, D., Mouchiroud, L., Andreux, P.A., Katsyuba, E., Moullan, N., Nicolet-dit-Felix, A.A., Williams, E.G., Jha, P., Lo Sasso, G., Huzard, D., Aebischer, P., Sandi, C., Rinsch, C.*,and Auwerx, J.* (2016) Urolithin A induces mitophagy and prolongs lifespan in C.elegans and increases muscle function in rodents. Nature Medicine 22: 879-888. (*co-last and co-corresponding authors) »» Ryu, D., Zhang, H., Ropelle, E.R., Sorrentino, V., Mázala, D.A.G., Mouchiroud, L., Marshall, P.L., Campbell, M.D., Ali, A.S., Knowels, G.M., Bellemin, S., Iyer, S.R., Wang, X., Gariani, K., Sauve, A.A., Cantó, C.,. Conley, K.E., Walter, L., Lovering, R.M., Chin, E.R., Jasmin, B.J., Marcinek, D.J., Menzies, K.J.* and J. Auwerx* (2016) NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation. Sci. Transl. Med. 361ra139; doi: 10.1126/scitranslmed.aaf5504 (*co-last and co-corresponding authors)

Syed Uddin Easin (EPFL) Aashima Goyal (IIT Delhi) Tao Lin (EPFL) Peiling Luan (EPFL) Virginie Peter (UNIL) Francesca Potenza (Italy) Solene Rietsch (UTC Compiègne, FR) Mario Romani (Italy) Lisa Vrijens (KU Leuven) Sophie You (UC Berkeley) Civiilist

Leo Diserens Lab Techinicians

Sabrina Bichet Norman Moullan Administrative Assistant

Valérie Stengel

Baekkeskov Lab Steinunn Baekkeskov - Visiting Professor

Steinunn Baekkeskov received her PhD in Biochemistry from the University of Copenhagen in 1984 identifying and characterizing target antigens of the autoimmune response involved in pancreatic beta cell destruction and development of type 1 diabetes. She held positions of Research Scientist and Senior Research Scientist and group leader at the Hagedorn Research Laboratory in Copenhagen until 1989 when she was appointed Assistant Professor in the Departments of Medicine and Microbiology/Immunology, University of California San Francisco (UCSF). She was a full professor at UCSF 1998-2014. In 2012 she became a part time Visiting Professor in the School of Life Sciences at EPFL.

baekkeskov-group.epfl.ch

Introduction

Results Obtained

Type 1 Diabetes (T1D) in humans develops following an autoimmune destruction of pancreatic beta cells in the islets of Langerhans. In earlier work, we and others identified two intracellular human beta cell membrane proteins which are targeted in this process, GAD65, a synthesizing enzyme for GABA, localized to the membrane of microvesicles and IA-2, a non-functional tyrosine phosphatase localized to the membrane of insulin granules. Autoantibodies to those proteins are detected in the blood several years before clinical onset of T1D and identify individuals at risk. While T1D can be prevented in the NOD mouse model of diabetes, this model differs in significant ways from T1D in man and no safe methods are currently available in humans. Pancreatic beta cells have a well developed, extensive, and highly active ER, reflecting their role in synthesizing and secreting large amounts of insulin. Beta cells are particularly susceptible to ER stress, which is implicated in beta cell dysfunction and loss during the pathogenesis of T1D.

Development of monolayer cultures of rat and human islet cells. The islet of Langerhans consist of a microsociety and signalling hub containing 10005000 endocrine cells, including insulin secreting beta cells interconnected with three other hormone producing endocrine cells. The lack of a method to culture primary islet cells as inter-connected and functional monolayer cultures on glass has hampered studies of islet cell biology. We have developed a method using a combination of optimized cell matrix and growth factors resulting in robust and highly functional monolayer culture of islet cells enabling live and fixed cell imaging and providing structural details of cellular processes of unprecedented resolution (Figure 1).

The focus of current research is: • Testing the hypothesis that ER stress is an important factor in inducing autoimmunity to GAD65 and IA2 • Studying how the intracellular membrane proteins, GAD65, IA-2 and proinsulin become visible to the immune system during ER stress • Understanding the function of GABA-ergic signalling in islets of Langerhans

Keywords Type 1 diabetes, autoantigens, membrane trafficking, ER-stress, GAD65, IA2, GABA.

Aberrant accumulation of GAD65 in Golgi membranes in conditions of ER stress and autoimmunity. ER-stress may facilitate the formation and release of immunogenic forms of intracellular proteins into an inflammatory environment contributing to antigen presentation and induction of autoimmunity. We have shown that induction of ER stress in primary beta cells perturbs the palmitoylation cycle controlling GAD65 endomembrane distribution, resulting in aberrant accumulation of the palmitoylated form in trans-Golgi membranes. The palmitoylated form has heightened immunogenicity, exhibiting increased uptake by antigen presenting cells and T cell stimulation compared to the nonpalmitoylated form. Similar accumulation of GAD65 in Golgi membranes is observed in human beta cells in pancreatic sections from GAD65 autoantibody positive individuals, who have not yet progressed to clinical onset of T1D, and T1D patients with residual beta cell mass and ongoing T cell infiltration of islets. We propose that aberrant accumulation of immunogenic GAD65 in Golgi membranes facilitates inappropriate presentation to the immune system following release from stressed and/or damaged beta cells, triggering autoimmunity.

IBI - Institute of Bioengineering

Team Members Post Doctoral

Edward Phelps PhD Students

Chiara Cianciaruso Techinicians

Miriella Pasquier Administrative Assistant

Miriella Pasquier

Figure 1. Breaking the diffraction barrier to image beta cells up close A two-color stimulated emission depletion (STED) super-resolution image of a primary human beta cell immunostained for α-tubulin and insulin illustrates the spatial relationship between microtubule cytoskeleton and insulin secretory granules.

Selected Publications »» Phelps, E. A., Cianciaruso, C., Santo-Domingo, J., Pasquier, M., Galliverti, G., Piemonti, L., Berishvili, E., Burri, O., Wiederkehr, A., Hubbell, J. A. and Baekkeskov, S. (2017) Advances is pancreatic islet monolayer culture on glass surfaces enable super-resolution microscopy and insights into beta cell ciliogenesis and proliferation. Submitted. »» Cianciaruso, C., Phelps, E. A., Pasquier, M., Hamelin, R., Demurtas, D., Alibashe Ahmed, M., Piemonti, L., Hirosue, S., Swartz, M. A., De Palma, M., Hubbell, J. A. and Baekkeskov, S. (2016) Primary human and rat beta cells release the intracellular autoantigens GAD65, IA-2 and Proinsulin in exosomes together with cytokine induced enhancers of immunity. Diabetes 66: 460-473. »» Phelps, E. A., Cianciaruso, C., Michael, I.P., Pasquier, M., Kanaani, J., Nano, R., Lavallard, V., Billestrup, N., Hubbell, J.A. and Baekkeskov, S. (2016) Aberrant accumulation of the diabetes autoantigen GAD65 in Golgi membranes in conditions of ER stress and autoimmunity. Diabetes 65: 2686-2699. »» Kanaani, J., Cianciaruso, C., Phelps, E.A., Pasquier, M., Brioudes, E., Billestrup, N. and Baekkeskov S. (2015) Compartmentalization of GABA synthesis by GAD67 differs between pancreatic beta cells and neurons. PLoS One 10(2) : e0117130

Barrandon Lab Yann Barrandon - Professor

ldcs.epfl.ch

Introduction

Results Obtained

The laboratory of Stem Cell Dynamics at EPFL and Experimental Surgery at the CHUV has three main objectives: first, to understand the relationship between stem/progenitors cells expressing p63 (stratified epithelia and related epithelia), second to understand the impact of the environment on stem cell behavior (self-renewal) and third to comprehend stem cell engraftment. All projects ultimately aim at improving cell and gene therapy using epithelial stem/progenitor cells.

There is a widespread agreement from patient and professional organizations alike that the safety of stem cell therapeutics is of paramount importance, particularly for ex vivo autologous gene therapy. Yet current technology makes it difficult to thoroughly evaluate the behaviour of genetically corrected stem cells before they are transplanted. To address this, we have developed a strategy that permits transplantation of a clonal population of genetically corrected autologous stem cells that meet stringent selection criteria and the principle of precaution. As a proof of concept, we have stably transduced epidermal stem cells (holoclones) obtained from a patient suffering from recessive dystrophic epidermolysis bullosa. Holoclones were infected with self-inactivating retroviruses bearing a COL7A1 cDNA and cloned before the progeny of individual stem cells were characterised using a number of criteria. Clonal analysis revealed a great deal of heterogeneity among transduced stem cells in their capacity to produce functional type VII collagen (COLVII). Selected transduced stem cells transplanted onto immunodeficient mice regenerated a non-blistering epidermis for months and produced a functional COLVII. Safety was assessed by determining the sites of proviral integration, rearrangements and hit genes and by whole-genome sequencing. The progeny of the selected stem cells also had a diploid karyotype, was not tumorigenic and did not disseminate after long-term transplantation onto immunodeficient mice. In conclusion, a clonal strategy is a powerful and efficient means of bypassing the heterogeneity of a transduced stem cell population. It guarantees a safe and homogenous medicinal product, fulfilling the principle of precaution and the requirements of regulatory affairs. Furthermore, a clonal strategy makes it possible to envision exciting gene-editing technologies for next-generation gene therapy.

Keywords Yann Barrandon, MD PhD. Joint professor of Stem Cell Dynamics at the Swiss Federal Institute of Technology Lausanne (EPFL) and Lausanne University (UniL), and Head of the Department of Experimental Surgery at the Lausanne University Hospital (CHUV) since 2002. PhD in Paris, post-doc (1982-1990) at Stanford Medical School and at Harvard Medical School (HMS) with Pr. Howard Green. Initiative Director of the Joint Doctoral Program between Singapore-A*Star and the EPFL, and a consultant for the Institute of Medical Biology A*Star, Biopolis.

Stem cell, microenvironment, epithelia, epidermis, cornea, thymus, cell and gene therapy

IBI - Institute of Bioengineering

Team Members Senior Scientists

Rochat Ariane Claudinot Stéphanie Post Doctoral Scientists

Bureau Jean-Baptiste Kanemitsu Michiko Maggioni Melissa Mosig Johannes PhD Students

Arlabosse Tiphaine De Lageneste Marine Hémon Diane Muller Georges Manti Pierluigi Pluchinotta Matteo Zaffalon Andrea Master Students

De Meyer Sara Urni Clémence Transversal section of a hair bulb of a whisker of the mouse. E-Cadherin (red), EdU (green), dapi (blue)

Research Assistants

Burki Marco De Souza Silva Olga Savoy Dorinne Administrative Assistant

Guex Nathalie

Selected Publications »» Nowell, C.S., Odermatt, P.D., Azzolin, L., Hohnel, S., Wagner, E.F., Fantner, G.E., Lutolf, M.P., Barrandon, Y., Piccolo, S., Radtke, F. (2016). Chronic inflammation imposes aberrant cell fate in regenerating epithelia through mechanotransduction. Nat. Cell Biol. 18(2):168-180. »» Nanba, D., Toki, F., Tate, S., Imai, M., Matsushita, N., Shiraishi, K., Sayama, K., Toki, H., Higashiyama, S., Barrandon, Y. (2015). Cell motion predicts human epidermal stemness. J Cell Biol. 209(2):305-315. »» Droz-Georget Lathion, S., Rochat, A., Knott, G., Recchia, A., Martinet, D., Benmohammed, S., Grasset, N., Zaffalon, A., Besuchet Schmutz, N., Savioz-Dayer, E., Beckmann, J.S., Rougemont, J., Mavilio, F., Barrandon, Y. (2015). A single epidermal stem cell strategy for safe ex vivo gene therapy. EMBO Mol. Med. 7(4):380-393.

Dal Peraro Lab Matteo Dal Peraro - Associate Professor and EDBB Doctoral School Director

Introduction

Results Obtained

The main goal of my laboratory is to understand the physical and chemical properties of complex biological systems, in particular their function emerging from structure and dynamics. To address these questions, we use and develop a broad spectrum of computational tools fully integrated with experimental data. Multiscale models and dynamic integrative modeling are used to investigate the assembly and function of molecular assemblies mimicking conditions of the cellular environment.

In 2015/2016 we have significantly advanced to a more realistic and consistent modeling of the molecular components of the cell. With the aim of capturing the complex physical and chemical features of biological membranes we developed LipidBuilder (lipidbuilder.epfl.ch), a framework that enables the assembly of realistic bilayers featuring asymmetric distribution on layer leaflets and concentration of given membrane constituents as determined by lipidomics experiments. Using this platform we studied the transmembrane (TM) domain of the amyloid precursor protein (APP). The proteolytic cleavage of APP by γ-secretase releases amyloid-β (Aβ) peptides, which accumulation in the brain tissue is an early indicator of Alzheimer’s disease. We used multiscale molecular dynamics simulations to investigate the stability of APP-TM dimer in realistic models of the synaptic plasma membrane (SPM, see Figure). We discovered that the chemical composition of the SPM is responsible of selecting one (G700XXXG704XXXG708) between the two possible APP dimerization motifs previously proposed by NMR and EPR. Our results will help better understanding APP’s biological function and Aβ production as well as promoting a rational improvement of γ-secretase modulators currently under development.

Keywords Matteo Dal Peraro graduated in Physics at the University of Padova in 2000 and obtained his Ph.D. in Biophysics at the International School for Advanced Studies (SISSA, Trieste) in 2004. After a postdoctoral training at the University of Pennsylvania (Philadelphia, USA), he was nominated Tenure Track Assistant Professor at the School of Life Sciences in 2007, and became Associate in 2014. Prof. Dal Peraro’s research at the Laboratory for Biomolecular Modeling, within the Institute of Bioengineering (IBI), focuses on the multiscale modeling of large macromolecular systems.

lbm..epfl.ch

Structural Biology Biophysics and Biochemistry Integrative Modeling Molecular Simulations Macromolecular Assembly Algorithm Development High-Performance Computing

With the same aim of modeling systems as close as possible to physiological conditions, we used NMR and molecular dynamics simulations to study the effect of molecular crowding on proteins’ hydration, electrostatics, and dynamics. We observed that small polar uncharged crowding molecules are sticky on the protein surface, whereas charged small molecules are not, but the latter still perturb the internal protein electrostatics as they diffuse nearby. Meanwhile, interactions with larger molecular crowders are favored mainly through hydrophobic, but not through polar, surface patches. Our results shed new lights for understanding proteins’ properties inside living cells, and reinforce the idea that proteins should be studied in native-like media to achieve a faithful description of their function.

IBI - Institute of Bioengineering

Team Members Post Doctoral

Luciano Andres Abriata Maria Josefina Marcaida Lopez Nuria Cirauqui PhD Students

Martina Audagnotto Aydin Deniz Fonti Giulia Prunotto Alessio Alexandra Kalantzi Styliani Giorgio Elikem Tamo Sylvain Traeger Administrative Assistant

Julia Prébandier

Amyloid Precursor Protein (APP) can dimerize through its transmembrane segment. Using molecular modeling and simulations of APP embedded in a realistic model of the synaptic plasma membrane we observed that the specific membrane composition has the ability to select a specific dimeric conformation, which in turn becomes the most relevant entity at physiological conditions (Audagnotto et al. JPCL 2016).

Selected Publications »» Audagnotto, M., Lemmin, T., Barducci, A. and Dal Peraro, M. (2016) Effect of the synaptic plasma membrane on the stability of the amyloid precursor protein homodimers. The Journal of Physical Chemistry Letters 7(18): 3572-3578. »» Abriata, L.A., Spiga, E. and Dal Peraro. M. (2016) Molecular effects of concentrated solutes on protein hydration, dynamics, and electrostatics. Biophysical Journal 111(4):743-755. »» Iacovache, I., De Carlo, S., Cirauqui, N., Dal Peraro, M., Van Der Goot, F.G. and Zuber, B. (2016) Cryo-EM structure of aerolysin variants reveals a novel protein fold and the pore-formation process. Nature Communications 7: 12062. »» Song, A.S., Poor, T.A., Abriata, L.A., Jardetzky, T.S., Dal Peraro, M. and Lamb, R.A. (2016) Immobilization of the N-terminal helix stabilizes prefusion paramyxovirus fusion proteins. Proceedings of the National Academy of Sciences 113(27): E3844-E3851. »» Bovigny, C., Tamò, G., Lemmin, T., Maïno, N. and Dal Peraro, M. (2015) LipidBuilder: A framework to build realistic models for biological membranes. Journal of Chemical Information and Modeling 55(12): 2491-2499. »» Tamò, G., Abriata, L.A. and Dal Peraro, M. (2015) The importance of dynamics in integrative modeling of supramolecular assemblies. Current Opinion in Structural Biology 31: 28-34. »» Palermo, G., Cavalli, A., Klein, M.L., Alfonso-Prieto, M., Dal Peraro, M. and De Vivo, M. (2015) Catalytic metal ions and enzymatic processing of DNA and RNA. Accounts of Chemical Research 48(2): 220-228

Deplancke Lab Bart Deplancke - Associate Professor

Bart Deplancke received his M.Sc. in bio-engineering from Ghent University (Belgium), and his Ph.D. from the University of Illinois (UrbanaChampaign, USA). After a postdoc at Harvard Medical School and then the University of Massachusetts Medical School, he moved to the EPFL at the end of 2007. His group develops and uses integrative and population genomics approaches to study the gene regulatory properties of the metazoan genome. He is currently also guest professor at Ghent University and cofounded the BioTech-IT company Genohm SA.

deplanckelabl..epfl.ch

Introduction

Results Obtained

Gene regulatory networks play a vital role in metazoan development and function, and deregulation of these networks is often implicated in disease. The interactions between genes and their respective regulatory transcription factors (TFs) that form the basis of gene regulatory networks have however been poorly characterized. Our main focus is to unravel the metazoan gene regulatory code and to examine the impact of genomic on molecular and organismal variation.

Our laboratory published two studies that provide novel insights into how genetic variation leads to molecular and organismal diversity. In Waszak et al. (Cell, 2015), we investigated why most variable transcription factor (TF) DNA binding events between humans are not driven by local variation in the motifs of the studied TFs. We found that many of these events are in fact controlled by the activity state of “variable chromatin modules” (VCMs) in which the variable TF-DNA interactions are embedded (Figure 1).

We have three major research pillars:

In Bou Sleiman et al. (Nat Comm, 2015), we investigated how genetic variation influences gut immunocompetence. To allow for an unbiased comparison between genotypes, we decided to study this question in Drosophila melanogaster for which important environmental factors such as diet can be controlled and standardized. Intriguingly, we found very important differences between distinct fly genotypes in the overall ability to survive an enteric infection in that some fly lines died rapidly, whereas others proved completely resistant (Figure 1). While physiological differences between resistant and susceptible lines were manifest, genetic and molecular factors were more difficult to find. This may indicate that the genetic architecture underlying gut immunocompetence variation is inherently complex. However, we did find evidence for small, but systematic expression differences of genes involved in ROS metabolism, suggesting that this process may at least be partially responsible for the observed phenotypic variation.

1. “Adipo” in which we study mesenchymal stem cell function and differentiation with a specific focus on understanding the regulatory mechanisms mediating white and brown fat cell differentiation. 2. “Geno” in which we study how regulatory genomic variation mediates phenotypic diversity. For this purpose, we focus on gut immunity and aging in Drosophila and obesity in humans. 3. “Techno” in which we pursue the development of new research tools or pipelines (e.g. single cell, targeted proteomics, microfluidics) that feed into the two other pillars.

Keywords Systems genetics, regulatory genomics, adipogenesis, microfluidics, HTsequencing, single cell, transcription factor.

Finally, in Isakova et al. ( JBC; 2016), we used a microfluidic protein-DNA interaction characterization platform to quantify cooperativity between TFs that form heterodimers. Through a nice collaboration with the Hatzimanikatis lab, we subsequently used mechanistic modelling to uncover that the nucleotide composition of the heterodimer binding site has an important impact on the extent of DNA binding cooperativity.

IBI - Institute of Bioengineering

Team Members Post Doctoral

Daniel Alpern Wanze Chen Vincent Gardeux Brian Hollis (Ambizione Fellow) Antonio Meireles Filho Petra Schwalie PhD Students

VCMs represent modules of molecular phenotypes that are highly coordinated over multiple kbp of DNA and that are orchestrated by cis-acting genetic variation. As such, they constitute functional entities of higher-order chromatin organization embedded within topologically associating domains (TADs), providing a molecular rationale as to how chromatin state changes and TF-DNA binding can be affected by distal genetic variation. That is, the molecular activity of individual molecular phenotypes is dependent on the overall activity status of the VCM in which they are embedded.

Roel Bevers Marjan Biocanin Johannes Bues Riccardo Dainese Michael Frochaux Maria Litovchenko Gerard Llimos Rachana Pradhan Magda Zachara Technicians

Julie Russeil Virginie Braman Administrative Assistant

Magali Masson

Selected Publications »» Deplancke, B., Alpern, D., and Gardeux, V. (2016). The genetics of transcription factor DNA binding variation. Cell 166:538-554. »» Isakova, A., Berset, Y., Hatzimanikatis, V. and Deplancke, B. (2016) Quantification of cooperativity in heterodimer-DNA binding improves the accuracy of binding specificity models. Journal of Biological Chemistry 291:10293-10306. »» Mezan, S., Feuz, J.D., Deplancke, B. and Kadener, S. (2016). PDF signaling Is an integral part of the Drosophila circadian molecular oscillator. Cell Reports 17: 708–719. »» Waszak, S.M., Delaneau, O., Gschwind, A.R., Kilpinen, H., Raghav, S.K., Witwicki, R. M., Orioli, A., Wiederkehr, M., Panousis, N.I., Yurovsky, A., et al. (2015) Population variation and genetic control of modular chromatin architecture in humans. Cell 162:1039-1050. »» Bou Sleiman, M.S., Osman, D., Massouras, A., Hoffmann, A.A., Lemaitre, B. and Deplancke, B. (2015) Genetic, molecular and physiological basis of variation in Drosophila gut immunocompetence. Nature Comm. 6:7829. »» Schertel, C., Albarca, M., Rockel-Bauer, C., Kelley, N.W., Bischof, J., Hens, K., van Nimwegen, E., Basler, K. and Deplancke, B. (2015). A large-scale, in vivo transcription factor screen defines bivalent chromatin as a key property of regulatory factors mediating Drosophila wing development. Genome Research 25:514-523. »» Simicevic, J., Moniatte, M., Hamelin, R., Ahrné, E. and Deplancke, B. (2015). A mammalian transcription factor-specific peptide repository for targeted proteomics. Proteomics 15: 752-756

Hubbell Lab Jeffrey A. Hubbell - Full Professor - Merck-Serono Chair in Drug Delivery

Introduction

Results Obtained

We design novel materials for applications in medicine such as regenerative medicine, vaccination and tolerogenic vaccination.

Regenerative medicine: We had previously observed that a broad collection of extracellular matrix proteins comprise high affinity binding sites for a broad collection of growth factors. We have utilized this knowledge to develop growth factor variants that display superaffinity for extracellular matrix proteins used in wound healing matrices, and we are presently both studying and developing therapeutics for diabetic wound healing in the non-obese diabetic mouse model of chronic wounds. We have further shown a connection between innate immune signaling in the extracellular matrix with adaptive immune responses.

Regenerative medicine: We study the interaction of protein growth factors, which induce tissue morphogenesis, with proteins of the extracellular matrix, seeking to understand the complex interplay between these two classes of signaling molecules in vivo. Based on this interaction, we design and develop novel biomaterial and growth factor designs, to present these molecules in vivo in a molecular context that resembles their natural biological function. Jeffrey Hubbell was trained as a chemical engineer from Kansas State University (B.S.) and Rice University (Ph.D.) in the United States. Previous to moving to Lausanne, he was on the faculty at the Swiss Federal Institute of Technology Zurich, at the California Institute of Technology, and at the University of Texas in Austin. He is author of more than 250 papers in peer-reviewed journals and inventor on more than 100 patents. He is a member of the National Academy of Engineering, USA. and the National Academy of Inventors, USA.

Vaccines and immunotherapeutics: With the laboratory of Prof. M.A. Swartz, we develop approaches to target vaccine antigen and adjuvant formulations to the lymph nodes that drain an injection site. We are particularly interested in situations where one must induce a CD8+ T cell response, for example generating cancer-fighting cytotoxic T lymphocytes for anti-cancer therapeutic vaccination. Tolerogenic vaccination: In addition to effector immune responses, we are also keenly interested in protein engineering approaches to tolerize versus cellular immunity, harnessing the tolerogenic antigen presentation that occurs with antigen from apoptotic cells yet using simple engineered antigen forms that are clinically tractable. We explore ways to deliver antigens to induce these aspects of peripheral tolerance.

Keywords Immunoengineering, tissue engineering, protein engineering, biomaterials.

lmrp.epfl.ch

Vaccines and immunotherapeutics: In collaboration with the laboratory of Prof. M.A. Swartz, we have developed a novel polymeric vaccine platform that targets dendritic cells that are resident in the lymph nodes. We have shown that this platform induces very diverse B cell responses for neutralization of viruses in addition to strong cellular immune responses capable of mounting anti-tumor immunity with vaccination against tumor-associated antigens. We continue to investigate these materials in both infectious disease and cancer contexts. Tolerogenic vaccination: We have shown that antigens can be engineered to mimic the nature of antigens on apoptotic debris, which are naturally collected and processed tolerogenically in the liver. We have accomplished this targeting by binding antigens to cells that age on a predictable timescale, such as red blood cells; and we have in a second approach mimicked the glycome of aged cells using glyco-functional polymers. We have shown tolerance in mouse models of type 1 diabetes. This technology is being developed by two companies located in Cambridge, Massachusetts, USA, in various contexts for prevention and treatment of autoimmunity, including Celiac disease and type 1 diabetes.

IBI - Institute of Bioengineering

Team Members Post Doctoral

Gai Shuning Hirosue Sachiko Ishihara Jun Phelps Edward Allen Wilson David Scott PhD Students

Briquez Priscilla Suhasna Maithili Brünggel Kym Cianciaruso Chiara Damo Martina Grimm Alizée Vardar Elif Technicians

Diaceri Giacomo Gaudry Jean Philippe Quaglia-Thermes Xavier Fredy René Administrative Assistant

Bonzon Carol Margot Ingrid

Adjunct Professor Development of anti-drug antibodies to the protein drug asparaginase, used to treat acute lymphocytic leukemia. Red is response to wild-type drug, and blue is the non-response to an engineered form of the drug, designed to be tolerogenic.

Frey Peter

Selected Publications »» »» »» »» »» »» »»

Julier Z., de Titta, A., Grimm, A.J., Simeoni, E., Swartz, M.A. and Hubbell, J.A. (2016) Fibronectin EDA and CpG synergize to enhance antigen-specific Th1 and cytotoxic responses. Vaccine 34:2453-9 Damo, M., Wilson, D.S., Simeoni, E. and Hubbell, J.A. (2016) TLR-3 stimulation improves anti-tumor immunity elicited by dendritic cell exosome-based vaccines in a murine model of melanoma. Sci Rep 5:17622. Lorentz, K.M., Kontos, S., Diaceri, G., Henry, H. and Hubbell, J.A. (2015) Engineered binding to erythrocytes induces immunological tolerance to E. coli asparaginase. Sci Adv 1:e1500112. Grimm, A.J.J., Kontos, S., Diaceri, G., Quaglia-Thermes, X. and Hubbell, J.A. (2015) Memory of tolerance and induction of regulatory T cells by erythrocyte-targeted antigens. Sci Rep 5:15907. Ballester, M. et al. (2015) Nanoparticle conjugation enhances the immunomodulatory effects of intranasally delivered CpG in house dust mite-allergic mice. Sci Rep 5:14274. Damo, M., Wilson, D.S., Simeoni, E. and Hubbell, J.A. (2015) TLR-3 stimulation improves anti-tumor immunity elicited by dendritic cell exosome-based vaccines in a murine model of melanoma. Sci Rep 5:17622. Julier, Z., Martino, M.M., de Titta, A., Jeanbart, L. and Hubbell, J.A. (2015) The TLR4 agonist fibronectin extra domain A is cryptic, exposed by elastase-2; use in a fibrin matrix cancer vaccine. Sci Rep 5:8569.

Jensen Lab Jeffrey D. Jensen - Assistant Professor

jensenlab.epfl.ch

Introduction

Results Obtained

We use a variety of approaches from population genetics in order to study evolutionary forces. This can be summarized by the following three focal points:

In 2015 we largely focused on the development of statistical methodology applicable to time-sampled polymorphism data, with a particularly focus on the evolution of viral populations (influenza virus, and human cytomegalovirus). The aim of these studies was both to characterize the demographic history of host infection, as well as to quantify the evolution of drug resistance.

Statistical & Computational Methodology: A major focus of the group is using population genetic theory to describe patterns of polymorphism associated with beneficial fixations, and the associated development of statistical approaches to identify these patterns in population genomic data.

Jeff Jensen is a population geneticist, broadly interested in the study of adaptation in natural populations. He received a BS / BA from the University of Arizona in 2002 in Ecology & Evolutionary Biology and Biological Anthropology, respectively. Jeff earned his PhD in Molecular Biology & Genetics at Cornell University in 2006, and did his postdoc work as an NSF Biological Informatics Fellow at UCSD and UC Berkeley. He founded the Jensen Lab at the University of Massachusetts Medical School in the Program for Bioinformatics & Integrative Biology in 2009, and re-located the lab to EPFL in the Fall of 2011. In 2016, he joined the Arizona State University as Full Professor.

Studying Adaptation in Natural Populations: Utilizing our developed methodology, we study the evolutionary processes involved when a population colonizes a novel habitat.

In 2016 we had a major focus on studying the effects of linked selection in dictating genomic variation, and in utilizing experimentally evolved populations in order to quantify the distribution of fitness effects and the role of epistasis in shaping the underlying fitness landscape.

Studying Adaptation in Experimental Populations: As an alternative approach, we also utilize experimentally evolved populations in order to gain insight in to the distribution of fitness effects and the underlying fitness landscapes characterizing populations.

Keywords Genetics, Evolution

IBI - Institute of Bioengineering

Team Members Post Doctoral

Stefan Laurent Sebastian Matuszewski Susanne Pfeifer Severine Vuilleumier PhD Students

Mado Kapopoulou Louise Ormond Hyunjin Shim Technicians

Kristen Irwin Administrative Assistant

Geneviève Rossier

From Bank, Matuszewski, et al. (PNAS, 2016): the empirical fitness landscape, by mutational distance to the parental type (X-axis). Each line represents a mutational substitution in the HSP90 gene of yeast. On the Y-axis is growth rate, a proxy for fitness. Yellow lines represent the paths to the optimal fitness peak. Green lines represent the fitness trajectories when combining individually beneficial mutations. Purple lines represent fitness trajectories when combining individually deleterious mutations. Thus, this demonstrates a global pattern of negative epistasis, except for strong positively epistatic interactions leading to the fitness peak.

Selected Publications »» Renzette, N., T.F. Kowalik, and J.D. Jensen, 2016. The relative roles of background selection and genetic hitchhiking in shaping human cytomegalovirus diversity. Molecular Ecology 25(1): 403-13. »» Ewing, G. and J.D. Jensen, 2016. The consequences of not accounting for background selection in demographic inference. Molecular Ecology 25(1): 135-141. »» Bank, C., N. Renzette, P. Liu, S. Matuszewski, H. Shim, M. Foll, D.N. Bolon, T.F. Kowalik, R.W. Finberg, J.P. Wang, and J.D. Jensen, 2016. An experimental evaluation of drug-induced mutational meltdown as an antiviral treatment strategy. Evolution 70: 2470-84. »» Pfeifer, S.P., and J.D. Jensen, 2016. The impact of linked selection in chimpanzees: a comparative study. Genome Biology & Evolution 8: 3202-8. »» Bank, C. *, S. Matuszewski*, R.T. Hietpas, and J.D. Jensen, 2016. On the (un)predictability of a large intragenic fitness landscape. PNAS 113(49): 14085-90. »» Foll, M., Poh, Y.P., Renzette, N., Ferrer, A., Shim, H., Malaspinas, A., Ewing, G., Bank, C., Liu, P., Wegmann, D., Caffrey, D., Zeldovich, K., Bolon, D., Wang, J., Kowalik, T., Schiffer, C., Finberg, R., and Jensen, J.D. (2014). Influenza virus drug resistance: a time-sample population genetics perspective. PLoS Genetics 10: e1004185. »» Bank, C., Hietpas, R., Wong, A., Bolon, D., and Jensen, J.D. (2014). A Bayesian MCMC approach to assess the complete distribution of fitness effects of new mutations: uncovering the potential for adaptive walks in challenging environments. Genetics 196: 841-52. »» Jensen, J.D. (2014) On the unfounded enthusiasm for soft selective sweeps. Nature Communications 5: 5281. »» Montano, V., Didelot, X., Foll, M., Linz, B., Moodley, Y., and Jensen, J.D. (2015). Worldwide population structure, long-term demography, and local adaptation of Helicobacter pylori. Genetics 200: 947-63. »» Renzette, N., Pfeifer, S., Matuszewski, S., Kowalik, T., and Jensen, J.D. (2017). On the analysis of intra-host and inter-host viral populations: human cytomegalovirus as a case study of pitfalls and expectations. Journal of Virology 91(5): e01976-16.

Lutolf Lab Matthias Lutolf - Associate Professor - Director of the Institute of Bioengineering - IBI

Matthias Lutolf was trained as a Materials Scientist at ETH Zurich where he also carried out his Ph.D. studies (awarded with the ETH medal in 2004). Lutolf carried out postdoctoral studies at the Baxter Laboratory in Stem Cell Biology at the Stanford University. He started up his independent research group at EPFL in 2007 with a European Young Investigator (EURYI) award. Lutolf serves as an editorial board member of four international journals and he is founder of the biotech company QGel SA.

lscb.epfl.ch

Introduction

Results Obtained

By interfacing advanced biomaterials engineering, microtechnology and stem cell biology, the overarching goal in the Lutolf Laboratory is to uncover mechanisms of stem cell fate regulation; knowledge that will contribute to better ways to grow stem cells in culture and use them for various applications. The major current focus of the lab is on coaxing stem cells in vitro in 3D into miniature, organ-mimicking constructs, termed ‘organoids’, by exposing them to instructive, spatiotemporally patterned signaling microenvironments. The lab’s ambition is to achieve organoid development in a more robust and ultimately predictable manner. Beyond contributing to a better understanding of stem cell-based self-organization, this research should open up exciting prospects for drug discovery and regenerative medicine.

Over the past decade, stem cell-derived organoids have stepped into the limelight as promising models of development and disease, drug screening platforms and sources of transplantable tissue, owing to the previously unmatched fidelity with which they approximate real organs. These structures have been developed from adult, embryonic or induced pluripotent stem cells, and a wide range of organs have received organoid counterparts. One common problem for virtually all organoid models remains the pervasive use of animalderived matrices such as Matrigel – a basement membrane-like gel secreted by the Engelbreth-Holm-Swarm mouse sarcoma cells – as the three-dimensional (3D) matrix necessary to grow them. To address this issue, we have been developing well-defined alternatives to Matrigel, customized for the culture of various stem cell-based organoids. For example, we have discovered chemically defined matrices for the culture of intestinal stem cells (ISCs) and intestinal organoids (Gjorevski et al., Nature, 2016). These matrices comprise a poly(ethylene glycol) (PEG) hydrogel backbone and are functionalized with specific ECM ligands required for organoid formation. As such, the hydrogels present a defined and reproducible, but also tunable environment, allowing us to manipulate physical and chemical parameters, and examine their influence on ISC fate and organoid formation.

Keywords Stem cells, self-renewal, differentiation, niche, self-organization, stem cellbased organogenesis, single cell analysis, hydrogel, microfluidics.

IBI - Institute of Bioengineering

Team Members Post Doctoral

Sara Geraldo Nikolce Gjorevski Andrea Manfrin Giuliana Rossi Nathalie Brandenberg PhD Students

Delphine Blondel Yannick Devaud Sonja Giger Mehmet Girgin Laura Kolb Gennady Nikitin JiSoo Park Francois Rivest Yoji Tabata Vincent Trachsel Staff members

Thibaud Cherbuin Evangelos Panopoulos Master Students

Luis Ayala Intestinal stem cell colonies and organoids formed in PEG-based hydrogels. a) Bright-field image of day 4 ISC colonies in PEG RGD. b) Immunofluorescent image of day 4 ISC colonies in PEG RGD, showing expressing of Lgr5-EGFP. c) Bright-field image of organoids formed in PEG RGD LAM matrices. d) Immunofluorescent image of an organoid formed in PEG RGD LAM, showing mucin-2-expressing goblet cells. Scale bar, 50 μm.

Administrative Assistant

Maria João Fernandes Coelho

Selected Publications »» »» »» »» »» »» »»

Gjorevski, N., Sachs, N., Manfrin, A., Giger, S., Bragina, M.E., Ordóñez-Morán, P., Clevers, H. and Lutolf, M.P.* (2016) Designer matrices for intestinal stem cell and organoid culture. Nature 539: 560-564. Vannini, N., Girotra, M., Naveiras, O., Nikitin, G., Campos, V. and Lutolf, M.P.* (2016) Specification of haematopoietic stem cell fate via modulation of mitochondrial activity. Nature Comm. 7: 13125. Caiazzo, M., Okawa, Y., Ranga, A., Piersigilli, A., Tabata, Y. and Lutolf, M.P.* (2016) Defined three-dimensional microenvironments boost induction of pluripotency. Nature Materials 15: 344–352. Brandenberg, N.and Lutolf, M.P.* (2016) In situ patterning of microfluidic networks in 3D cell-laden hydrogels. Advanced Materials 28(34): 7450. Ranga, A., Girgin, M., Meinhardt, A., Eberle, D., Caiazzo, M., Tanaka, E.M. and Lutolf, M.P.* (2016) Neural tube morphogenesis in synthetic 3D microenvironments. Proc. Natl. Acad. Sci. 113 (44): E6831–E6839. Allazetta, S., Kolb, L., Zerbib, S., Bardy, J. and Lutolf, M.P.* (2015) Cell‐instructive microgels with tailor‐made physicochemical properties. Small 11 (42): 5647-5656. Roch, A., Trachsel, V. and Lutolf, M.P.* (2015) Single‐cell analysis reveals cell division‐independent emergence of megakaryocytes from phenotypic hematopoietic stem cells. Stem Cells 33 (10): 3152-3157

Naef Lab Felix Naef - Associate Professor

naef-lab.epfl.ch

Introduction

Felix Naef studied theoretical physics at the ETHZ and obtained his PhD from the EPFL in 2000. He then received postdoctoral training at the Center for Studies in Physics and Biology at the Rockefeller University (NYC) under the guidance of Prof. Magnasco. His research at the interface of physics and biology focuses on the gene regulation, transcription, circadian rhythms and single cell analysis. He joined EPFL in 2006 where he is currently Associate Professor in the Institute of Bioengineering (IBI).

Our lab likes to work on interdisciplinary projects related to circadian rhythms, developmental patterning, gene expression networks, and stochastic transcription in single cells. To study these systems we combine theoretical, computational and experimental approaches. Diurnal oscillations of gene expression controlled by the circadian clock underlie rhythmic physiology across most living organisms. In this context our lab is highly interested in combining functional genomics (RNA-seq, ChIP-seq, DNaseI-seq, mass spectrometry), bioinformatics and mathematical modeling to understand how the circadian clock impinges on many of the regulatory layers underlying rhythmic gene expression. The ultimate goal is to better understand daily rhythms in physiology, notably in the mouse liver, but also in other tissues. We are also very keen on using microscopy to monitor cellular rhythms in individual mammalian cells. Notably, we have been intrigued by the interactions of the circadian and cell cycles, since previously work has argued that the clock might control cell division timing. Better understanding of how the two systems mutually interact is currently of great interest, notably with regards to the role of circadian clocks in proliferating tissues, such as the epidermis, immune or stem cells. Another main focus is our group is on transcriptional kinetics in single mammalian cells. Mammalian genes are often transcribed discontinuously as short bursts of RNA synthesis followed by longer silent periods. However, how these “on” and “off ” transitions, together with the burst sizes, are controlled in single cells is still poorly characterized. To address this problem, we combine single-cell time-lapse luminescence imaging with stochastic modeling of the time traces.

Results Obtained

“Circadian and feeding rhythms differentially affect rhythmic mRNA transcription and translation in mouse liver.”, Atger et al. PNAS 2015. This work continues our longstanding collaboration with the Gachon lab at the NIHS (Nestle Institute of Health Sciences) and our interest in monitoring temporal gene expression in the liver. Our aim there is to understand which steps are regulated by the circadian clock and feeding/fasting rhythms, in particular translation (using ribosome footprinting). We found that translation efficiency was differentially regulated during the diurnal cycle for genes with 5’-TOP sequencesand for genes involved in mitochondrial activity, many harboring a 5’TISU motif. Together this study emphasizes the complex interconnections

between circadian and feeding rhythms at regulating translation. “Structure of silent transcription intervals and noise characteristics of mammalian genes”, Zoller et al. MSB 2015. We had shown earlier that transcription in individual mammalian cells occurs stochastically in short bursts interspersed by silent intervals showing a refractory period. Here, we used single allele time-lapse recordings in mouse cells to identify minimal models of promoter cycles, which inform on the number and durations of rate-limiting steps responsible for refractory periods. The structure of promoter cycles was found to be gene specific and independent of genomic location. Typically, five rate-limiting steps underlie the silent periods of endogenous promoters. Strikingly, promoters with TATA boxes showed simplified two-state promoter cycles. These findings have implications for basic transcription biology and shed light on interpreting single-cell RNA-counting experiments. “Temperature regulates splicing efficiency of the cold-inducible RNA-binding protein gene Cirbp.” Gotic et al. Genes Dev. 2016. In mammals, body temperature fluctuates diurnally around a mean value of 36°C-37°C. Despite the small differences between minimal and maximal values, body temperature rhythms can drive robust cycles in gene expression in cultured cells and, likely, animals. In collaboration with the Schibler lab, we studied the mechanisms responsible for the temperature-dependent expression of cold-inducible RNA-binding protein (CIRBP). In NIH3T3 fibroblasts exposed to simulated mouse body temperature cycles, Cirbp mRNA oscillated about threefold in abundance, as it does in mouse livers. This daily mRNA accumulation cycle is directly controlled by temperature oscillations and does not depend on the cells’ circadian clocks. Using many complementary techniques including total RNA-seq, we showed that the temperature-dependent accumulation of Cirbp mRNA is controlled primarily by the regulation of splicing efficiency, defined as the fraction of Cirbp premRNA processed into mature mRNA. As revealed by genome-wide “approach to steady-state” kinetics, this post-transcriptional mechanism is widespread in the temperature-dependent control of gene expression.

Keywords Gene regulation, circadian rhythms, chronobiology, single cell analysis, transcriptional bursting, computational biology.

IBI - Institute of Bioengineering

Team Members Post Doctoral

Jonathan Bieler Kyle Gustafson Daniel Mauvoisin Saeed Omidi Eric Paquet Nicholas Philipps Jingkui Wang Benjamin Zoller PhD Students

The promoter cycle as a generic stochastic gene expression model. A) The model describes gene activation, transcription, translation, and degradation of mRNA and proteins. The promoter follows an irreversible cycle of one transcriptionally active state and multiple (N) sequential inactive states. B) Simulation of protein numbers, mRNA numbers, and gene activity with N = 1 inactive state. C) With N = 6 states. Modified from Zoller et al., MSB 2015.

Rosamaria Cannavo Colas Droin Cedric Gobet Clémence Hurni Jérôme Mermet Damien Nicolas Jonathan Sobel Onur Tidin Ambroise Vuaridel Jake Yeung Internship students

Jonathan Baeriswyl Hilal Güler Gianrocco Lazzari Cécile Le Sueur François Mouvet Alexis Murciano Cécile Piot

Administrative Assistant

Selected Publications

Sophie Barret

»» Atger, F., Gobet, C., Marquis, J., Martin, E., Wang, J., Weger, B., Lefebvre, G., Descombes, P., *Naef, F. and *Gachon, F. (2015) Circadian and feeding rhythms differentially affect rhythmic mRNA transcription and translation in mouse liver. Proc Natl Acad Sci USA 112(47): E6579-88. *co-corresponding »» Zoller, B., Nicolas, D., Molina, N. and Naef, F. (2015) Structure of silent transcription intervals and noise characteristics of mammalian genes. Mol Syst Biol 11(7): 823. »» Blanchoud, S., Nicolas, D., Zoller, B., Tidin, O. and Naef, F. (2015) CAST: An automated segmentation and tracking tool for the analysis of transcriptional kinetics from single-cell time-lapse recordings. Methods 85: 3-11. »» Blanchoud, S., Busso, C., Naef, F. and Gönczy, P. (2015) Quantitative analysis and modeling probe polarity establishment in C. elegans embryos. Biophys J 108(4): 799-809. »» Gotic, I., Omidi, S., Fleury-Olela, F., Molina, N., Naef, F. and Schibler U. (2016) Temperature regulates splicing efficiency of the cold-inducible RNA-binding protein gene Cirbp. Genes Dev. 30(17): 2005-2017. »» Bischofberger, M., Iacovache, I., Boss, D., Naef, F., van der Goot, F.G. and Molina, N. (2016) Revealing assembly of a pore-forming complex using single-cell kinetic analysis and modeling. Biophys J 110(7): 15741581.

Naveiras Lab Olaia Naveiras - SNSF Professor, IBI (50%) - Haematology Service, CHUV (50%)

Olaia Naveiras obtained a Medical Degree from Universidad AutĂłnoma de Madrid (Spain), studied Immunology at the Pasteur Institute (Paris, France) and pursued her PhD in Experimental Haematology with George Q. Daley in Harvard Medical School (Boston, USA). She moved to Switzerland to gain medical training in Internal Medicine and Haematology, while being a parttime postdoctoral fellow with Prof. Matthias Lutolf at EPFL. In 2014, she founded the Laboratory of Regenerative Haematopoiesis. She shares her research time at EPFL with clinical responsibilities at the local CHUV Haematology Service.

Introduction

Results Obtained

The Laboratory of Regenerative Hematopoiesis is interested in understanding the regulation of the reversible transition between mammalian yellow (adipocytic) and red bone marrow (hematopoietic). This naturally occurring process reflects the plasticity of tissue-specfic, bone-marrow derived mesodermal and skeletal stem cells (BM-MSCs and SSCs) to support hematopoietic progenitors at different degrees. We have demonstrated that the yellow-tored transition can enhance hematopietic progenitor proliferation, and that the red-to-yellow transition enhances hematopoietic stem cell (HSC) quiescence. Currently, all clinical approaches to increase HSC engraftment and to enhance haematopoiesis target the HSC itself. Contrarily, we focus on studying how manipulations of the HSC niche can enhance haematopoiesis. We hypothesize that pharmacologic manipulation of the BM-MSC to adipocyte axis can be modulated to decrease the toxicity of hematopoietic stem cell (HSC) transplantation or intensive ablative chemotherapy, and, possibly, to slow the progression of myelodysplasia or even aplastic anaemia into overt leukaemia. Specifically, we are developing several strategies to induce metabolic changes in the HSC niche and to regulate the function of MSCs, the main precursor to stromal supportive cells within the hematopoietic marrow.

Our laboratory was established in 2014. Since then, we have optimized complex models of hematopoietic stem cell (HSC) transplantation including single HSC transplants and NSG human-into-mouse xenotransplantation. We have established a high-throughput screening platform for mesenchymal stem cell differentiation based on digital holographic microscopy (DHM), adapted for the study of bone marrow adipogenesis, and have developed a quantitative method (MarrowQuant) to assess the red-to-yellow and yellow-to-red bone marrow transition in histological samples upon bone marrow transplantation. Thanks to these methods, we have identified novel natural compounds and FDA-approved inhibitors of adipogenesis that we are in the process of validating for their potential use in HSC transplantation. Additionally, we are developing systems for HSC/MSC organoid co-culture in custom designed, 3D-printed bench top bioreactors.

The relevance of this research relies on the early mortality associated to ablative chemotherapy regimes, and HSC transplantation in particular, due to the severe infectious complications that happen during the 2-6 weeks when patients have no circulating white blood cells. Reducing the toxicity of the preparative regimen and accelerating the time to engraftment is critical to improving the safety of HSC transplantation and making this most successful stem cell therapy available to a wider subset of patients.

Keywords Hematopoietic stem cell (HSC), Bone marrow transplantation, Preadipocyte, Adipocyte, Brown fat, Beige/Brittle adipocytes, Mesenchymal Stem Cell (MSC), HSC niche, Regenerative Hematopoiesis.

naveiras-lab.epfl.ch

Aside from method-development, we have demonstrated together with the Laboratory of Stem Cell Bioengineering the capacity of specific mitochondrial modulators within the NAD pathway to accelerate the yellow-to-red bone marrow transition upon HSC transplant, opening the possibility of translating these findings to reduce the mortality associated to HSC transplant in patients suffering from leukemia, lymphoma or autoimmune attack to the hematopoietic system. Interestingly, we have found that NAD boosting causes increased autophagy and increased mitochondrial recycling specifically within the most-primitive hematopoietic stem cell compartment, which in turn increases the potency of HSCs. Our current focus is on characterizing the stromal components of the bone marrow within the mesenchymal stem cell (MSC) to adipocyte differentiation axis in relation to the expanding hematopoietic compartment. For this purpose, we study homeostatic marrow adipose tissue in the distal bones (also called constitutive marrow adipose tissue or cMAT) and both in homeostasis A special emphasis will be placed on developing in vivo screening tissue-based bioassays for the creation of microenvironments capable of mediating hematopoietic progenitor expansion.

IBI - Institute of Bioengineering

Team Members Ludwig Project Leader

Nicola Vannini

Post Doctoral Fellow

Shanti Rojas-Sutterlin PhD Students

Vasco Campos Josefine Tratwal Medical Students

Frédérica Schyrr

Master Students

Bone marrow adipogenesis as measured in the laboratory by: Top left: Oil Red O stain of primary mesenchymal stem cells (MSCs) before and after in in vitro differentiation into adipocytes with Dexamethasone, IBMX and insulin. Center: “marroid” spheroids formed by 5 day 3D co-culture of DsRed hematopoietic stem cells (HSCs) and MSCs; green: lipid droplet accumulation as measured by Bodipy-FL. Bottom left: Bioreactor designed for the ex-vivo expansion of HSC/ MSC co-cultures. Right: Quantification of bone marrow adipocytes in the distal tibia by tetraosmium stain coupled to micro computerassisted tomography (mCT). The grey zone represents the lipid-containing volume, as stained by Os4O, and the blue area represents the calcified bone overlay.

Aurélien Oggier Tereza Koliqi

Research Assistant

Yannick Yersin

Administrative Assistant

Laura Bischoff

Selected Publications »» Vannini, N. *, Girotra, M.*, Naveiras, O., Nikitin, G, Campos, V., Giger, S., Roch, A., Auwerx, J. and Lutolf , M.P. (2016) Metabolic specification of hematopoietic stem cell fate. Nature Communications 7:13125. »» Diaz, M.F., Li, N., Lee, H.J., Adamo, L., Evans, S.M., Willey, H.E., Arora, N., Torisawa, Y.S., Vickers, D.A., Morris, S.A., Naveiras, O., Murthy, S.K., Ingber, D.E., Daley, G.Q., García-Cardeña, G. and Wenzel, P.L. (2015) Biomechanical forces promote blood development through prostaglandin E2 and the cAMP-PKA signaling axis. J. Exp. Med. 212: 665–680. »» McKinney-Freeman, S., Cahan, P., Li, H., Lacadie, S.A., Huang, H.T., Curran, M., Loewer, S., Naveiras, O., Kathrein, K.L., Konantz, M., Langdon, E.M., Lengerke, C., Zon, L.I., Collins, J.J. and Daley, G.Q. (2012) The transcriptional landscape of hematopoietic stem cell ontogeny. Cell Stem Cell 11: 701–714. »» Vannini, N., Roch, A., Naveiras, O., Griffa, A., Kobel, S. and Lutolf, M.P. (2012) Identification of in vitro HSC fate regulators by differential lipid raft clustering. Cell Cycle 11(8):1535-1543. »» Naveiras, O., Nardi, V., Wenzel, P.L., Hauschka, P., Fahey, F. and Daley, G.Q. (2009) Bone marrow adipocytes as negative regulators of the hematopoietic microenvironment. Nature 460: 259-263. »» Adamo, L.*, Naveiras, O.*, Wenzel, P.L., McKinney-Freeman, S., Mack, P.J., Gracia-Sancho, J., Suchy-Dicey, A., Yoshimoto, M., Lensch, M.W., Yoder, M.C., García-Cardeña, G. and Daley, G.Q. (2009) Biomechanical forces promote embryonic haematopoiesis. Nature 459(7250): 1131-1135.

Schoonjans Lab Kristina Schoonjans - Associate Professor

Kristina Schoonjans obtained her Ph.D in Molecular Biology and Pharmacology from the University of Lille, France in 1995. After her postdoctoral training at the Pasteur Institute in Lille in 1999, she moved to the IGBMC in Strasbourg and was appointed Research Director with INSERM in 2007. In 2008, Kristina Schoonjans joined the EPFL, where she is currently pursuing her research on bile acid and metabolite signaling to identify novel mechanisms and strategies to target metabolic disorders.

schoonjans-lab.epfl.ch

Introduction

Results Obtained

The mission of our laboratory is to identify the mechanisms by which nutrientderived metabolites in general and bile acids in particular coordinate metabolism, immune function and cancer. A major part of our research involves the study of a subset of nuclear receptors that are directly or indirectly affecting metabolite and bile acid signaling, including LRH-1 (NR5A2), SHP (NROB2) and FXR (NR1H4). The other main research axis focuses on the non-genomic effects of bile acids by investigating the role of the bile acid-responsive GPCR, TGR5. We are using state-of-the-art approaches in biochemistry, metabolomics, molecular and cellular biology, pharmacology and mouse genetics to investigate these different research topics. An integrative approach combining functional studies and metabolic phenotyping in genetically engineered mouse models together with in-depth molecular profiling in cellular models is used to reconstruct the networks that are modified by metabolite signaling. By investigating the molecular basis by which metabolites signal to convey adaptive responses in metabolic organs, our laboratory aims to identify novel mechanisms and strategies to prevent and treat metabolic disorders.

In the past we established the metabolic role of several enterohepatic nuclear receptors and causally linked their functions to metabolic control, immune regulation and cancer. In the case of the entero-hepatic nuclear receptor, LRH-1, we identified SUMOylation as a prime mode of LRH-1 regulation. We discovered that SUMOylation of LRH-1 promotes its interaction with the co-repressor, PROX1, and selectively inhibits gene programs linked to reverse cholesterol transport. By generating an LRH-1 K289R knockin mouse model, we showed that SUMOylation-defective LRH-1 mice display enhanced cholesterol and bile acid fluxes in the liver and are protected against atherosclerosis, highlighting the physiological and pathophysiological importance of this posttranslational modification of LRH-1. More recently, we discovered that disruption of LRH-1 function in the liver protects mice against the development of hepatocellular carcinoma. We showed that this protection is caused by the loss of coordination of a non-canonical glutamine pathway that is known to fuel anabolic metabolism in distinct types of cancer. The robust reduction in glutaminolysis and the limiting availability of Îą-ketoglutarate furthermore inhibits mTORC1 signaling to eventually block cell growth and proliferation. These studies emphasize the importance of LRH-1 in coordinating glutamine-induced metabolism and signaling to promote hepatocellular carcinogenesis. Within the research angle of TGR5-mediated bile acid signaling, we have highlighted the role of macrophage TGR5 in the context of inflammationdriven metabolic disorders, such as atherosclerosis. In a follow-up study, we provided evidence that the anti-inflammatory response of TGR5 also directly contributes to the insulin sensitizing effects of bile acids. More specifically, we showed that TGR5 activation reduces chemokine expression in macrophages via mTOR-dependent stimulation of translation of the dominant-negative C/ EBPď ˘-LIP isoform, thereby ameliorating obesity-induced insulin resistance. More recently, we showed that TGR5 plays a substantial, but indirect role, in adipose tissue browning induced by intestinal-restricted FXR agonists. Further studies analyzing the role of this GPCR in browning, central control of energy metabolism, and bone homeostasis are ongoing.

Keywords Bile acids, TGR5, nutrient sensing, intermediary metabolism, metabolic syndrome.

IBI - Institute of Bioengineering

Team Members Post Doctoral Associates

Hadrien Demagny Alessia Perino Ning Shen (until March 2015) Matthias Stein (until 31.12.2015) Laura Velazquez Villegas PhD Students

Qingyao Huang Charlotte Kern Vera Lemos Maria Luna Perciato Pan Xu (until 30.10.2016) Project Students

Sara Ancel Herehau Blais Veronica Pagano Lorenzo Petrini Paul Philipp Lab Technicians

Hepatoma cell line AML-12 as an in vitro model to study metabolite signaling.

Thibaud Clerc Andreane Fouassier Soline Odouard (until 31.12.2015) Roxanne Pasquettaz Administrative Assistant

Soledad Andany

Selected Publications »» Stein, S. and Schoonjans, K. (2015).Molecular basis for the regulation of the nuclear receptor LRH-1. Curr. Opin. Cell Biol. 33:26-34. »» Fang, S., Suh, J.M., Reily, S.M., Yu, E., Osborne, O., Lackey, D., Yoshihara, E., Perino, A., Jacinto, S., Lukasheva, Y., Atkins, A.R., Khvat, A., Schnabl, B., Yu, R.T., Brenner, D.A., Coulter, S., Liddle, C., Schoonjans, K., Olefsky, J.M., Saltiel, A.R., Downes, M. and Evans, R.M. (2015) Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat. Med. 21:159-165. »» Lefèvre, L., Authier, H., Stein, S., Majorel, C., Couderc, B., Dardenne, C., Eddine, M.A., Meunier, E., Bernard, J., Valentin, A., Pipy*, B., Schoonjans*, K. and Coste*, A. (2015) LRH-1 mediates anti-inflammatory and antifungal phenotype of IL-13 activated macrophages through PPAR ligand synthesis. Nat. Commun. 6:6801. »» Perino, A. and Schoonjans, K. (2015) TGR5 and immunometabolism: insights form physiology and pharmacology. Trends Pharmacol Sci. 36:847-857. »» Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., D’Amico, D., Ropelle, E.R., Lutolf, M.P., Aebersold, R., Schoonjans, K., Menzies, K.J. and Auwerx, J. (2016) NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352:1436-1443. »» Xu, P., Oosterveer, M.H., Stein, S., Demagny, H., Ryu, D., Moullan, N., Wang, X., Can, E., Zambon,i N., Comment, A., Auwerx, J. and Schoonjans K. (2016) LRH-1-dependent programming of mitochondrial glutamine processing drives liver cancer. Genes Dev. 30:1255-1260.

Suter Lab David Suter - Tenure-track Assistant Professor and SNSF Professor - Sponsored Stem Cell Research Chair

David Suter studied medicine at the University of Geneva and obtained a MD/PhD in 2007, followed by a first postdoctoral training in Geneva with Ueli Schibler, before moving to the group of Sunney Xie at Harvard University. Since June 2013, he is a Swiss National Science Foundation Professor and Tenure Track assistant Professor at the Bioengineering Institute of the EPFL School of Life Sciences.

Introduction

Results Obtained

Embryonic stem (ES) cells are derived from the inner cell mass of the embryo at the blastocyst stage. They can be maintained in culture and instructed to differentiate towards virtually any cell type of the body, thereby providing a powerful tool to study developmental processes in vitro. In addition, they are a promising source for future cell therapy applications, which aim at replacing cells lost in pathological conditions such as Parkinsonâ&#x20AC;&#x2122;s disease, myocardial infarction, diabetes, and other major human diseases. We are interested in using ES cells to study the molecular basis of cell fate choices during early developmental events. To address this question, we are using new single-cell and single-molecule approaches to investigate the dynamics of gene expression during embryonic stem (ES) cell differentiation and their relationship to cell fate choices.

Mitotic bookmarking within the pluripotency network. We discovered that Sox2 and Oct4, two transcription factors essential in maintaining ES cell pluripotency remain bound to mitotic chromosomes. We thoroughly characterized their biophysical properties, showing that both display specific and non-specific binding to mitotic chromosomes. Most importantly, when Sox2 is absent at the end of mitosis, pluripotency maintenance and neuroectodermal induction are severely perturbed. These findings were recently published (Deluz et al. 2016). We also started screening 750 transcription factors for their binding to mitotic chromosomes. The screen is 65% complete, and we already discovered 50 new mitotic chromosome binding transcription factors.

We are particularly interested in the following questions: 1. How does gene expression fluctuate in ES cells, and to what extent do these fluctuations influence cell fate decisions ? 2. What are the gene regulatory networks active at different stages of differentiation ? 3. What is the role of mitotic bookmarking of transcription factors in the maintenance and differentiation of ES cells ? 4. What confers mitotic chromosome binding properties to transcription factors ?

Keywords Embryonic stem cells, Gene expression dynamics, Single cell analysis, Single molecule imaging, Cell fate choice, High throughput screening, Mitotic bookmarking.

suter-lab.epfl.ch

Protein synthesis/degradation balance during mitosis. In 2015, using a library of fluorescent timer-tagged ES cell lines, we discovered that about half of the proteome displays altered synthesis and degradation during mitosis. We confirmed these results by an alternative strategy allowing to monitor degradation rates in single unsynchronized cells. We are currently characterizing the extent of these changes for different proteins and exploring the underlying molecular mechanisms and quantifying the magnitude of these changes by computational analysis. Fluctuations of proteins in single living cells and correlation to cell fate decisions. We developed new tools that allow us to perform absolute quantification of Sox2 in living embryonic stem cells. We are now characterizing Sox2 fluctuations in pluripotency and differentiation, and correlating these fluctuations to neuroectodermal differentiation. Transmission of gene expression fluctuations to daughter cells. We discovered that active genes in ES cells exhibit a transcriptional memory of 1 to 6 cell cycles; we are now characterizing how this memory relates to the variance in expression levels of each gene.

IBI - Institute of Bioengineering

Team Members PhD Students

Andrea Alber Elias Friman Aleksandra Mandic Mahé Raccaud Daniel Strebinger Onur Tidin Technicians

Cédric Deluz Administrative Assistant

Laura Bischoff

Fluorescent time-lapse imaging of YPet-Sox2 during cell division in NIH-3T3, highlighting its colocalization with mitotic chromosomes.

Selected Publications »» Deluz, C.*, Friman, E.T.*, Strebinger, D.*, Benke, A., Raccaud, M., Callegari, A., Leleu, M., Manley, S. and Suter, D.M.† (2016) A role for mitotic bookmarking of SOX2 in pluripotency and differentiation. Genes & Development 30(22):2538-2550. *Equal contribution; †Corresponding author

BIOS Lab Hatice Altug - Associate Professor

Dr. Altug received her Ph.D. in Applied Physics from Stanford University in 2006. In 2013, she joined EPFL as an associate professor of Biomedical Engineering with tenure. In 2007-2013 she has been assistant/associate professor of Boston University Electrical Engineering and Biomedical Engineering departments.

bios.epfl.ch

Introduction

Results Obtained

In BIOS we are inspired by the challenges to have new biosensors that can allow study of biological phenomena to enhance our fundamental understanding of living entities and also point-of-care diagnostic tools for emerging personalized and global healthcare applications. Towards these goals, we work on interdisciplinary projects employing physics and engineering toolboxes, such as nanophotonics, metamaterials, nanofabrication, micro/nanofluidics, together with biology and chemistry. Our cutting edge nanophotonic devices enable ultra-sensitive spectroscopy and biosensing technologies for real-time, label-free and high-throughput detection. In parallel, we investigate novel nanophotonic effects and newly discovered low dimensional materials such as graphene to introduce new biosensing schemes.

We exploit nanoscale photonics with plasmonics and engineered metasurfaces. Nanophotonics enables means to confine light below the fundamental diffraction limit and create extremely intense electromagnetic fields in volumes much smaller than the wavelength of light. These features which results in dramatically enhanced light-matter interaction are especially promising for biosensing, spectroscopy and lab-on-chip applications.

Keywords Optical Nano-Biosensors, Nanofabrication.

Lab-on-a-chip

Systems,

Microfluidics,

One of our research lines is mid-infrared nanophotonics where we combine unique capabilities of vibrational infrared (IR) spectroscopy with nanophotonics. IR absorption spectroscopy is a powerful technique enabling chemical identification of molecules through their vibrational fingerprints. Recently we showed an IR plasmonic biosensor for chemical-specific detection and monitoring of biomimetic lipid membranes in a label-free and real-time fashion. Lipid membranes constitute the primary biological interface mediating cell signaling and interaction with drugs and pathogens. By exploiting the plasmonic field enhancements, the proposed biosensor captures the vibrational fingerprints of lipid molecules and monitors in real time the formation kinetics of planar biomimetic membranes in aqueous environments. Most recently we showed that graphene could revolutionize biosensing due to its exceptional opto-electronic properties. Graphene plasmons can be tuned by electrostatic gating, in contrast to conventional plasmonic materials such as metals. By exploiting this unique feature we demonstrated a dynamically tunable plasmonic mid-IR biosensor that can extract complete optical properties of proteins over a broad spectrum. In addition, the extreme light confinement in graphene produces an unprecedentedly strong overlap with nanometric biomolecules, enabling superior sensitivity. The combination of tunable spectral selectivity and enhanced sensitivity of graphene opens exciting prospects for sensing, not only proteins but also a wide range of chemicals and thin films.

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Andreas Tittl Filiz Yesilköy Kosmas Tsakmakidis Maria Soler Aznar PhD Students

Alexander Belushkin Aleksandrs Leitis Aurélian John-Herpin Cenk I. Özdemir Dordaneh Etezadi Xiaokang Li Administrative Assistants

Rosana Blanchard

Figure (a) Mid-Infrared graphene nano-biosensor (b) Graphene nanoribbons are electrically biased for dynamic tuning. Mid-IR light is incident, and chemical specific Mid-IR signature of biomolecules on the device surface signal is collected in transmission. Resultant signal is enhanced by the sensor.

Selected Publications »» »» »» »»

Limaj, O., Etezadi, D., Wittenberg, N. J., Rodrigo, D., Yoo, D., Oh, S.-H. and Altug, H. (2016) Infrared plasmonic biosensor for real-time and label-free monitoring of lipid membranes. Nano Letters 16: 1502–1508. Rodrigo, D., Limaj, O., Janner, D., Etezadi, D., García-de-Abajo, F.J., Pruneri, V. and Altug, H. (2015) Mid-infrared plasmonic biosensing with graphene. Science 349: 165-168. Altug, H. et al. (2015). Nano-optics gets practical. Nature Nanotechnology 10: 11-15. Adato, R., Aksu, S. and Altug, H. (2015). Engineering mid-infrared nanoantennas for surface enhanced infrared absorption spectroscopy. Materials Today 18: 436-446.

Aminian Lab Kamiar Aminian - Adjunct Professor - School of Engineering (STI)

Introduction

Results Obtained

Our research focus on wearable and implanted technologies for characterizing physical behaviour and assessment of pathologies affecting motor function (osteoarthritis, frailty in aging, pain, stroke, neurologic disorder), devising assistive technologies for personalized rehabilitation purpose, and evaluating motor performances in sport and exercise.

Activity monitoring and gait analysis: An instrumented shoe was designed and validated for classifying daily activities. It shows the improvement of activity profile, movement complexity, gait and foot loading after rehabilitation of patients with hip fracture. The analyses of daily activity on elderly subjects revealed the decline of complexity of movement with aging, frailty, fall, risk and fear of fall. In the framework of Cohorte65+ we showed the significance of foot clearance as a predictor of fall in elderly subjects. Modelling activity behaviour using a wrist sensor revelled minimum duration of monitoring and showed different distribution of cadence in elderly subjects at different health status.

Five main topics are concerned:

Kamiar Aminian received his PhD degree in biomedical engineering in 1989 from EPFL. He is currently Professor of medical instrumentation and the director of the Laboratory of Movement Analysis and Measurement of EPFL. His research interests include methodologies for human movement monitoring and analysis in real world conditions mainly based on wearable technologies and inertial sensors with emphasis on gait, physical activity and sport. He is author or co-author of more than 500 scientific papers published in reviewed journals and presented at international conferences and holds 11 patents related to medical devices.

lmam.epfl.ch

1. Wearable activity monitoring: monitoring in human and animal using different configuration of body worn sensors and characterizing the physical behaviour using complexity analysis 2. Gait analysis and functional tests: instrumented functional tests for balance and locomotion in clinical environment 3. Sport biomechanics and performance: extraction of relevant features for improving sport technics, prevention of injury and safe training 4. Joints Biomechanics: modelling and robotic simulation of human joint to improve surgery procedure and implant design, modelling of soft tissue artefact for accurate measurement of kinematics 5. Assistive technology for rehabilitation: interactive exergames for prevention of accident, ICT based feedback for personalized intervention and rehabilitation program

Keywords Biomechanics, Sport, Rehabilitation, Wearable systems, Gait, Physical behaviour.

Sport biomechanics and performance: In alpine skiing, a new system was designed to track accurately body segments orientation, speed and position of CoM by combining GNSS, inertial sensor and the magnetic field generated by the magnet inserted into each gate pole. In cross-country skiing, using ski mounted sensors the spatio-temporal parameters for diagonal stride were estimated with a good accuracy allowing to detect significant difference in skiing. The algorithm was adapted for ski mountaineering and allowed to find optimal slopes and speed to minimize energy expenditure. Joints Biomechanics: A 5 DoF robotic shoulder simulator was designed tested for the estimation humeral head translation. The system is used to predict both the risk of loosening and the risk of subluxation for a specific patient and implant configuration. Assistive technology for rehabilitation: two new kinect-based exergames were designed for daily exercises and prevention of accident in professional environment. The first exergames used projection of dynamic virtual obstacle while the second one used a full- immersive in a virtual environment. The usability of both systems was tested successfully in a workshop with 25 subjects and game environment was adapted for professional situation.

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Wei Zhang Hooman Dejnabadi Senior Researcher

Anisoara Inonescu PhD Students

Lena Carcreff Pritish Chakravarty Mathieu Falbriard Benedikt Fasel Matteo Mancuso Christopher Moufawad El Achkar Abolfazl Soltani Technicians

Pascal Morel Administrative Assistants

Francine Eglese

Decline of movement complexity with age. Lempel-Ziv complexity is estimated from the entropy of the physical activity (PA) barcode obtained by dividing PA into several levels based on type, intensity and duration of activities. PA are classified using trunk inertial sensor.

Selected Publications »» Paraschiv-Ionescu, A., Perruchoud, C., Rutschmann, B., Buchser, E. andAminian, K.(2016) Quantifying dimensions of physical behavior in chronic pain conditions. Journal of NeuroEngineering and Rehabilitation 13(1):85. »» Moufawad el Achkar, C., Lenoble-Hoskovec, C., Paraschiv-Ionescu, A., Major, K., Büla, K. and Aminian, K. (2016) Instrumented shoes for activity classification in the elderly. Gait and Posture 44: 12-17. »» Fasel, B., Favre, J., Chardonnens, J., Gremion G. and Aminian, K. (2015) An inertial sensor-based system for spatio-temporal analysis in classic cross-country skiing diagonal technique. Journal of Biomechanics 48(12): 3199-3205. »» Dadashi, F., Millet, G. and Aminian, K. (2015) Front-crawl stroke descriptors variability assessment for skill characterisation, Journal of Sports Sciences 34: 1405-1412. »» Arami, A., Vida Martins, N. and Aminian, K. (2015) Locally linear neuro-fuzzy estimate of the prosthetic knee angle and its validation in a robotic simulator. IEEE Sensors Journal 15:6271-6278. »» Massé, F., Gonzenbach, R.R., Arami, A., Paraschiv-Ionescu, A., Luft, A.R. and Aminian, K. (2015) Improving activity recognition using a wearable barometric pressure sensor in mobility-impaired stroke patients. Journal of NeuroEngineering and Rehabilitation 12: 72-86. »» Barré, A., Jolles, B.M., Theumann, N. and Aminian, K. (2015) Soft tissue artifact distribution on lower limbs during treadmill gait: Influence of skin markers’ location on cluster design. Journal of Biomechanics 48: 1965-1971.

Fantner Lab Georg Ernest Fantner - Tenure-Track Assistant Professor - School of Engineering (STI)

Georg Fantner received his PhD from UCSB in 2006. After a post doc at MIT he joined the faculty at Ă&#x2030;cole Polytechnique FĂŠderale de Lausanne in 2010 as tenuretrack assistant professor for bioengineering. He is the founder of two nanotechnology companies, inventor on 5 international patents, author of 71 publications, ISI H-index of 23.

lnbi.epfl.ch

Introduction

Results Obtained

Our research aims to advance nanoscale measurement technology for lifescience applications, with a special focus on time resolved atomic force microscopy (AFM). Towards this end, we work on the integration of highspeed AFM with super-resolution optical microscopy, micro-and nano-fluidics for high throughput AFM sample handling and NEMS cantilever design. Using these new technologies we study the structure of cell membranes and lipid model-membranes with nanometer resolution, and can observe changes two orders of magnitude faster than previously possible with AFM. Recently we have also developed long-term AFM imaging to characterize bacterial cell division with nanometer resolution. The high spatial resolution images recorded over multiple cell generations yield unprecedented insights into the cell division process.

In 2015 we have developed methods for long time nanoscale imaging of bacterial cell growth and division. By enabling continuous AFM imaging of growing bacterial cells for over one week we are able to investigate some fundamental questions regarding what governs cell elongation rates and growth symmetry in Mycobacteria smegmatis. Using high resolution time lapse AFM imaging we have demonstrated that cell seperation in M.smegmatis is governed by mechanical properties, rather than biochemical processes. By using the AFM cantilever as a means to apply mechanical forces we induced pre-mature cell separation and demonstrated that turgor pressure is one of the main driving forces in cell separation. We have built the worlds first combined high-speed AFM/super resolution optical microscope and were able to perform the first correlated live cell HS-AFM/live cell PALM microscopy experiments. In addition we have developed a new mode for nanomechanical characterization using force distance based AFM that operates at two orders of magnitude faster than existing methods. This allows the characterization of mechanical changes on the cell surfaces as cells undergo growth or react to environmental stimuli such as antibiotic stress.

Keywords High speed Atomic force microscopy, nanomechanics, lipid membranes, MEMS, NEMS, correlated microscopy, Superresolution microscopy/AFM, microfluidics, bone, single molecule force spectroscopy, live cell imaging, mycobacteria.

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Haig-Alexander Eskandarian Nikola Pascher PhD Students

Maja Dukic Mélanie Hannebelle Nahid Hosseini Adrian Nievergelt Oliver Peric Pascal Odermatt Joëlle Ven Yulia Gazizova Technicians

Santiago Andany Administrative Assistants

Tamina Sissoko 3D rendering of a combined AFM/PALM image of a mammalian cell showing the 3D cell morphology measured by AFM and paxcillin clusters measured in PALM.

Selected Publications »» Adams, J. D., Erickson, B. W., Grossenbacher, J., Brugger, J., Nievergelt, A. and Fantner, G. E. (2015) Harnessing the damping properties of materials for high-speed atomic force microscopy. Nat. Nanotechnol. 11: 147–151. »» Dukic, M., Adams, J. D. and Fantner, G. E. (2015) Piezoresistive AFM cantilevers surpassing standard optical beam deflection in low noise topography imaging. Sci. Rep. 5: 16393. »» Nievergelt, A. P., Erickson, B. W., Hosseini, N., Adams, J. D. and Fantner, G. E. (2015) Studying biological membranes with extended range high-speed atomic force microscopy. Sci. Rep. 5: 11987. »» Nowell, C. S., Odermatt, P. D., Azzolin, L., Hohnel, S., Wagner, E. F., Fantner, G. E., Lutolf, M. P., Barrandon, Y., Piccolo, S. and Radtke, F. (2015) Chronic inflammation imposes aberrant cell fate in regenerating epithelia through mechanotransduction. Nat. Cell Biol. 18: 168–180. »» Odermatt, P. D., Shivanandan, A., Deschout, H., Jankele, R., Nievergelt, A. P., Feletti, L., Davidson, M. W., Radenovic, A. and Fantner, G. E. (2015) High-Resolution Correlative Microscopy: Bridging the Gap between Single Molecule Localization Microscopy and Atomic Force Microscopy. Nano Lett. 15: 4896–4904. »» Dukic, M., Winhold, M., Schwalb, C. H., Adams, J. D., Stavrov, V., Huth, M. and Fantner, G.E. (2016) Direct-write nanoscale printing of nanogranular tunnelling strain sensors for sub-micrometre cantilevers. Nat. Commun. 7: 12487. »» Hosseini, N., Nievergelt, A. P., Adams, J. D., Stavrov, V. T. and Fantner, G. E. (2016) A monolithic MEMS position sensor for closed-loop high-speed atomic force microscopy. Nanotechnology 27: 135705.

Ghezzi Lab Diego Ghezzi - Tenure-Track Assistant Professor - Center for Neuroprosthetics - School of Engineering (STI)

Diego Ghezzi received his MSc in Biomedical Engineering (2004) and PhD in Bioengineering (2008) from Politecnico di Milano. He completed his postdoc at Istituto Italiano di Tecnologia (Neuroscience and Brain Technologies department), where he was promoted Researcher in 2013. In 2015, he was appointed PATT at EPFL, as member of the CNP.

Introduction

Results Obtained

Worldwide 190 million people are severely visually impaired and about 32 million are blind. In Europe, macular degeneration (16%) and glaucoma (12.2%) are considered the leading causes of blindness. Blindness is a widespread global public health issue, representing a significant personal and societal burden, limiting educational opportunities, affecting economic possibilities and reducing the quality of life. Retinal diseases, such as Retinitis pigmentosa or macular degeneration, represent an important cause of blindness, for which there is still no established prevention, treatment or cure. The mission of the laboratory is focused on the implementation of novel technological approaches for fighting blindness, providing a fundamental advancement towards sight restoration in patients affected by retinal dystrophies, and translating our research findings into clinical practice. Currently the laboratory is active on 2 research lines: i) the development of an injectable, self-opening, and freestanding organic retinal prosthesis and ii) the development an intra-neural prosthesis for the direct stimulation of the optic nerve in blind patients.

In 2015 the activities has been focused mostly on the setting up of the laboratory arena. Moreover, our research effort has been dedicated in the design and fabrication of an injectable, self-opening, and freestanding organic retinal prosthesis. We are designing an injectable structure housing photovoltaic elements for the light stimulation of retinal cells. In parallel, we started working on the optimization of the photovoltaic elements for retinal stimulation. In 2016 we significantly moved forward in both projects. First, we concluded the fabrication of the injectable, self-opening, and freestanding organic retinal prosthesis; preliminary results show the potential of organic photovoltaic technology in the fabrication of a retinal prosthesis with large surface area and high stimulation efficiency. Second, we provided the proof-of-concept in the use of intra-neural electrodes for optic nerve stimulation. The prostheses have been fabricated and characterized in-vitro and with animal experiments. These data show the capability of intra-neural optic nerve stimulation to induce cortical activation with high spatial and temporal resolution.

Keywords Neuroprosthetics, Visual prostheses, Organic neuroprosthetics, Fighting blindness, Neuro-optoelectronic interfaces, Optical stimulation

lne.epfl.ch

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Laura Ferlauto PhD Students

Marta JI Airaghi Leccardi Paola Vagni Naïg Chenais Vivien Gaillet Administrative Assistants

Manuela da Silva

Injectable, self-opening, and freestanding organic retinal prosthesis.

Selected Publications »» Antognazza, M.R., Di Paolo, M., Ghezzi, D., Mete M., Di Marco, S., Maya-Vetencourt, J. F., Maccarone, R., Desii, A., Di Fonzo, F., Bramini, M., Russo, A., Donelli, I., Cilli, M., Freddi, G., Pertile, G., Lanzani, G., Bisti, S. and Benfenati, F. (2016) Characterization of a polymer-based, fully organic prosthesis for implantation into the subretinal space of rats. Adv. Healthcare Mater. 5(17): 2271–2282. »» Feyen, P., Colombo, E., Endeman, D., Nova, M., Laudato, L., Martino, N., Antognazza, M.R., Lanzani, G., Benfenati, F. and Ghezzi, D. (2016) Light-evoked hyperpolarization and silencing of neurons by conjugated polymers. Sci. Rep. 6: 22718. »» Szczurkowska, J., Cwetsch, A., dal Maschio, M., Ghezzi, D., Ratto G.M. and Cancedda, L. (2016) Targeted in vivo genetic manipulation of the mouse or rat brain by in utero electroporation with a triple-electrode probe. Nat. Prot. 11(3): 399-412.

Guiducci Lab Carlotta Guiducci - Tenure-Track Assistant Professor

clse.epfl.ch

Introduction

Results Obtained

In the clinical research and practice, the need to dramatically increase the number of analyzed samples and the push towards “companion diagnostics” can only be fulfilled by fully-automatized devices integrating processing and analytical functions.

Therapeutic drug monitoring and portable molecular assays. We developed a portable, palm-sized transmission-localized surface plasmon resonance (T-LSPR) setup coupled with DNA-based aptamers specific to the antibiotic tobramycin (467 Da). The presented T-LSPR system shows for the first time label-free direct detection and quantification of a small molecule in the complex matrix of filtered undiluted blood serum. The DNA-based aptamers against tobramycin were selected in the lab, based on a capture-SELEX approach modified to address the limitations in the production of DNA aptamers against small molecules. The best aptamers displayed KD of approximately 200 nM, similar to RNA and DNA-based aptamers previously selected for tobramycin.

In the fields of lab-on-chip systems and miniaturized analytical devices, we develop novel technological solutions for BioMEMS/circuit integration and for the co-fabrication of electronic sensors and microfluidic functional modules.

Carlotta Guiducci received her Ph.D. degree in Electrical Engineering from University of Bologna. She has been visiting scientist at Minatech, Grenoble and ParisTech (ESPCI). She joined EPFL in 2009 as a tenure track assistant professor with IBI and IEL. She holds the Swiss Up Chair on Engineering and she is the recipient of the Intel Early Career Faculty Award. Her work and interview on the role of Silicon in personalized medicine have been featured in “IET Electronics Letters” in 2012. In 2013, she has been invited by Nature Methods to comment on the novel pHbased electronic solutions for quantitative PCR.

The crucial challenge on sensitivity is met by the research on scalable sensors and by the combination of solid-state devices with suitable and stable ligands. The lab has contributed with important advancements in the areas on nanosensors for the monitoring of nucleic acid amplification and on assays for the quantification of drug molecules in serum for therapeutic drug monitoring purposes. In the field of cellular analytics, the lab is developing high-throughput strategies for the single-cell level manipulation and continuous observation of cellular samples based on arrays of singularly-addressable vertical microelements which generate highly-confined electric fields in microfluidics chambers. These systems are showing their interests in the characterization and elaboration of T-lymphocytes samples.

Keywords Miniaturized bioanalytical systems, lab-on-a-chip devices, 3D sensor technologies, drug monitoring, aptamers, DNA quantification, chemosensing transistor, microfluidic flow cytometry.

Nanodevices for high-density pH sensing arrays In collaboration with LETI-CEA (Grenoble, France) and the University of Udine (Italy) we worked on CMOS-compatible highly-controlled top-down fabricated silicon nanowires to assess the limits of scaling pH sensing. We show that tri-dimensional, multi-wire devices achieve unprecedented pH resolution per footprint area. These findings are of great relevance for the evolution of semiconductor-based DNA analytics, since this requires arrays of everincreasing density. Analytics of cellular samples Electric fields can be effectively used to sense, manipulate and move cells in labon-a-chip devices. Nevertheless, the existing implementations don’t meet the high-throughput requirements of single-cell analysis, mostly due to the design limitations entailed by planar electrodes in microfluidic configurations. These could be overcome by vertical electrodes, either integrated in microchannel sidewalls or as free-standing structures. We realized various developments of lab-on-chip devices for impedance-based cell sensing and electrokinetic manipulation based on a 3D-electrode technology integrable with ICs that we developed at EPFL CMi.

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Marco Letizia Pietro Maoddi Enrico Tenaglia Miyuki Tbata PhD Students

Diana Burghelea Samuel Kilchenmann Enrica Rolo Kevin Keim Administrative Assistants

Monica Navarro Suarez

Multi-gate impedance flow cytometer for the detection and differentiation of single cells in flow. Cells are differentiated on the basis of their intrinsic electrical properties, hence without the use of labels. Several channels can be implemented on a single chip to increase the cell detection rate.

Selected Publications »» Kilchenmann, S.C., Rollo, E., Maoddi, P. and Guiducci, C. (2016) Metal-coated SU-8 structures for high-density 3D microelectrode arrays. JMEMS 25 (3 ) »» Accastelli, E., Scarbolo, P., Ernst,T., Palestri, P., Selmi, L. and Guiducci, C. (2016) Multi-wire tri-gate silicon nanowires reaching milli-units pH resolution in one micron square footprint. Biosens., 6(1), pii: E9. »» Scarbolo, P., Accastelli, E., Pittino, F., Ernst, T. and Guiducci C., (2015) Characterization and modelling of differential sensitivity of nanoribbon-based pH-sensors. TRANSDUCERS 2015, Anchorage, Alaska USA: 2188 - 2191 »» Cappi, G., Spiga, F.M., Moncada, Y., Ferretti, A., Beyler, M., Bianchessi, M., Decosterd, L., Buclin, T. and Guiducci C. (2015). Label-free detection of Tobramycin in Serum by Transmission-LSPR. ACS Analyt. Chem. 87(10):5278–5285. »» Spiga, F.M., Maietta, P. and Guiducci, C. (2015). More DNA−aptamers for small drugs: a capture−SELEX coupled with Surface Plasmon Resonance and High Throughput Sequencing. ACS Combinatorial Science 17(5): 326–333. »» ietta, P., Guiducci, C., (2015). More DNA−aptamers for small drugs: a capture−SELEX coupled with Surface Plasmon Resonance and High Throughput Sequencing. ACS Combinatorial Science, 17(5) : 326–333.

Hatzimanikatis Lab Vassily Hatzimanikatis - Associate Professor

PhD (1996) and MS (1994) in Chemical Engineering from the California Institute of Technology; Diploma (1991) in Chemical Engineering from the Uni Patras. Positions held: Group leader (ETH Zurich); Senior research Scientist (DuPont and Cargill); Assistant Professor (Northwestern University). Over 110 technical publications and 3 patents and patent applications. Over 150 invited lectures. Recipient of the 2014 International Metabolic Engineering Award. Associate editor of the journals Biotechnology & Bioengineering, Metabolic Engineering, and Biotechnology Journal. On the editorial advisory board of four biotechnology journals.

lcsb.epfl.ch

Introduction

Results Obtained

The Laboratory of Computational Systems Biotechnology (LCSB) focuses on the development of mathematical models and systems engineering frameworks for accelerating the design and purposeful manipulation of complex cellular processes. LCSB develops expertise in the formulation of mathematical models of cellular processes, in process systems engineering methods for the integration, and in the analysis of experimental information from different levels. As most of this information in biological systems is partial and it is subject to uncertainty, researchers in LCSB develop methods that can account quantitatively for the uncertainty in the available information and can provide guidance on solving problems in biotechnology and medicine. LCSB is one of the leading laboratories in the study of energetics and thermodynamics of complex cellular processes. Research in LCSB has also pioneered the development of computational methods for the discovery of novel metabolic pathways for metabolic engineering and synthetic biology. The applications areas of research in LCSB are: metabolic engineering and metabolic diseases, bioenergetics, protein synthesis, lipidomics, and drug discovery for infectious diseases.

• • • •

Genome-scale metabolic reconstruction and analysis of metabolism in human pathogen Toxoplasma gondii and Plasmodium falciparum Global database of novel biochemical reactions for the discovery of biosynthetic routes for the production of useful or novel chemicals Computational retrobiosynthesis framework for the rational design of de novo synthetic pathways An algorithm for the stochastic simulation of protein synthesis on a genome-scale level

Keywords Mathematical modeling, Metabolic Engineering, Synthetic Biology

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Georgios Fengos Noushin Hadadi Vikash Kumar Pandey Georgios Savoglidis Stepan Tymoshenko Meric Ataman PhD Students

Yves Berset Anush Chiappino Pepe Tiziano Dallavilla Jasmin Maria Hafner Tuure Hameri Zhaleh Hosseini Maria Masid Barcon Joana Raquel Pinto Vieira Pierre Salvy Milenko Tokic Sofia Tsouka Daniel Robert Weilandt Master Students General workflow and design elements for computational retrobiosynthesis framework

Selected Publications »» Hadadi, N., Hafner, J., Shajkofci, A., Zisaki, A. and Hatzimanikatis, V. (2016). ATLAS of Biochemistry: A Repository of All Possible Biochemical Reactions for Synthetic Biology and Metabolic Engineering Studies. ACS Synthetic Biology. 5(10): 1155-1166 »» Savoglidis, G. dos Santos, A.X.D., Riezman, I., Angelino, P., Riezman, H. and Hatzimanikatis, V. (2016). A method for analysis and design of metabolism using metabolomics data and kinetic models: Application on lipidomics using a novel kinetic model of sphingolipid metabolism. Metabolic Engineering. 37:46-62. »» Isakova, A., Berset, Y., Hatzimanikatis, V. and Deplancke, B. (2016). Quantification of Cooperativity in Heterodimer-DNA Binding Improves the Accuracy of Binding Specificity Models. Journal of Biological Chemistry. 291(19):10293- 10306 »» Dallavilla, T., Abrami, L., Sandoz, P.A., Savoglidis, G., Hatzimanikatis, V. and van der Goot, F.G. (2016) Model-Driven Understanding of Palmitoylation Dynamics: Regulated Acylation of the Endoplasmic Reticulum Chaperone Calnexin. PLOS Computational Biology. 12(2):e1004774. »» Andreozzi, S., Miskovic, L. and Hatzimanikatis., V. (2916). iSCHRUNK - In Silico Approach to Characterization and Reduction of Uncertainty in the Kinetic Models of Genome-scale Metabolic Networks. Metabolic Engineering. 33:158-168. »» Hadadi, N., and Hatzimanikatis, V. (2015). Design of computational retrobiosynthesis tools for the design of de novo synthetic pathways. Current Opinion in Chemical Biology. 28:99-104. »» Ataman, M., and Hatzimanikatis, V. (2015). Heading in the right direction: thermodynamics-based network analysis and pathway engineering. Current Opinion in Biotechnology. 36:176-182. »» Tymoshenko, S., Oppenheim, R. D., Agren, R., Nielsen, J., Soldati-Favre, D., Hatzimanikatis, V. (2015) Metabolic Needs and Capabilities of Toxoplasma gondii through Combined Computational and Experimental Analysis. PLOS Computational Biology. 11(5): e1004261.

Zhaleh Hosseini Maria Masid Barcon Joana Raquel Pinto Vieira Milenko Tokic Sofia Tsouka Daniel Robert Weilandt Research Associates

Ljubisa Miskovic

Administrative Assistants

Kupper Christine

Ijspeert Lab Auke Jan Ijspeert - Full Professor - School of Engineering (STI)

Auke Ijspeert is a Full professor at the EPFL in the Institutes of Bioengineering and of Mechanical Engineering (courtesy affiliation), and head of the Biorobotics Laboratory. He has a “diplôme d’ingénieur” in physics from the EPFL (1995), and a PhD in artificial intelligence from the University of Edinburgh (1998). He is member of the Board of Reviewing Editors of Science magazine.

biorob.epfl.ch

Introduction

Results Obtained

We work on the computational aspects of locomotion control, sensorimotor coordination, and learning in animals and in robots. We are interested in using robots and numerical simulation to study the neural mechanisms underlying movement control and learning in animals, and in return to take inspiration from animals to design new control methods for robotics as well as novel robots capable of agile locomotion in complex environments.

In terms of biorobotics, we have developed a new salamander-like robot Pleurobot that closely mimics its biological counterpart, Pleurodeles waltl. The robot was designed with an approach that combines high-speed cineradiography, optimization, dynamic scaling, 3D printing, high-end servomotors, and a tailored dry-suit. Pleurobot is a dynamically-scaled amphibious salamander robot with a large number of actuated degrees of freedom (27 in total). Because of our design process, the robot can capture most of the animal’s degrees of freedom and range of motion, especially at the limbs. We demonstrate the robot’s abilities by imposing raw kinematic data, extracted from X-ray videos, to the robot’s joints for basic locomotor behaviors in water and on land. The robot closely matches the behavior of the animal in terms of relative forward speeds and lateral displacements. Ground reaction forces during walking also resemble those of the animal (manuscript under review).

Our research interests are therefore at the intersection between robotics, computational neuroscience, nonlinear dynamical systems, and machine learning. We carry out research projects in the following areas: neuromechanical simulations of locomotion and movement control, systems of coupled nonlinear oscillators for locomotion control, adaptive dynamical systems, design and control of amphibious, legged, and reconfigurable robots, control of humanoid robots and of exoskeletons.

Keywords Biorobotics, computational neuroscience, locomotion control, neuromechanical simulations.

In terms of locomotion control, we have developed and improved locomotion controllers for different types of robots: amphibious robots, humanoid robots, cat-like robots, and reconfigurable robots. Within the European project Symbitron we have characterized slow locomotion in healthy human subjects in terms of kinematics, ground reaction force, and EMG signals. We have also developed and tested a promising controller for a power exoskeleton to provide locomotion support to paraplegic patients. The controller is based on ideas from our neuromechanical models of human locomotion.

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Behzad Bayat Alessandro Crespi Susanne Lipfert Kamilo Melo Philippe Müllhaupt Hamed Razavi Amy Wu PhD Students

Romain Baud Florin Dzeladini Peter Eckert Salman Faraji Simon Hauser Tomislav Horvat Jessica Lanini Mehmet Mutlu Shravan Ramalingasetty Robin Thandiackal Alexandre Tuleu Nicolas Van der Noot Comparison of walking gaits from X-ray videos of the salamander P. waltl and our new salamander-like robot Pleurobot (Karakasiliotis et al. 2016)

Technicians

François Longchamp Administrative Assistants

Sylvie Fiaux

Selected Publications »» Karakasiliotis, K., Thandiackal, R., Melo, K., Horvat, T., Mahabadi, N.K., Tsitkov, S., Cabelguen, J.M. and Ijspeert, A.J. (2016) From cineradiography to biorobots: an approach for designing robots to emulate and study animal locomotion. Journal of The Royal Society Interface 13(119): pii20151089. »» Ijspeert, A.J., Bicanski, A., Knuesel, J., Cabelguen, J.M. (2016) Motor pattern generation. In From Neuron to Cognition (M. Arbib Editor), MIT Press. »» Vitiello, N., Ijspeert, A.J. and Schaal, S. (2016) Bioinspired motor control for articulated robots. IEEE Robotics & Automation Magazine 23 (1): 20-21. »» Ryczko, D., Knüsel, J., Crespi, A., Lamarque, S., Mathou, A., Ijspeert, A.J. and Cabelguen, J.M. (2015) Flexibility of the axial central pattern generator network for locomotion in the salamander. Journal of Neurophysiology 113(6):1921-1940. »» Gams, A., Van den Kieboom, J., Dzeladini, F., Ude, A. and Ijspeert, A.J. (2015) Real-time full body motion imitation on the COMAN humanoid robot. Robotica, 33(05): 1049-1061. »» Pouya, S., Khodabakhsh, M., Spröwitz, A. and Ijspeert, A. (2015) Spinal joint compliance and actuation in a simulated bounding quadruped robot. Autonomous Robots: 1-16. »» Righetti, L., Nylén, A., Rosander, K. and Ijspeert, A.J. (2015) Kinematic and gait similarities between crawling human infants and other quadruped mammals. Frontiers in Neurology 6. »» Ijspeert, A.J. and Cabelguen, J.M. (2015). Control of aquatic and terrestrial gaits in Salamander. Encyclopedia of Computational Neuroscience, Springer: 812-820.

Johnsson Lab Kai Johnsson - Full Professor - School of Basic Science (SB)

Introduction

Results Obtained

Current research interests focus on the development and application of chemical approaches to visualize and quantify proteins and their activity, as well as to manipulate their function in cells.

We demonstrated that employing the SNAP-tag technology genetic targeting of chemical indicators is possible in live animals. This allows manipulation of behavior and monitoring of cellular fluorescence from the same reporter. We have identified that a metabolite of the kynurenine pathway inhibits tetrahydrobiopterin biosynthesis, which links two important metabolic pathways upregulated in inflammation. A far-red dye for DNA labelling was developed. A new class of near-infrared fluorophores suitable for superresolution microscopy was developed. A general approach for increasing the performance of fluorescent protein biosensors based on unnatural amino acid technology was developed. A novel principle for the modulation of a proteinâ&#x20AC;&#x2122;s activity was developed: steric exclusion. This was applied to control the activity of e.g. luciferase or carbonic anhydrase.

Keywords Chemical Biology. Protein Engineering. Directed Evolution of Protein Function. Semi-synthetic sensor proteins. Molecular interactions and concentrations. Kai Johnsson obtained his PhD at ETHZ in Organic Chemistry. After a postdoctoral stay at UC Berkeley he took a position as a tenuretrack assistant professor at EPFL in 1999. Continuing at the EPFL, Prof. Johnsson then became an Associate Professor (2005) and finally a Full Professor (2009). He has received several awards for his ground breaking work in protein engineering and chemical biology.

lip.epfl.ch

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Broichhagen Johannes Griss Rudolf Hiblot Julien Hovius Ruud Karpenko Iuliia Reymond Luc Schena Alberto Xue Lin Yamauchi Shinnosuke PhD Students

Small-molecule sensors comprising engineered proteins, synthetic small-molecule analyte analogues and designer fluorophores allow the detection of e.g. anti-cancer drugs in patient samples.

Farrants Helen Rebecca Ostlund Goeldel Nicolas Peter Lee Fook Seng Ronald Pierson Yann Mathieu Salim Aleksandar Sallin Olivier Vincent Scarabelli Silvia Yu Qiuliyang Technicians

Rengifo Gonzalez Monica Administrative Assistants

Claudia Gasparini

Selected Publications »» Xue, L., Prifti, E. and Johnsson, K.(2016) A general strategy for the semisynthesis of ratiometric fluorescent sensor proteins with increased dynamic range. J Am Chem Soc 138 (16): 5258-5261. »» Lukinavicius, G., Reymond, L., Umezawa, K., Sallin, O., D’Este, E., Gottfert, F., Ta, H., Hell, S. W., Urano, Y. and Johnsson, K. (2016) Fluorogenic probes for multicolor imaging in living cells. J Am Chem Soc 138 (30): 9365-9368. »» Haruki, H., Hovius, R., Pedersen, M.G. and Johnsson, K. (2016) Tetrahydrobiopterin biosynthesis as a potential target of the kynurenine pathway metabolite Xanthurenic acid. J Biol Chem 291 (2): 652-657. »» Xue, L., Karpenko, I.A., Hiblot, J. and Johnsson, K. (2015) Imaging and manipulating proteins in live cells through covalent labeling. Nature Chemical Biology 11 (12): 917–923. »» Lukinavičius, G., Blaukopf, C., Pershagen, E., Schena, A., Reymond, L., Derivery, E., Gonzalez-Gaitan, M., D’Este, E., Hell, S.W., Gerlich, D.W. and Johnsson, K. (2015) SiR–Hoechst is a far-red DNA stain for livecell nanoscopy. Nature Communications 6: 8497. »» Lee, R.F.S., Escrig, S., Croisier, M., Clerc-Rosset, S., Knott, G.W., Meibom, A., Davey, C.A., Johnsson, K. and Dyson, P.J. (2015) NanoSIMS analysis of an isotopically labelled organometallic ruthenium(II) drug to probe its distribution and state in vitro. Chemical Communications 51: 16486-16489. »» Schena, A., Griss, R., and Johnsson, K. (2015) Modulating protein activity using tethered ligands with mutually exclusive binding sites. Nature Communications 6: 7830

Lacour Lab Stéphanie P. Lacour - Full Professor - Center for Neuroprosthetics - Laboratory for Soft Bioelectronic Interfaces

Prof. Stéphanie P. Lacour received her PhD in Electrical Engineering from INSA de Lyon, France, and completed postdoctoral research at Princeton University (USA) and the University of Cambridge (UK). She is the recipient of the 2006 MIT TR35, a University Research Fellowship from the Royal Society (UK), a European Research Council ERC Starting Grant, a SNSF-ERC Consolidator Grant and was elected a 2015 Young Global Leader by the World Economic Forum.

lsbi.epfl.ch

Introduction

Results Obtained

Bioelectronics integrates principles of electrical engineering to biology, medicine and ultimately health. My lab challenges and seeks to advance our fundamental concepts in man-made electronic systems applied to biology. Specifically, the focus is on designing and manufacturing electronic devices with mechanical properties close to those of the host biological tissue so that long-term reliability and minimal perturbation are induced in vivo and/or truly wearable systems become possible.   We use fabrication methods borrowed from the MEMS and microelectronics industries and adapt them to soft substrates like elastomers. We develop novel characterization tools adapted to mechanically compliant bioelectronic circuits. We evaluate in vitro, in animal models and ultimately on humans our soft bioelectronic interfaces.

Soft bioelectronics is a new class of implantable and wearable electronic systems that mimic the physical format of the body and can establish longterm dialogue with the host tissue. We are developing the engineering toolbox that consists of materials and assembly processes borrowed from flexible and stretchable electronics, and innovative additive fabrication techniques to manipulate, shape and integrate device materials into constructs of structure and compliance analogous to biological tissues.

Keywords Thin film electronics; soft materials; neural implants; artificial skin.

In a review, we discussed the importance of materials-based approaches to overcome the physical and mechanical mismatch at the implant-tissue interface (Nat. Rev. Mat. 2016). We explored how to design a stimulating environment for peripheral neurons to regrow robustly and fast after injury. We developed soft surfaces based on micro/nano-patterned PDMS (Biomat. 2016; Adv. Funct. Mat., 2017) and three-dimensional scaffolds prepared with degradable gels loaded with stem cells to stimulate in vitro then in vivo the regeneration of peripheral neurons ( J. TERM, in revision). We pursued our efforts in the evaluation of a range of tissue-matched implants including conformable auditory brainstem implants (ABI), soft electrocorticography implants (ECoG), electronic dura mater for the spinal cord, and optoelectronic and optical nerve implants. We exploited our soft metallization process (based on biphasic Gallium thin films) to demonstrate epidermal mechanical sensors and have secured an ERC Proof of Concept Grant, starting early 2017, to evaluate the potential of commercializing our soft technology. Most of our results originate from synergic collaborations with colleagues in materials science, engineering and neuroscience.

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Alba de Luca Aaron Gerratt Ivan Minev Jennifer Macron Giuseppe Schiavone Xiaoyang Kang PhD Students

Laurent Dejace Florian Fallegger Sandra Gribi Amélie Guex Arthur Hirsch Aaron Lee Hadrien Michaud Frédéric Michoud Nicolas Vachicouras Master’s Students Confocal image of adipose-derived stem cells cultured on a 1µm groove-size textured fibers surface (green, phalloidin; red, focal adhesions; blue, DAPI) (scale bar: 50 µm ; timepoint : day 3).

Philippe Campiche Frédéric Giraud Christina Tringides Administrative Assistants

Christel Daidié

Selected Publications »» de Luca, A.C., Fonta, C.M., Rafful, W., di Summa, P.* and Lacour, S.P.* (2017) Encapsulation of adipose-derived stem cells in degradable gels supports in vivo nerve regeneration through long silicone conduits. J. Tissue Eng. & Regen. Med. (in revision). »» Nguyen-Dang, T., de Luca, A.C., Yan, W., Qu, Y., Page, A., Lacour, S.P. and Sorin, F. (2017) Controlled sub-micrometer hierarchical textures engineered in polymeric fibers and micro-channels via thermal drawing. Advanced Functional Materials (2017), available on-line. »» Lacour, S.P., Courtine, G. and Guck, J. (2016) Materials and technology for soft implantable neuroprostheses. Nature Reviews Materials 1: 16063. »» Lantoine, J., Grevesse, T., Villers, A., Delhaye, G., Mestdagh, C., Versaevel, M., Mohammed, D., Bruyère, C., Alaimo, L., Lacour, S.P., Ris, L. and Gabriele, S. (2016) Matrix stiffness modulates formation and activity of neuronal networks of controlled architectures. Biomaterials 89:14-24. »» Hirsch, A.*, Michaud, H.O.*, Gerratt, A.P., de Mulatier, S. and Lacour, S.P. (2016) Intrinsically stretchable biphasic (solid-liquid) thin metal films. Advanced Materials 28(22): 4506. »» Wenger, N. et al. (2016) Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury. Nature Medicine 22(2): 138-14.

Lasser Lab Theo Lasser - Full Professor - School of Engineering (STI)

lob.epfl.ch

Introduction

Theo Lasser is heading the Laboratoire d’Optique Biomédicale (LOB). He and his coworkers are focusing their research on functional imaging for biological and medical applications. The main research topics are coherent microscopy for small animal imaging applied to diabetes research, functional brain imaging related to neurodegenerative disease and super-resolution fluorescence microscopy for advanced cell imaging. Before joining EPFL he pursued an industry career at Carl Zeiss as R&D manager for ophthalmic instruments and in his last assignment as director of Carl Zeiss Research, Jena.

Our lab investigates new optical methods and techniques for applications in life sciences and medicine. Topics of interest are: • Coherent imaging including OCM, and correlation spectroscopy • Fluorescence microscopy and in particular super resolution microscopy • Research efforts are taking place at two complementary levels: • Fundamental research on coherence imaging including new detection modalities as well as image processing in close cooperation within our institute and faculty • Application-oriented projects in collaboration with research teams in medicine and biology as well as industrial partners.

Keywords Optics, Microscopy, Imaging, super-resolution, tomography

Results Obtained Reduction of Alzheimer’s disease beta-amyloid pathology in the absence of gut microbiota Despite clinical and experimental evidence implicating the intestinal microbiota in a number of brain disorders, its impact on Alzheimer’s disease is not known. To this end we sequenced bacterial 16S rRNA from fecal samples of Aβ precursor protein (APP) transgenic mouse model and found a remarkable shift in the gut microbiota as compared to non-transgenic wildtype mice. Subsequently we generated germ-free APP transgenic mice and found a drastic reduction of cerebral Aβ amyloid pathology when compared to control mice with intestinal microbiota. Our results indicate a microbial involvement in the development of Abeta amyloid pathology.

3D time-lapse imaging and quantification of mitochondria dynamics We developed 3D time-lapse imaging for monitoring mitochondrial dynamics in living HeLa cells based on photothermal optical coherence microscopy and using novel surface functionalization of Au-nanoparticles (AuNP). The protein based biopolymer coating contains multiple functional groups which impart better cellular uptake and mitochondria targeting efficiency. The high stability of the AuNP allows imaging up to 3000 seconds without significant cell damage. Statistical parametric mapping of stimuli evoked changes in total blood flow velocity in the mouse cortex obtained with extended-focus optical coherence microscopy fMRI exploits local changes in blood oxygenation to map neuronal activity over the entire brain. However, its spatial resolution is limited to a few hundreds of microns. Here we use extended-focus optical coherence microscopy (xfOCM) to quantitatively measure changes in blood flow velocity during functional hyperaemia at high spatio-temporal resolution in the somatosensory cortex of mice. We present the proof-of-principle of an optimised statistical parametric mapping framework to analyse quantitative blood flow timetraces acquired with xfOCM using the general linear model such demonstrating cortical hemodynamic reactivity at the capillary level. Complementarity of PALM and SOFI for super-resolution live cell imaging of focal adhesions We combined photoactivated localization microscopy (PALM) with super-resolution optical fluctuation imaging (SOFI) and investigate the complementarity between PALM and SOFI in terms of spatial and temporal resolution. This PALM-SOFI framework is used to image focal adhesions in living cells, while obtaining a temporal resolution below 10 s. We visualize the dynamics of focal adhesions, and reveal local mean velocities around 190 nm min−1. The complementarity of PALM and SOFI is assessed in detail with a methodology that integrates a resolution and signal-to-noise metric.

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Corinne Berclaz Jérôme Extermann Taoufiq Harach Amir Nahas Daniel Szlag PhD Students

3D bSOFI superresolution HeLa cell Vimentin structure R < 90 nm

Séverine Coquoz Tomas Lukes Paul James Marchand David Nguyen Azat Sharipov Miguel Sison Technicians

Antonio Lopez Administrative Assistants

Noelia Simone

Selected Publications »» Harach, T., Marungruang, N., Dutilleul, N., Cheatham, V., McCoy, K.D., Frisoni, G., Neher, J.J., Fåk, F., Jucker, M., Lasser, T. and Bolmont, T. (2017) Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Scientific Reports 7: 41802. »» Sison, M., Lasser, T., Weil, T., Chakrabortty, S., Extermann, J., Nahas, A., Marchand, P. and Lopez, A. (2017) 3D time-lapse imaging and quantification of mitochondria dynamics. Scientific Reports 7: 43275. »» Marchand, P., Bouwens, A., Bolmont, T., Shamaei, V., Nguyen, D., Szlag, D., Extermann, J. and Lasser, T. (2017) Statistical parametric mapping of stimuli evoked changes in total blood flow velocity in the mouse cortex obtained with extended-focus optical coherence microscopy. Biomedical Optics Express 8(1): 1-15. »» Deschout, H., Lukes, T., Sharipov, A., Szlag, D., Feletti, L., Vandenberg, W., Dedecker, P., Hofkens, J., Leutenegger, M., Lasser, T. and Radenovic, A. (2016) Complementarity of PALM and SOFI for super-resolution live cell imaging of focal adhesions. Nature Communications 7: 13693. »» Berclaz, C., Schmidt-Christensen, A., Szlag, D., Extermann, J., Hansen, L., Bouwens, A., et al. (2016) Longitudinal three-dimensional visualisation of autoimmune diabetes by functional optical coherence imaging. Diabetologia 2016;59(3):550-559 . »» Vandenberg, W., Leutenegger, M., Lasser, T., Hofkens, J. and Dedecker, P. (2015) Diffraction‐unlimited imaging: from pretty pictures to hard numbers. Cell Tissue Res. 360(1):151‐178. »» Geissbuehler, S., Sharipov, A., Godinat, A., Bocchio, N.L., Sandoz, P.A., Huss, A., et al. (2014) Live-cell multiplane three-dimensional super-resolution optical fluctuation imaging. Nat Commun. 5: 5830.

Maerkl Lab Sebastian Maerkl - Associate Professor - School of Engineering (STI)

Prof. Maerkl received his PhD from the Biophysics and Biochemistry Option at Caltech and was awarded the Demetriades-Tsafka-Kokalis prize for the best Caltech PhD thesis in the field of Biotechnology. In 2008 he joined EPFL the Institute of Bioengineering and the School of Engineering and was promoted to Associate Professor in 2015.

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Introduction

Results Obtained

The Maerkl lab conducts research at the interface of engineering and biology and we are active in the areas of systems biology, synthetic biology and molecular diagnostics. We are driven by a desire to learn how to rationally design and engineer biological systems. Unfortunately, despite a vast foundation of biological knowledge accumulated over the last century, it remains difficult to engineer biological systems, indicating that basic biological research alone is not sufficient to enable biological engineering. We propose that injecting engineering concepts into biology such as reverse engineering, quantitative analysis, and computational/biophysical modeling will enable biological engineering and fundamentally change how the scientific community and the general public applies biological systems in the 21st century. Our specific biological interests lie primarily in reverse engineering gene regulatory networks, transcriptional regulation, transcription factor biophysics, cell-free synthetic biology, protein engineering, and in developing next-generation molecular diagnostic devices. Progress in biological engineering is also heavily dependent on technological and methodological innovation. To address these requirements we are developing novel, state-of-the-art microfluidic technologies and molecular methods to address current limitations in biological engineering.

In 2015 we primarily reported work in the area of cell-free synthetic biology and protein engineering. We were able to show that genetic networks can be implemented and characterized in an in vitro system and that these networks can then be transferred in vivo. We also developed a microfluidic platform to enable the rapid synthesis and quantitative characterization of proteins, and applied this approach to the development of novel Zinc-Finger transcription factors. In 2016 we reported the development of the first digital-analog microfluidic diagnostics platform. Our point-of-care device is also capable of quantitating several biomarkers from a single drop of whole blood.

Keywords Microfluidics, synthetic biology, systems biology, molecular diagnostics

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Nadanai Laohakunakorn Francesco Piraino PhD Students

Fabien Jammes Gregoire Michielin Barbora Lavickova Ivan Istomin Ekaterina Petrova Zoe Swank Francesca Volpetti Kristina Woodruff Simone Giaveri Amanda Verpoorte Administrative Assistants

Helen Chong-Horrigan

The in vitro design cycle for rapid prototyping of genetic networks.

Selected Publications »» »» »» »»

Piraino, F., Volpetti, F., Watson C. and Maerkl, S.J. (2016) A digital-analog platform for patient-centric multiplexed biomarker diagnostics of ultra-low volume samples. ACS Nano. 10: 1699-1710. Woodruff K., and Maerkl S.J. (2016). A high-throughput microfluidic platform for mammalian cell transfection and culturing. Scientific Reports 6: 23937. Blackburn, M.C., Petrova, E., Correia, B.E. and Maerkl, S.J. (2015). Integrating gene synthesis and microfluidic protein analysis for rapid protein engineering. Nucleic Acids Research 44(7): e68. Maddalena L.L., Niederholtmeyer H., Turtola M., Swank Z., Belogurov G.A., and Maerkl S.J. (2015). GreA and GreB enhance Escherichia coli RNA polymerase transcription rate in a reconstituted transcriptiontranslation system. ACS Synthetic Biology 5:929-935. »» Niederholtmeyer, H., Sun, Z.Z., Hori, Y., Yeung, E., Verpoorte, A., Murray, R.M. and Maerkl S.J. (2015) Rapid cell-free forward engineering of novel genetic ring oscillators. eLife 4: e09771.

Mermod Lab Nicolas Mermod - Full Professor - IBI - UNIL

unil.ch/biotech/en/home/menuinst/presentation

Introduction

Results Obtained

Our translational research activities are focused on the elucidation of the mechanisms that control gene expression in mammalian cells, to obtain more reliable gene transfer expression for medical use, for instance to express therapeutic proteins in the bioreactor or for gene and cell-based therapies. Four research lines are currently being followed by the laboratory.

We have understood some of the mechanisms governing the illegitimate integration of foreign DNA into cell genomes by a novel type of Rad51dependent microhomology mediated end-joining DNA repair mechanism, and how such genomic integration events can be controlled by epigenetic regulatory DNA elements in cancer cells.

Keywords

We have linked the regulation of cell cycle initiation and progression to the functional status of DNA damage repair recombination mechanisms.

Molecular biotechnology, epigenetics, genomics, gene expression PhD on bacterial gene regulation and environmental biotechnology at the University of Geneva. Postdoc with Bob Tjian at the University of California at Berkeley. Joined the University of Lausanne as an assistant Professor fellow of the Swiss National Science Foundation, to become full professor and director of the Institute of Biotechnology.

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We have developed novel non-viral vectors for the transfer of very large therapeutic genes, e.g. encoding full length dystrophin, in gene and stem cellbased therapeutic approaches, and evaluated an atomic force microscopy-based assay of muscle function and diseases. We have uncovered a regulatory role for transcription factor NF1 in adult stem cell mobilisation in response to tissue injuries and in tissue regeneration in the context of the murine liver.

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Elena Aritonovska Audrey Berger Solenne Bire Pierre-Olivier Duroy Lucille Pourcell PhD Students

Pavithra Iyer Sandra Bosshard informatician

Daniel Peter Technicians

Yves Dusserre Jacqueline Masternak Armindo Texeira Ione Gutscher Administrative Assistants

Nassim Berberat Homogeneity of GFP expression , as mediated by some epigenetic regulators, in stably transfected CHO cells

Selected Publications »» Droz, X., Harraghy, N., Lançon, E., Le Fourn, V., Calabrese, D., Colombet, T., Liechti, P., Rida, A., Girod, P.A. and Mermod, N. (2017) Automated microfluidic sorting of mammalian cells for those that efficiently express and secrete a protein of interest. In revision. »» Kostyrko, K., Neuenschwander, S., Junier, T., Regamey, A., Iseli, C., Schmid-Siegert, E., Bosshard, S., Majocchi, S., LeFourn, V., Girod, P.A., Xenarios, I. and Mermod, N. (2017) MAR-mediated transgene integration into permissive chromatin and increased expression involve an SD-MMEJ-like DNA repair pathway. Biotechnol. Bioeng. 114: 384-396. »» Mee, E.T., Preston, M.D., CS533 study participants, Minor, P.D. and Schepelmann, S. (2016) Development of a candidate reference material for adventitious virus detection in vaccine and biologicals manufacturing by deep sequencing. Vaccine 34: 2035-2043. »» Kostyrko, K. and Mermod, N. (2016) Assays for DNA double-strand break repair by microhomology-based end-joining repair mechanisms. Nucl. Acids Res. 44(6): e56. »» Van Zwieten, R.W., Majocchi, S., Puttini, S., Messina, G., Tedesco, F.S., Cossu, G. and Mermod, N. (2015) MAR-mediated dystrophin expression in mesoangioblasts for Duchenne muscular dystrophy cell therapy. Molec. Biol. 4:134.

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Micera Lab Silvestro Micera - Associate Professor - Center for Neuroprosthetics - School of Engineering (STI)

Silvestro Micera is currently Associate Professor of Biomedical Engineering at the EPFL where he is holding the Bertarelli Foundation Chair in Translational NeuroEngineering. He is also Professor of Biomedical Engineering at the Scuola Superiore Sant’Anna (Italy). In 2009 he was the recipient of the “Early Career Achievement Award” of the IEEE Engineering in Medicine and Biology Society.

Introduction

Results Obtained

The main goal of our laboratory is to develop implantable neural interfaces and robotic systems aimed at restoring sensorimotor function in people with different kind of disabilities (spinal cord injury, stroke, amputation, etc...), starting from basic scientific knowledge in the field of neuroscience, neurology and geriatrics, and investigating further to gain new information by using advanced technologies and protocols. For this reason our activities combine (i) technological developments (robotics, implantable neural interfaces, algorithms for closed-loop control and signal processing), (ii) experiments to understand the basic neuroscientific principles of motor control; (iii) integration and test of different types of hybrid neuroprosthetic systems to restore sensory and motor functions. Starting from a background on signal processing and closed-loop control, we have been able to enlarge the focus of his scientific activities and now our team has the ability to investigate all the different issues related to the development and test of effective neural and rehabilitation systems. We are one of the few groups in the world able to study all these issues in an integrated and harmonized manner.

Bionic limbs In the recent past, our “bionic” prosthesis was tested for a month, during which the intraneural TIME electrodes were implanted. In 2016 we investigated the possibility to restore the ability to judge textural features. We sought to achieve this goal via an integrated approach to mimic natural coding using a neuromorphic, real-time, mechano-neuro-transduction process (MNT). The MNT process was tested in four intact subjects by delivering electrical stimulation to their sensory peripheral nerve fibers during microstimulation via tungsten needle microelectrodes and with one amputee using TIME electrodes. The participants achieved excellent performance in terms of texture discrimination confirming that this feature can be artificially restored. We also investigated the long-term usability of our approach with two patients. The first one was implanted in November 2015, for six months. The second one was implanted from June 2016 also for six months. The sensations elicited from electric current injected in 4 TIME electrodes implanted in the median and ulnar nerves, have been recorded weekly up to 80 days after the implant, in terms of type, location, extension and intensity of the sensation elicited over the missing (phantom) hand.

Keywords Neuroprosthetics, Bionics, Hand prosthesis, Modelling and control

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Closed-loop control of epidural electrical stimulation (EES) to restore locomotion In 2016 we further exploited the collaboration with Prof. Courtine to restore locomotion after spinal cord injury using EES. We provided evidence that epidural electrical stimulation interacts with muscle spindle feedback circuits and that the stretch reflex is sufficient to explain the well-known modulation of muscle activity during locomotion. We have also demonstrated the feasibility of interfacing sensorimotor cortex signals with electrical spinal cord stimulation to improve locomotion during rehabilitation after a severe spinal cord contusion in non-human primates and in rats.

IBI - Co-affiliated Research Groups

Team Members Scientists & Postdoctoral Fellows

Fiorenzo Artoni Beatrice Barra Marco Capogrosso Martina Coscia Ivan Furfaro T. Khoa NGuyen Francesco M. Petrini Camilla Pierella Stanisa Raspopovic Ivo Strauss Giacomo Valle Katie Zhuang PhD Students

The experiments performed to restore texture information in healthy subjects and trans-radial amputees.

Marion Badi-Dubois Marco Bonizzato Andrea Crema Edoardo D’Anna Emanuele Formento Beryl Jehenne (visiting) Nawal Kinany Theo Lemaire Jenifer Miehlbradt Elvira Pirondini Flavio Raschellà Sophie Wurth Master’s Students

Selected Publications »» Alia, C., Spalletti, C., Lai, S., Panarese, A., Micera, S. and Caleo, M. (2016) Reducing GABA(A)-mediated inhibition improves forelimb motor function after focal cortical stroke in mice. Sci Rep 6: 37823. »» Capogrosso, M., Milekovic, T., Borton, D., Wagner, F., Moraud, E.M., Mignardot, J.B., Buse, N., Gandar, J., Barraud, Q., Xing, D., Rey, E., Duis, S., Jianzhong, Y., Ko, W.K., Li, Q., Detemple, P., Denison, T., Micera, S., Bezard, E., Bloch, J. and Courtine, G. (2016) A brain-spine interface alleviating gait deficits after spinal cord injury in primates. Nature 539(7628): 284-288. »» Oddo, C.M., Raspopovic, S., Artoni, F., Mazzoni, A., Spigler, G., Petrini, F., Giambattistelli, F., Vecchio, F., Miraglia, F., Zollo, L., Di Pino, G., Camboni, D., Carrozza, M.C., Guglielmelli, E., Rossini, P.M., Faraguna, U. and Micera, S. (2016) Intraneural stimulation elicits discrimination of textural features by artificial fingertip in intact and amputee humans. Elife 5:e09148.. »» Moraud, E.M., Capogrosso, M., Formento, E., Wenger, N., DiGiovanna, J. and Courtine, G. and Micera, S. (2016) Mechanisms underlying the neuromodulation of spinal circuits for correcting gait and balance deficits after spinal cord injury. Neuron 89(4): 814-828. »» Wenger, N, Moraud, E.M., Gandar, J., Musienko, P., Capogrosso, M., Baud, L, Le Goff, C.G., Barraud, Q., Pavlova, N., Dominici, N., Minev, I.R., Asboth, L., Hirsch, A., Duis, S., Kreider, J., Mortera, A., Haverbeck, O., Kraus, S., Schmitz, F., DiGiovanna, J., van den Brand, R., Bloch, J., Detemple, P., Lacour, S.P., Bézard, E., Micera, S. and Courtine, G. (2016) Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury. Nat Med 22(2): 138-145. »» DiGiovanna, J., Dominici, N., Friedli, L., Rigosa, J., Duis, S., Kreider, J., Beauparlant, J., van den Brand, R., Schieppati, M., Micera, S. and Courtine, G. (2016) Engagement of the rat hindlimb motor cortex across natural locomotor behaviors. J Neurosci 36(40): 10440-10455.

Guy Aymeric Orset Bastien Pham Hoang Mac Administrative Assistants

Anouk Hein

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Millán Lab José del R. Millán - Associate Professor - Center for Neuroprosthetics - School of Engineering (STI)

Prof. José del R. Millán holds the Defitech Chair since 2009, where he designs neuroprostheses (brain-controlled devices like robots, exoskeletons and communication aids) for augmenting interaction experiences and restoring lost functions. His research on brain-machine interfaces has received a number of awards and recognitions.

cnbi.epfl.ch

Introduction

Results Obtained

The Chair in Brain-Machine Interface laboratory (CNBI) carries out research on the direct use of human brain signals to control devices and interact with our environment. In this multidisciplinary research, we are bringing together our pioneering work on the two fields of brain-machine interfaces and adaptive intelligent robotics. Our approach to design intelligent neuroprostheses balances the development of prototypes‚ where robust real-time operation is critical‚ and the exploration of new interaction principles and their associated brain correlates. A key element at each stage is the design of efficient machine learning algorithms for real-time analysis of brain activity that allow users to convey their intents rapidly, on the order of hundred milliseconds. Our neuroprostheses are explored in cooperation with clinical partners and disabled volunteers for the purpose of motor restoration, communication, entertainment and rehabilitation.

As in previous years, our work is focused on both: translational work with end users and basic research on Brain-Machine Interfaces (BMI). In the first line we put particular emphasis on evaluating the robustness of non-invasive BMIs. On the one hand, successful translation of these technologies requires them to be able to operate for long periods of time. We showed that our methods for adaptive shared control enabled a severely paralyzed user to control a motor-imagery BMI without external recalibration for more than 8 months (Saeedi et al., 2017). On the other hand, the first ever Cybathlon allowed us to test our systems in a very challenging situation. Users with disabilities competed in front of a big crowd in a BMI-controlled computer race. Our team won the competition (http://www.cybathlon.ethz.ch/en/) showing that the BMI allowed pilots to send commands to their avatars in a reliable and timely manner. Moreover, we also work on new BMI-based assistive solutions including adaptive systems for spelling applications (Perdikis et al., 2016), lower limb exo-skeletons (Lee et al., 2016). Last but not least, we have continued our work on BMI-mediated motor neurorehabilitation. Our work on shared control and neurorehabilitation received prizes to the best student posters at the International BCI meeting 2016.

Keywords Brain-machine interfaces, Neuroprosthetics, Machine learning, Robotics, EEG

In addition, Prof. Millán spent six months of sabbatical leave at the University California Berkeley establishing new collaborative lines of research.. Publications in 2016 covered the following main research lines: • Adaptive shared control strategies for long-term operation of BMI-based applications • BMI control of spelling devices and exo-skeletons • Decoding of electro-corticogram correlates of speech • Research methodologies for brain-computer interfacing • BMI mediated motor neurorehabilitation

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IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Maria Laura Blefari Ricardo Chavarriaga Iñaki Iturrate Kyuhwa Lee Robert Leeb Serafeim Perdikis Luca Tonin Andrea Biasiucci Andrea Maesani PhD Students

CNBI won the Cybathlon BCI race. Our pilot, Numa Poujouly, in the podium with the gold medal. Dr. Luca Tonin is behind. See http://www.cybathlon.ethz.ch/en/ for more details.

Ruslan Aydarkhanov Tiffany Corbet Lucian Gheorghe Ping-Keng Jao Zahra Khaliliardali Stéphanie Martin Michael Pereira Luca Randazzo Sareh Saeedi Christoph Schneider Visiting PhD Students

Dong Liu (Beihang University, Beijing, China) Wilfredo Alfonso (Universidad del Valle, Cali, Colombia) Research Engineers

Géraud L’Eplattenier Arnaud Desvachez Master’s Students

Selected Publications »» »» »» »» »»

Martin S., Brunner P., Iturrate I., Millán J.d.R. and G. Schalk et al. (2016) Word pair classification during imagined speech using direct brain recordings. Scientific Reports, 6:25803. Perdikis S., Leeb R. and Millán J.d.R. (2016) Context-aware adaptive spelling in motor imagery BCI. Journal of Neural Engineering, 13(3): 036018. Saeedi S., Chavarriaga R., Leeb R. and Millán J.d.R. (2016) Adaptive assistance for brain-computer interfaces by online prediction of command reliability. IEEE Computational Intelligence Magazine, 11:32-39. Lee K., Liu D., Perroud L., Chavarriaga R. and J. d. R. Millán. (2016) A brain-controlled exoskeleton with cascaded event-related desynchronization classifiers. Robotics and Autonomous Systems, To appear. Saeedi S., Chavarriaga R., and Millán J.d.R. (2017) Long-term stable control of motor-imagery BCI by a locked-in user through adaptive assistance. IEEE Transactions on Neural Systems and Rehabilitation Engineering, To appear

Arnaud Desvachez Naik Londoño Administrative Assistants

Christel Daidié

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Pioletti Lab Dominique Pioletti - Associate Professor - Center of Translational Biomechanics - School of Engineering (STI)

Prof. Dominique Pioletti received his Master in Physics from EPFL in 1992. He pursued his education in the same Institution and obtained his PhD in biomechanics in 1997. Then he spent two years at UCSD as post-doc fellow where he evaluated the reaction of bone cells in contact to orthopedic implant. From 2006 to 2013, he was an Assistant Professor at EPFL and since August 2013, was appointed Associate Professor of Biomechancis at EPFL.

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Introduction

Results Obtained

The research topics of the laboratory include biomechanics and tissue engineering of musculo-skeletal tissues; mechano-transduction, and development of orthopedic implant as drug delivery system. The laboratory is pioneer in the development of orthopedic implants used as drug delivery systems. The drug is delivered either passively from implant surface or through a smart delivery system using dissipative phenomena to trigger spatially and temporally the release of a drug. These approaches offer versatile solutions to the release of a drug for cartilage or nucleus pulposus tissues. Projects in tissue engineering combine biomechanical analysis for scaffold development, use of biomechanical stimulation to control and enhance tissue formation in scaffold and cell therapy for bone and cartilage tissues.

Hydrogel for load-bearing clinical applications present the disadvantages of having low mechanical properties. They could also have fragile behaviour under loading. By controlling the dissipative properties of hydrogel, we were able to drastically increase their toughness, so that new load-bearing applications could be proposed with biodegradable HEMA-based hydrogels. In parallel, we have developed in collaboration with the LPAC and LAPD, a new photopolymerized composite hydrogel which can be locally injected in a minimally invasive way while presenting very good fatigue resistance. From the implant biomechanical point of view, we are continuing our effort toward patient specific model for knee or shoulder implants as well as comparing with ex vivo measurements the micromotion distribution around implant, a marker useful in evaluation the outcome of an implant.

Keywords Biomechanics, orthopedics, mechanobiology, implant, tissue engineering, translational research

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

A. Terrier (group leader) U.Kettenberger C. Delabarde A. Latypova PhD Students

P.A. Aeberhard D. Cuttica A. Jens T. Hausherr P Karami V. Malfroy Y. Meharzi N. Nasrollahzadeh Technicians

S. Jaccoud R. Obrist

Administrative Assistants Disc height of bovine tail IVD (n 1⁄4 3) before surgery (degenerated state), after surgery (repaired state) and after 0.5 million cycles of ex vivo compressive loading (loaded state) are compared to the initial disc height (healthy disc). The disc height significantly increased after implantation of the PEGDMA-NFC composite hydrogel. The increase in disc height remained significant after loading (from: Schmocker, A., Khoushabi, A., Frauchiger, D.A., Schizas, C., Gantenbein, B., Moser, C., Bourban, P.E., and Pioletti, D.P. (2016) A photopolymerized composite hydrogel and surgical implanting tool for a nucleus pulposus replacement. Biomaterials 88: 110-119).

V. Kokocinski

Selected Publications »» Nassajian Moghadam, M., and Pioletti D.P. (2016) Biodegradable HEMA-based hydrogels with enhanced mechanical properties. J Biomed Mat Res B, 104: 1161-1169. »» Schmocker, A., Khoushabi, A., Frauchiger, D.A., Schizas, C., Gantenbein, B., Moser, C., Bourban, P.E. and Pioletti D.P. (2016) A photopolymerized composite hydrogel and surgical implanting tool for a nucleus pulposus replacement. Biomaterials 88: 110-119. »» Nasrollahzadeh, N. and Pioletti D.P. (2016) Experimental method to characterize the strain dependent permeability of tissue engineering scaffolds. J Biomechanics 49: 3749-3752. »» Latypova, A., Arami, A., Becce, F., Jolles-Haeberli, B., Aminian, K., Pioletti, D.P. and Terrier, A. (2016) A patient-specific model of total knee arthroplasty to estimate patellar strain: a case study. Clin Biomech 32: 212-219. »» Malfroy Camine, V.M., Rüdiger, H., Pioletti, D.P. and Terrier A. (2016) Full-field measurement of micromotion around a cementless femoral stem using micro-CT imaging and radiopaque markers. J Biomechanics 49: 4002-4008. »» Nassajian Moghadam, M. and Pioletti, D.P. (2015) Improving hydrogels’ toughness by increasing the dissipative properties of their network. J Mech Behav Biomed Mat 41: 161-167. »» Kettenberger, U., Latypova, A., Terrier, A. and Pioletti, D.P. (2015) Time course of bone screw fixation following a local delivery of zoledronate in a rat femoral model – a micro-finite element analysis. J Mech Behav Biomed Mat 45: 22-31.

107

Psaltis Lab Demetri Psaltis - Full Professor - Optics Laboratory

Demetri Psaltis was educated at Carnegie-Mellon University where he received his Bachelor of Science in Electrical Engineering and Economics degree in 1974, the Master’s degree in 1975 and his PhD in Electrical Engineering in 1977. In 1980, he joined the faculty at the California Institute of Technology, Pasadena, California. He served as Executive Officer for the Computation and Neural Systems department from 1992-1996. From 1996 until 1999, he was the Director of the National Science Foundation research center on Neuromorphic Systems Engineering at Caltech and also the director of the Center of Optofluidic Integration. In 2007, he moved to the EPFL where he is a professor and director of the Optics Laboratory, as well as the Dean of the School of Engineering (until 2016).

http://lo.epfl.ch

Introduction

Results Obtained

Biophotonics and Optofluidics are the two main research areas that describe the core of the Optics Laboratory. Imaging and tissue ablation are the current projects in biophotonics. In optofluidics, we are focusing on developing technologies for energy harvesting purposes by leveraging the advantages of microfluidic systems.

In the research area of Optofluidics, studies about the plant’s functionalities present a great interest as they involve mechanisms combining optics, fluidics and biochemistry. On the bioimaging side, optical fibers have shown impressive possibilities for endoscopic imaging. Pixelation-free images of fluorescent samples have been demonstrated through multicore fibers (MCFs) using speckle scanning microscopy with no calibration step. Bending does not affect the image quality as long as it does not happen during one single scan. In addition, the twophoton fluorescence microscopy has been implemented for endoscopic imaging of biological samples. Using wavefront shaping techniques, the laser beam is focused and scanned at the distal end of the fiber exciting the samples, and the fluorescence signal is collected back through the MCF. These results, open the path for advanced endoscopic imaging through optical fibers. Moreover, optical tomographic imaging has been studied in order to improve the current limitations due to artifacts and noise that other known techniques suffer from. A novel computational method for the estimation of the refractive index distribution of a 3D object from the measurements of the transmitted light-field has been presented showing promising results.

Biophotonics Imaging and tissue ablation are the current projects of this area. We are developing optical imaging techniques, for biological applications such as the diagnosis of hearing loss due to deterioration of the cochlea. The small size of the cochlea and the thick bone surrounding it place challenging obstacles for producing cochlear images in humans. We are developing endsoscopes and ablation instruments that can reach the cochlea through the middle ear and produce images of the cells in the cochlea, ablate bone, and deliver medications. Multi-mode fibers can support multiple spatial degrees of freedom. As a result it is possible to transmit images through them. We use wavefront shaping techniques to build imaging devices for advanced endoscopic designs. Additionally, fiber surgical tools that could ablate the area of interest are studied using different kinds of optical fibers. Optofluidics In optofluidics, we are focusing on developing technologies for energy harvesting purposes by leveraging the advantages of microfluidic systems. The efforts range from solar water splitting devices to solar thermal energy conversion. Current projects include the development of membraneless watersplitting devices, air-based electrolyzers, and photoelectrochemical hydrogen generators.

Keywords Optofluidics, nanoparticles, holography, optical fibers, endoscopy, phase conjugation, laser ablation, solar energy, digital confocal microscope, tomography, optical microsurgery, photopolymerisation.

108

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Ye Pu Alexandre Goy Fauzia Albertin Nicolino Stasio PhD Students

(a) The polydimethylsiloxane (PDMS) is a common material used in the area of microfluidics and can be further used to create multicore fibers by two-photon polymerization for endoscopic applications. The PDMS sample is swollen with monomer and photoinitiator (PI); after the sample is subjected to laser light illumination that provides photons with the desired energy E=hv, two-photon polymerization of the molecules is triggered, causing the formation of the optical waveguides. (b) Core-tocore coupling and variations between the cores in multicore fibers results in slight differences in the phase emerging of each core, which scrambles the input wavefront, resulting in a speckle pattern at the output. By using wavefront shaping techniques to shape the light coupled into a multicore fiber, a focus spot can be created at the output. Controlling the wavefront of the input pulse allows scanning of the focus spot around the area of interest. When the peak intensity of the focus spot exceeds the threshold for ablation of the desired material, micro-pattern formation is achieved.

Seyyed Mohammad Hosseini Hashemi Marilisa Romito Morteza Hasani Shoreh Eirini Kakkava Alexandre Burnand Pooria Hadikhani JooWon Lim Giulia Panusa Administrative Assistants

Silke Jan

Selected Publications »» Demetri Psaltis, Andreas E. Vasdekis, Jae-Woo Choi. Optofluidics of plants. APL Photonics. 1, 020901 (2016) »» Nicolino Stasio, Christophe Moser and Demetri Psaltis. Calibration-free imaging through a multicore fiber using speckle scanning microscopy. Optics Letters, Vol 41, Issue 13, 3078-3081 (2016) »» Donald Conkey, Nicolino Stasio, Marilisa Romito, Edgar E. Morales-Delgado, Christophe Moser and Demetri Psaltis. Lensless two-photon imaging through a multicore fiber with coherence-gated digital phase conjugation. Journal of Biomedical Optics, 21, 045002 (2016) »» Ulugbek S. Kamilov, Ioannis N. Papadopoulos, Morteza H. Shoreh, Alexandre Goy, Cedric Vonesch, Michael Unser and Demetri Psaltis. Optical tomographic image reconstruction based on beam propagation and sparse regularization. IEEE Transactions on Computational Imaging, Vol 2, No. 1, 59-70 (2016) »» Thomas Lanvin, Donald B. Conkey, Aurelien Frobert, Jeremy Valentin, Jean-Jacques Goy, Stéphane Cook, Marie-Noelle Giraud, and Demetri Psaltis. Subsurface ablation of atherosclerotic plaque using ultrafast laser pulses. Biomed. Opt. Express 6(7), 2552-2561 (2015) »» Ulugbek S. Kamilov, Ioannis N. Papadopoulos, Morteza H. Shoreh, Alexandre Goy, Cedric Vonesch, Michael Unser and Demetri Psaltis. Learning Approach to Optical Tomography. Optica Volume 2, Issue 6, pp. 517-522 (2015) »» Olivier Simandoux, Nicolino Stasio, Jerome Gateau, Jean-Pierre Huignard, Christophe Moser, Demetri Psaltis, Emmanuel Bossy. Optical-resolution photoacoustic imaging through thick tissue with a thin capillary as a dual optical-in acoustic-out waveguide. Applied Physics Letters 106, 094102 (2015)

109

Radenovic Lab Aleksandra Radenovic - Associate Professor - School of Engineering (STI)

Aleksandra Radenovic received her master’s degree in physics from the University of Zagreb in 1999 before joining Professor Giovanni Dietler’s Laboratory of Physics of Living Matter in 2000 at University of Lausanne. There she earned her Doctor of Sciences degree in 2003. In 2003 she was also awarded a research scholarship for young researchers from the Swiss Foundation for Scientific Research which allowed her to spend 3 years as postdoctoral fellow at the University of California, Berkeley (2004‐2007). Before joining EPFL as Assistant Professor in 2008, she spent 6 months at NIH and Janelia Farm. In 2010 she received the ERC starting grant, and in 2015 SNF Consolidator Grant. Her group is interested in using novel nanomaterials and single molecule experimental techniques to study fundamental questions in molecular and cell biology.

110

lben.epfl.ch

Introduction

Results Obtained

LBEN works in the research field that can be termed single molecule biophysics. We develop techniques and methodologies based on optical imaging, biosensing and single molecule manipulation with the aim to monitor the behaviour of individual biological molecules and complexes in vitro and in live cells. Our current research is focused on three major directions: (i) Developing and using nanopores as platform for molecular sensing and manipulation. In particular we focus on solid-state nanopores realized either in glass nanocapillaries, or on suspended 2d-material membranes and standard silicon-nitride membranes. (ii) Studying how biomolecules function, especially how proteins and nucleic acids interact, using force-based manipulation single-molecule techniques, in particular optical tweezers, optical wrench system, Anti- Brownian Electrokinetic (ABEL) trap and combination of nanopore/nanocapillaries with OT. (iii) Developing super-resolution optical microscopy, based on single molecule localizations (SMLM) in cells with molecular-scale resolution, with an aim to extract quantitative information.

Although single nucleotide identification and DNA sequencing using biological pores have already been demonstrated their fragility, difficulties related to measuring pA-range ionic currents together with their dependence on biochemical reagents, make solid state nanopores an attractive alternative. In 2015 our group was first to identify single nucleotides by using solid-state nanopores but as well go beyond DNA sequencing. We use novel solid state nanopore platform based on atomically thin nanopore membranes in 2D materials such as graphene or molybdenum disulphide for DNA detection, sequencing, water desalination and osmotic power generation.

Keywords Nanopores, 2D materials, nanocapillaries, biosensing, Optical tweezers AntiBrownian Electrokinetic (ABEL) trap, single molecule localization microscopy (SMLM) DNA, proteins, DNA-protein interaction

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Arno Pino Bouwens Huanyao Cun Hendrik Deschout Jochem Deen Ke Liu Taofiq Harach Jiandong Feng PhD Students Artistic impression of ion transport through sub-nanometer pores in 2D materials

Roman Bulushev Sebastian Davis Adrien Descloux Michael Graf Martina Lihter Arielle Planchette Lab assistant

Lely Feletti

Administrative Assistants

Helen Chong

Selected Publications »» Feng, J., Graf, M., Liu, K., Ovchinnikov, D., Dumcenco, D., Heiranian, M., Nandigana, V., Aluru, N.R., Kis, A. and Radenovic, A. (2016) Single-layer MoS2 nanopores as nanopower generators. Nature 536: 197-200. »» Bulushev, R.D., Marion, S., Petrova, E., Davis, S.J., Maerkl, S.J. and Radenovic A. (2016) Single molecule localization and discrimination of DNA-protein complexes by controlled trans-location through nanocapillaries. Nano Letters 16 (12): 7882–7890. »» Deschout, H., Lukes, T., Sharipov, A., Szlag, D., Feletti, L., Vandenberg, W., Dedecker, P., Hofkens, J.. Leutenegger, M., Lasser T. and Radenovic, A. (2016) Complementarity of PALM and SOFI for super-resolution live cell imaging of focal adhesions. Nature Communications 7: 13693. »» Feng, J., Liu, K., Graf, M., Dumcenco, D., Kis, A., Di Ventra, M. and Radenovic, A. (2016) Observation of ionic Coulomb blockade innanopores. Nature Materials 15: 850-855. »» Feng, J., Liu, K., Bulushev, R.D., Khlybov, S., Dumcenco, D., Kis, A. and Radenovic, A. (2015) Identification of single nucleotides in MoS2 nanopores. Nature Nanotechnology 10: 1070-1075. »» Feng, J., Liu, K., Graf, M., Lihter, M., Bulushev, R.D., Dumcenco, D., Alexander, D.T.L., Krasnozhon, D., Vuletic, T., Kis, A., et al. (2015) Electrochemical reaction in single layer MoS2: nanopores opened atom by atom. Nano Lett. 15: 3431-3438. »» Odermatt, P.D., Shivanandan, A., Deschout, H., Jankele, R., Nievergelt, A.P., Feletti, L., Davidson, M.W., Radenovic, A. and Fantner, G.E. (2015) High-resolution correlative microscopy: bridging the gap between single molecule localization microscopy and atomic force microscopy. Nano Lett. 15, 4896-4904.

111

Roke Lab Sylvie Roke - Associate Professor - School of Engineering (STI)

Introduction

Results Obtained

60 % of the human body is composed of water. Water is not the passive background against which biology unfolds, but rather an active participator in change. This change occurs at interfaces and in solution. To understand the molecular level details of water-related biological processes we investigate them on various length scales and with varying degrees of complexity.

Electrolytes are found to induce weak but long range changes in the hydrogen bond network of water that extend over many hydration shells. This slight ion induced change in the orientational order of water is a response of the hydrogen bond network to the total electrostatic field of the ions in water. This perturbation can be detected with femtosecond elastic second harmonic scattering at concentrations as low as 10 micromolar, varies significantly for H2O and D2O, and leads to surface tension anomalies.

Research Topics:

Sylvie Roke studied chemistry and physics at Utrecht University (highest honors) and graduated from Leiden University (PhD, highest honors, nonlinear optics). In 2005 she became MaxPlanck Group Leader position (Stuttgart). She moved to EPFL in 2011. She was awarded the LJ Oosterhoff prize (NL, 2003), an Alexander von Humboldt Fellowship (De, 2005), the Minerva Prize (NL, 2006), the Hertha Sponer prize (De, 2006), an ERC starting grant (EU, 2009), membership to the German Young Academy (De, 2010), the Julia Jacobi chair in photomedicine (EPFL, 2011), and an ERC consolidator grant (EU, 2014).

112

lbp.epfl.ch

• • • • • •

Water and Aqueous Solutions Aqueous Interfaces Emulsions / Liquid Droplets Lipid Droplets and Liposomes Dynamics in Living Systems Label-free Imaging of Mammalian Neurons

Liposomes bilayer membranes were found to be asymmetric in their hydration shells rather than in their lipid composition.

Techniques: • • • •

Second Harmonic Scattering Sum Frequency Scattering Wide-Field Multiphoton Microscopy Modelling

Keywords Water, Interfaces, Nonlinear optics , Imaging ,Spectroscopy, Nanodroplets, Membranes

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Carlos Macias-Romero Gabriele Tocci Chungwen Liang Halil Okur PhD Students

Yixing Chen Jan Dedic Marie Didier Filip Kovacik Cornelis Lütgebaucks Igor Nahalka Orly Tarun Nikolay Smolentsev Siyuan Wang Evangelia Zdrali Artistic impression of the long-range interactions between ions and water as probed with fs elastic second harmonic scattering and surface tension measurements. From: Science Advances, vol. 2, num. 4, p. e1501891e1501891.

Administrative Assistants

Rebecca Veselinov

Selected Publications »» Lütgebaucks, C., Gonella, G. and Roke, S. (2016) Optical label-free and model-freeprobe of the surface potential of nanoscale and microscopic objects in aqueous solution. Physical Review B 94 (19). »» De Beer, A.G.F. and Roke, S. (2016) What interactions can distort the orientational distribution of interfacial water molecules as probed by second harmonic and sum frequency generation? Journal of Chemical Physics, 145 (4): 044705. »» Gonella, G., Luetgebaucks, C., De Beer, A.G.F. and Roke, S. (2016) Second harmonic and sum-frequency generation from aqueous interfaces is modulated by interference. Journal of Physical Chemistry C 120 (17): 9165-9173. »» Chen, Y., Okur, H. I., Gomopoulos, N., Macias-Romero, C., Cremer, P.S., Petersen, P.B., Tocci, G., Wilkins, D.M., Liang, C., Ceriotti, M., Roke, S. (2016). »» Electrolytes induce long-range orientational order and free energy changes in the H-bond network of bulk water. Science Advances 2 (4): e1501891. »» Macias-Romero, C., Zubkovs, V., Wang, S. and Roke, S. (2016) Wide-field medium-repetition-rate multiphoton microscopy reduces photodamage of living cells. Biomedical Optics Express 7 (4): 1458. »» Smolentsev, N., Lütgebaucks, C., Okur, H. I., De Beer, A. G. F. and Roke, S. (2016) Intermolecular headgroup interaction and hydration as driving forces for lipid transmembrane asymmetry. Journal of the American Chemical Society, 138 (12) 4053-4060. »» Chen, Y., Jena, K.C., Lütgebaucks, C., Okur, H.I. and Roke, S. (2015) Three dimensional nano ‘Langmuir trough’ for lipid studies. Nano Lett.15: 5558−5563.

113

Stellacci Lab Francesco Stellacci - Full Professor - School of Engineering (STI) - Director of Integrative Food and Nutrition Center

Francesco Stellacci graduated in Materials Engineering at the Politecnico di Milano in 1998 with a thesis on photochromic polymers with Prof. Giuseppe Zerbi and Mariacarla Gallazzi. In 1999 he moved to the Chemistry Department of the University of Arizona for as a post-doc in the group of Joe Perry in close collaboration with the group of Seth Marder. In 2002 he moved to the Department of Materials Science and Engineering at the Massachusetts Institute of Technology as an assistant professor. He was then promoted to associate without (2006) and with tenure (2009). In 2010 he moved to the Institute of Materials at EPFL as a full Professor.

114

sunmil.epfl.ch

Introduction

Results Obtained

The supramolecular NanoMaterials and Interfaces Laboratory (SuNMIL) is a group of ~15 post-docs and graduate students headed by Prof Francesco Stellacci. SuNMILâ&#x20AC;&#x2122;s mission is to uncover the complex interactions that take place between supramolecular assemblies and the molecular world that surrounds them. To achieve this goal novel materials are synthesizes and characterized. A special attention is devoted to the creation, characterization, and understanding of supramolecular interfaces that present nanoscale domains. The group has made important contributions in nanoscience and nanotechnology, as well as in the science and engineering of supramolecular materials. It was the first to show the influence of morphology and curvature of NPs on controlling the conformation of the ligands in a monolayer molecular shell surrounding a metal nanoparticle. It has also shown the significance of morphology of mixed-ligand shell coated gold nanoparticles in their interactions with cell membranes, bacteria and viruses. Recent work has shown that only small changes in the mixed-ligand shell can have a very dramatic effect on a gold nanoparticles interaction with specific human pathogen viral strains.

Consolidated research relating to the study, characterisation and understanding of the interaction of nanoparticles with viruses or proteins.

Keywords Nanomaterials, supramolecular, advanced materials, interfaces, nanoscale

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Valeria Cagno Matej Janecek Emma-Rose Janecek Samuel Jones Alejandro Fernandez Lapresta Adam Sobczuk Huayan Yang PhD Students

Plots showing decreased viral titer after treatment with mercaptoundecyl sulphonic acid (MUS), Octane thiol (OT) mixed-ligand gold nanoparticles. (HPV – human papilloma virus, RSV – Respiratory syncytial virus, HSV2 – Herpes Simplex virus, VSV LV – vesicular stomatitis virus pseudo typed lenti virus)

Sergio Allegri Evangelia-Nefeli Athanasopoulou Ahmet Bekdemir Urszula Cendrowska Elif Bekdemir Ertem Simone Giaveri Zekiye Pelin Guven Paulo H. Silva Jacob Ozgun Kocabiyik Zhi Luo Daniel Migliozzi Anna Murello Marie Mueller Nikolaos Nianias Senior scientist

Quy Khac Ong

Administrative Assistants

Chiara Donini

Selected Publications »» Atukorale, P. U., Yang, Y.S., Bekdemir, A., Carney, R. P., Silva, P. J., Watson, N., Stellacci, F. and Irvine, D. J. (2015) Influence of the glycocalyx and plasma membrane composition on amphiphilic gold nanoparticles association with erythrocytes. Nanoscale 7: 11420. »» Le Ouay, B. and Stellacci, F. (2015) Antibacterial activity of silver nanoparticles: A surface science insight. Nano Today 10(3): 339. »» Salvati, E., Stellacci, F. and Krol, S. (2015) Nanosensors for early cancer detection and for therapeutic drug monitoring. Nanomedicine 10(23):3495. »» Sanchez-Ferrer, A., Carney, R. P., Stellacci, F., Mezzenga, R. and Isa, L. (2015) Isolation and characterization of monodisperse core shell nanoparticles fractions. Langmuir 31(41):11179. »» Ricci, M., Segura, J. J., Erickson, B. W., Fantner, G., Stellacci, F. and Voitchovsky, K. (2015), Growth and dissolution of calcite in the presence of adsorbed stearic acid. Langmuir 31(27):7563. »» Bekdemir, A. and Stellacci, F. A. (2016) Centrifugation-based physicochemical characterization method for the interaction between proteins and nanoparticles. Nature Communications 7:1321. »» Pelliccia, M., Andreozzi, P., Paulose, J., D’Alicarnasso, M., Cagno, V., Donalisio, M., Civra, A., Broeckel, R. M., Haese, N., Silva, P.J., Majormaki, V., Strebow, D.N., Lembo, D., Stellacci, F., Vitelli, V. and Krol, S. (2016) A Additives for vaccine storage to improve thermal stability of adenoviruses from hours to months. Nature Communications 7:1350.

115

Stergiopoulos Lab Nikos Stergiopoulos - Full Professor - School of Engineering (STI)

Nikos Stergiopulos studied Mechanical Engineering at the National Technical University of Athens, Greece and obtained his Ph.D. in Biomedical Engineering from Iowa State University in 1990. His research interests are Hemodynamics, Cardiovascular Mechanics and Medical Implant Technology. He has authored more than 150 publications and holds more than 15 patents in medical technology. He co-founded EndoArt, world leader in telemetric implants for the treatment of congenital heart disease and morbid obesity, Antlia SA, developer of implantable drug delivery pumps and Rheon Medical, developer of the implantable shunt for the surgical treatment of glaucoma.

116

lhtc.epfl.ch

Introduction

Results Obtained

The Laboratory of Hemodynamics and Cardiovascular Technology (LHTC) focuses is on the relation between blood flow and the development, progression and regression of cardiovascular disease. We study also the interaction between the heart and arterial system and the resulting wave propagation phenomena, with the goal of understanding hypertension and aging and also for improving diagnostic and blood flow monitoring techniques. Development of implants and non-invasive or mini-invasive technologies for the diagnosis and treatment of disease is also a major objective.

We found that diminazene, an angiotensin converting enzyme 2 (ACE2) activator compound, ameliorates atherosclerotic plaque composition and increases stability (Vascul Pharmacol 2015). We also showed that treatment with methyl beta-cyclodextrin reduced atherosclerotic plaque size by improving triglyceride serum levels and Th1-mediated response (Vascul Pharmacol 2015). Furthermore, we observed that anti-apoA-1 auto-antibodies seem to be active mediators of atherosclerotic plaque vulnerability, myocardial necrosis, and mortality in mice through TLR2- and TLR4-mediated pathways (Thromb Haemost 2015). We demonstrated that ACE2 plays an important role in erectile function, while diminazene improved hypercholesterolemia-induced corpus cavernosum injury ( J Sex Med 2015). Interestingly, we demonstrated that electro-stimulation of the cavernosal nerve evokes penile erection and might represent an alternative to treat post-prostatectomy erectile dysfunction.

Keywords cardiovascular mechanics, hemodynamics, atherosclerosis, hypertension, ocular mechanics and glaucoma filtration surgery, erectile dysfunction, implantable devices

Using Phase-Contrast X-ray Tomographic Microscopy (PCXTM) and PCXTM-guided histology we demonstrated that small side branches play a pivotal role in the formation of dissecting aneurysms in angiotensin II-infused mice (Cardiovasc Res, 2015a). We subsequently demonstrated how and why the abdominal lesions of this established mouse model had been interpreted differently in the past (Curr Pharm Des, 2015). We performed a metaanalysis to warn for the risk of publication bias (Cardiovasc Res, 2015b) and used in vivo ultrasound and pressure measurements to characterize the aortic properties of these small animals in vivo (PloS One, 2015). Via computational Fluid-Structure simulations we demonstrated that in control mice the highest stresses occur near the branches (Ann Biomed Eng, 2015). We investigated the formation of ascending aneurysms in mice with PCXTM and PCXTM-guided histology (ATVB 2016), and developed a 1D model to simulate pressures and flows in the arterial circulation of healthy mice (Altex 2016).

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Rodrigo Araujo Fraga da Silva Bram Trachet Augusto Martins Lima Mauro Ferraro PhD Students

Lydia Aslanidou Maiia Bragina Michael Sturny Stamatia Pagoulatou Research & technical staff Left: 3D representation based on PCXTM images of a dissecting aneurysm, with tunica media in (transparent) white, intramural hematoma in (transparent) orange, blood filled lumen in red. Top: PCXTM-guided histology showing (i) endothelization of the false channel parallel to an unchanged aortic lumen (CD31, endothelium in blue, left stain) and (ii) apparent dilatation as the hemorrhage resulting from the tear in the tunica media is enclosed within the distended adventitia (combined SR and Miller, media in brown, adventitia in red, right stain). Bottom: 2D PCXTM image with 6.5 micron resolution shows how a false channel is formed within the dissecting aneurysm (left); photograph of the gross anatomy (right).

Michel Bachmann Stéphane Bigler Fabiana Fraga Sébastien Pittet Sylvain Roy

Administrative Assistants

Sylvia Widmer

Selected Publications »» Trachet, B., Piersigilli, A., Fraga-Silva, R.A., Aslanidou, L., Sordet-Dessimoz, J., Astolfo, A., Stampanoni, M.F., Segers, P. and Stergiopulos, N. (2016) Ascending aortic aneurysm in angiotensin II-infused mice: formation, progression, and the role of focal dissections. Arterioscler Thromb Vasc Biol 36(4): 673-681. »» Aslanidou, L., Trachet, B., Reymond, P., Fraga-Silva, R.A., Segers, P. and Stergiopulos, N. (2016) A 1D model of the arterial circulation in mice. ALTEX 33(1): 13-28. »» Trachet, B., Fraga-Silva, R.A., Londono, F.J., Swillens, A., Stergiopulos, N. and Segers, P. (2015) Performance comparison of ultrasound-based methods to assess aortic diameter and stiffness in normal and aneurysmal mice. PLoS One 10(5): e0129007. »» Trachet, B., Fraga-Silva, R.A., Jacquet, P., Segers, P. and Stergiopulos, N. (2015) Dissecting abdominal aortic aneurysm in Angiotensin II-infused mice: the importance of imaging. Curr Pharm Des 21(28): 4049-4060. »» Fraga-Silva, R.A., Montecucco. F., Costa-Fraga. F.P., Nencioni, A., Caffa, I., Bragina, M.E., Mach, F., Raizada, M.K., Santos, R.A., da Silva, R.F. and Stergiopulos, N. (2015) Diminazene enhances stability of atherosclerotic plaques in ApoE-deficient mice. Vascul Pharmacol 74: 103-113. »» Trachet, B., Fraga-Silva, R.A., A. Piersigilli, A., Tedgui, A., Sordet-Dessimoz, J., Astolfo, A., Van der Donckt, C., Modregger, P., Stampanoni, M.F., Segers, P. and Stergiopulos, N. (2015) Dissecting abdominal aortic aneurysm in Ang II-infused mice: suprarenal branch ruptures and apparent luminal dilatation. Cardiovasc Res 105(2): 213-222. »» Fraga-Silva, R. A., Costa-Fraga, F.P., Montecucco, F., Sturny, M., Faye, Y., Mach, F., Pelli, G., Shenoy, V., da Silva, R.F., Raizada, M.K., Santos, R.A. and Stergiopulos, N. (2015) Diminazene protects corpus cavernosum against hypercholesterolemia-induced injury. J Sex Med 12(2): 289-302

117

Van de Ville Lab Dimitri Van de Ville - Associate Professor - Center for Neuroprosthetics - School of Engineering (STI)

M.S. and Ph.D. in Computer Sciences from Ghent University, Belgium (1998, 2002), Post-doctoral Fellow at EPFL (2002-2005), Junior Group Leader of the CIBM Signal Processing Unit at University of Geneva (2005-2009), awarded SNSF professorship (2009), Associate Professor of Bioengineering since 2015 jointly affiliated with University of Geneva (Department of Radiology & Medical Informatics).

118

miplab.epfl.ch

Introduction

Results Obtained

The Medical Image Processing Laboratory (MIP:lab) pursues the development and integration of innovative data-processing tools at various stages of the acquisition, analysis, and interpretation pipeline of neuroimaging data. We aim at obtaining new insights into brain function & dysfunction by approaches that are based on modeling the brain as a networked and as a dynamical system. We develop new signatures of brain function that allow interpreting and predicting cognitive and clinical conditions, and also provide avenues for neurofeedback based on real-time fMRI.

The first highlight is on modeling of functional brain networks at the systems level; i.e., based on whole-brain functional magnetic resonance imaging (fMRI). Using graph theory, multiscale techniques, and pattern recognition we are able to identify and characterize brain networks in a meaningful way during cognitive tasks, as well as alterations by neurological conditions, which opens the potential for new imaging-based biomarkers that might for instance complement neuropsychological testing in prodromal stage of Alzheimerâ&#x20AC;&#x2122;s Disease. The second highlight is on temporal dynamics of these networks during spontaneous activity. We have pioneered subspace discovery methods for dynamic functional connectivity, which reveal meaningful interactions between large-scale distributed networks in terms of ongoing fluctuations. These techniques bring us closer to capturing the global brain state, which is essential for future development of invasive and non-invasive neuroprosthetics, such as neurofeedback based on real-time fMRI. Finally, we also relate the slow dynamics of fMRI back to fast millisecond-scale EEG signals.

Keywords Computational neuroimaging, network science, brain dynamics, signal processing, functional magnetic resonance imaging, electroencephalography

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Luca Dodero Zafer Dogan Yury Koush Djalel Meskaldji Maria Giulia Preti Gwladys Rey Roy Salomon* PhD Students

Visualization of the human dynamic functional connectome, which is used to investigate functional interactions between brain regions. Brain regions are associated to rows/columns of the matrix. An element indicates the level of functional connectivity for each pair of brain regions, which is the strength of an edge between those regions. The color-coding goes from blue (anti-correlated activity) to red (correlated activity). In state-of-the-art approaches developed in the lab, we study the changes of connectivity over time, making the matrix time-dependent as evoked by the motion blur effect.

Thomas Bolton Eva Blondiaux* Kirsten Emmert Lorena Freitas Valeria Kebets Nawal Kinany** Rotem Kopel Naghmeh Ghazaleh David Nguyen Anjali Tarun Daniela Zöller jointly with LNCO/ Blanke Lab ** jointly with TNE/ Micera Lab *

Master’s Students

Isabel Barradas Claudia Bigoni Nicolo Capobianco Helena Cascos Robin Demesmaeker Ilya Grygoryev Yasaman Izadmehr Anaïs Haget Serafeim Loukas Martin Ndengera Gian Franco Piredda Nemanja Masala Giorgio Policella Antonios Poulakakis Merel Van der Thiel Laura Vilaclara Anna Vybornova Visiting Faculty

Omar Al-Kadi Michal Bola Younes Farouj Engineer

Nicolas Gninenko Interns

Akshay Kumar Stefano Moia Administrative Assistant

Selected Publications »» »» »» »» »» »» »»

Emmert, K. et al. (2016) Meta-Analysis of Real-Time fMRI Neurofeedback Studies using Individual Participant Data: How Is Brain Regulation Mediated? NeuroImage. 124:806-812. Kasten, J. A., Vetterli, T., Lazeyras, F., Van De Ville, D. (2016) 3D-Printed Shepp-Logan Phantom as a Real-World Benchmark for MRI. Magnetic Resonance in Medicine, 75:287-294. Kasten, J. A., Klauser, A., Lazeyras, F., Van De Ville, D. (2016) Magnetic Resonance Spectroscopic Imaging at Superresolution: Overview and Perspectives. Journal of Magnetic Resonance, 263:193-208. Meskaldji, D. E. et al. (2016) Prediction of Long-term Memory Scores in MCI Based on Resting-State fMRI. Neuroimage: Clinical, 12:785-795. Pirondini, E., Vybornova, A., Coscia, M., Van De Ville, D. (2016) Spectral Method for Generating Surrogate Graph Signals. IEEE Signal Processing Letters, 23:1275-1278. Karahanoglu, F. I., Van De Ville, D. (2015) Transient Brain Activity Disentangles fMRI Resting-date Dynamics in Terms of Spatially and Temporally Overlapping Networks. Nature Communications. 6:7751.

Manuela Da Silva

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GHI

Global Health Institute Since its foundation in 2006, the Global Health Institute (GHI) has contributed to the understanding, diagnosis, prevention and treatment of infectious diseases, which account for half of the deaths in the developing world and claim 18 million human lives every year. The GHI is comprised of 10 groups, all engaged in different facets of research linked to human health but with strong emphasis on diseases of truly global importance such as HIV/AIDS and tuberculosis. The current workforce comprises ~120 students, postdoctoral-fellows, technicians and scientists, representing more than 25 different nations. The research portfolio at the GHI includes a balanced mixture of basic and translational work. Mechanisms of host-pathogen interactions and innate and acquired immunity against disease are being studied using multidisciplinary approaches. A unique feature of the GHI is its ability to tackle crucial world health issues by harnessing cutting edge technologies developed elsewhere at EPFL to underpin research on diagnostics, drugs and vaccines as well as disease mechanisms. Prominent amongst these are the nanotechnologies, micro-engineering and bioinformatics. Aware of the impact of the microbiota on human health, the GHI is actively developing new programs in this area and in digital epidemiology. http://sv.epfl.ch/GHI

Stewart Cole - Director

121

Ablasser Lab Andrea Ablasser -Tenure-Track Assistant Professor

After graduating in medicine at the University of Munich, Germany in 2008, Andrea Ablasser moved to the University of Bonn to do her post-doctoral research which focused on understanding innate nucleic acid sensing mechanism that lead to an antiviral immune response. In 2014, the Ablasser lab was opened as part of the Global Health Institute in the School of Life Sciences of the EPFL.

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ablasserlab.epfl.ch

Introduction

Results Obtained

The sensing of foreign DNA is crucial for host defense against several pathogens. In the cytosol the enzyme cyclic GMP-AMP synthase (cGAS) is critical for the recognition of pathogen-derived DNA and provides key signals that initiate immune responses. Recently, we have shown that cGAS is an innate sensor for Mycobacterium tuberculosis. Beyond infection accumulating evidence indicates that cGAS is also active during autoimmune diseases and controls immune responses that underlie cancer immunosurveillance, which form the basis of our current research efforts.

Recently we have shown that cGAS is an essential for the innate recognition of Mycobacterium tuberculosis by macrophages.

Keywords Innate immunity, nucleic acid sensing, type I interferons.

GHI - Global Health Institute

Team Members Postdoctoral Fellows

Muhammet F. Gulen Baptiste Guey PhD Students

Simone Haag Sélène Glück Technicians

Nathalie Jordan Administrative Assistants

Valérie Pahud

cGAS-mediated signaling pathways Upon DNA sensing cGAS produces cGAMP, which activates STING to regulate de novo gene expression. STING-dependent signaling can also be activated by sensing cGAMP produced by neighboring cells and transferred through gap junctions or by recognition of cGAMP delivered in viral particles.

Selected Publications »» Wassermann, R., Gulen, M.F., Sala, C., Garcia Perin, S., Lou, Y., Rybniker, J., Schmid-Burgk, J.L., Schmidt, T., Hornung, V., Cole, S.T. and Ablasser A. (2015) The ESX-1 secretion system of Mycobacterium tuberculosis differentially regulates cGAS- and inflammasome-dependent intracellular immune responses. Cell Host & Microbe 17(6): 799-810.

123

Blokesch Lab Melanie Blokesch -Tenure-Track Assistant Professor

Melanie Blokesch studied biology at Ludwig-MaximiliansUniversity (LMU) in Munich, Germany. In 2004 she obtained her PhD degree with highest honor from the LMU Munich based on her work on bacterial hydrogen production and metalloenzyme maturation. From 2005 to 2009 she worked as a postdoctoral fellow at Stanford University (USA) before being appointed as tenure-track Assistant Professor (2009) and Associate Professor (2016) within the School of Life Sciences of EPFL.

blokesch-lab.epfl.ch

Introduction

Results Obtained

Our research focuses on the question “How and why do some bacteria evolve to become human pathogens?” Our model organism is Vibrio cholerae, the causative agent of cholera. Cholera is still widespread around the world with up to 4 million cases every year. The ultimate goal of our research is to link the ecology and evolution of the organism to the epidemiology of the disease. V. cholerae is a normal member of aquatic habitats and is often found associated with zooplankton. Under such growth conditions, V. cholerae induces a developmental program known as natural competence for transformation. Natural competence allows the bacterium to take up free DNA from the environment and to recombine this genetic material into its own genome. As a consequence, natural competence fosters horizontal gene transfer in bacteria and contributes to the spread of antibiotic resistance genes and virulence traits. Our previous work deciphered the regulatory circuits that drive natural competence in this organism and the molecular mechanism of the DNA uptake process. We also demonstrated that the type VI secretion system (T6SS) is part of the natural competence regulon, and as such, its production is induced by chitinous surfaces. The T6SS is a molecular weapon that is considered a virulence factor in many Gram-negative pathogens. As a consequence, chitininduced V. cholerae kill neighboring bacteria and absorb the released DNA via their DNA-uptake machinery, which contributes to the diversification of the pathogen’s genes and thus to its evolution. Apart from these topics, we are also interested in the interaction of V. cholerae with environmental hosts and the role that virulence factors play in this context. We suggest that predation is a driving force behind the evolution of pathogenicity in V. cholerae.

Killing for DNA: The type VI secretion system of Vibrio cholerae fosters horizontal gene transfer V. cholerae is considered an important model organism for elucidating virulence regulation. In this context, the involvement of bacterial cell-tocell communication known as quorum sensing (QS) has been extensively studied. More recently, researchers also became interested in the contribution of a molecular killing device, the type VI secretion system (T6SS), towards pathogenesis. However, much less is known about the bacterium’s environmental lifestyle, where it often associates with the carbon-rich chitinous surfaces (see Figure) and where it has to compete with other bacteria. We showed that growth on such chitinous surfaces triggers the production of the T6SS, which enhances horizontal gene transfer by deliberate killing of neighboring bacteria followed by the absorption up of their DNA. V. cholerae establishes a replication niche within free-living amoebae A driving force behind the evolution of pathogenic bacteria is predation. Current hypotheses suggest that virulence mechanisms might reflect immediate adaptations to predation in natural environments. We therefore investigated the interaction of V. cholerae with a co-habiting aquatic amoeba, Acanthamoeba castellanii, at the single-cell level. We observed that a subset of V. cholerae bacteria is capable of resisting digestion by A. castellanii; moreover, the undigested bacteria were either exocytosed by the amoebae or established a replication niche within the osmoregulatory organ of the amoeba. In the latter case, efficient growth of the bacteria occured within A. castellanii. Ultimately, V. cholerae returned to its aquatic habitat through lysis of the amoeba. This study therefore describes a new host-pathogen interaction for V. cholerae.

Keywords Horizontal gene transfer, evolution of pathogens, bacterial communities, regulatory networks, cholera.

124

GHI - Global Health Institute

Team Members Postdoctoral Fellows

David Adams Milena Jaskólska Lisa Metzger Charles Van der Henst PhD Students

Natália Drebes Dörr Noémie Matthey Technicians

Sandrine Stutzmann Candice Stoudmann Julien Chambaud (apprentice) Bioinformatician

Anne-Catherine Portmann Administrative Assistants

Marisa Marciano Wynn

In its natural habitat, the human pathogen Vibrio cholerae colonizes chitinous surfaces as shown in this SEM image. Such colonization fosters close contact between bacteria, which enhances the transfer of genetic material by means of horizontal gene transfer. Image credit: M. Blokesch & G. Knott.

Selected Publications »» »» »» »» »» »» »»

Metzger, L.C., Stutzmann, S., Scrignari, T., Van der Henst, C., Matthey, N. and Blokesch, M. (2016) Independent regulation of type VI secretion in Vibrio cholerae by TfoX and TfoY. Cell Rep. 15:951-958. Stutzmann, S. and Blokesch, M. (2016) Circulation of a quorum-sensing-impaired variant of Vibrio cholerae strain C6706 masks important phenotypes. mSphere 1:e000098-16. Matthey, N. and Blokesch, M. (2016) The DNA Uptake Process of Naturally Competent Vibrio cholerae. Trends Microbiol. 24:98-110. Van der Henst, C., Scrignari, T., Maclachlan, C. and Blokesch, M. (2016) An intracellular replication niche for Vibrio cholerae in the amoeba Acanthamoeba castellanii. ISME J. 10:897-910. Metzger, L.C. and Blokesch, M. (2016) Regulation of competence-mediated horizontal gene transfer in the natural habitat of Vibrio cholerae. Curr. Opin. Microbiol. 30:1-7. Blokesch, M. (2015) Competence-induced type VI secretion might foster intestinal colonization by Vibrio cholerae. BioEssays 37:1163-1168. Borgeaud, S., Metzger, L.C., Scrignari, T. and Blokesch, M. (2015) The type VI secretion system of Vibrio cholerae fosters horizontal gene transfer. Science 347:63-67.

125

Cole Lab Stewart T. Cole - Full Professor - Director of the Global Health Institute (GHI)

Professor Stewart Cole is an internationally acclaimed authority on the pathogenicity, drug resistance, evolution and genomics of the tubercle and leprosy bacilli. His laboratory is currently focused on discovering new drugs to treat tuberculosis. The findings of his research are of direct relevance to public health and disease-control in both the developing world and the industrialized nations. He has published over 300 scientific articles and been honored by many professional prizes, decorations and awards.

cole-lab.epfl.ch

Introduction

Results Obtained

UPCOL uses a multidisciplinary approach to tackle global health problems such as tuberculosis (TB), Buruli ulcer and leprosy. Using screening and genome biology as platforms we are actively involved in discovering new drugs to treat TB and other mycobacterial diseases. To date, we have discovered many interesting leads for development including the natural product, pyridomycin, the thienopyrimidines, the carboxyquinoxalines, the quinazolines and, above all, the benzothiazinone (BTZ) series. The latter gave rise to PBTZ169, a highly potent drug candidate that irreversibly inhibits an essential enzyme called DprE1, which plays a critical role in the biogenesis of the mycobacterial cell wall. The preclinical development of PBTZ169 was undertaken by the not-for-profit foundation Innovative Medicines for Tuberculosis (iM4TB), an EPFL spin-off. In 2017, iM4TB will supervise the first clinical trials of PBTZ169 to be held in Switzerland.

TB Drug Discovery Among our most notable achievements were taking the BTZ drugs from discovery to the clinic. We have also shown that PBTZ169 is compatible with all leading TB drugs and drug candidates and thus has the potential for inclusion in a new combination therapy. PBTZ169 is currently in phase 2 clinical trials in Russia. We are now developing an antivirulence approach to drug discovery by inhibiting the ESX-1 system.

Keywords Tuberculosis, leprosy, drug discovery, pathogenesis.

Protein secretion and pathogenicity The ESX-1 secretion system, the major virulence determinant of M. tuberculosis, exports small helical-hairpin proteins from the ESAT-6 family as well as other effector proteins of unknown function. We are using an integrated approach to elucidate the organization, architecture, structure and function of this ATPdriven secretory apparatus. We recently showed that the EspC component forms a filamentous structure in the cell envelope and could serve as a needle or a piston for protein export. A regulatory map of the M. tuberculosis genome We are studying gene regulation by using chromatin-immunoprecipitation of DNA-binding proteins in conjunction with high-throughput sequencing to localize the various binding sites along the genome. All the RNA polymerase, NusA, PhoP and EspR binding sites were mapped in two different strains in two different growth phases and the role of several nucleoid-associated proteins, including H-NS and mIHF, was investigated. Phylogeography of leprosy Leprosy remains a serious public health problem. We have developed an epidemiological tool that employs whole genome sequence (WGS) analysis of M. leprae, to monitor transmission of the disease and have used this to retrace the spread of leprosy and to explore animal reservoirs. By this means we showed that red squirrels in the UK are naturally infected with M. leprae. Together with the WHO, we are also monitoring the emergence of drug resistance worldwide using WGS and skin biopsies.

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GHI - Global Health Institute

Team Members Postdoctoral Fellows

Andrej Benjak Andréanne Lupien Jérémie Piton Florence Pojer Claudia Sala Rita Székely PhD Students

Charlotte Avanzi Shi-Yan Caroline Foo Nina Odermatt Paloma Arnedo Soler Raphael Sommer Lou Ye Master’s Students

Chloé Loiseau Technicians

Stefanie Boy-Röttiger Philippe Busso Anthony Vocat A red squirrel with signs of leprosy on its ear.

Administrative Assistants

Cécile Prébandier

Selected Publications »» Lou, Y., Rybniker, J., Sala, C. and Cole, S.T. (2017) EspC forms a filamentous structure in the cell envelope of Mycobacterium tuberculosis and impacts ESX-1 secretion. Mol Microbiol. 103: 26-38. »» Piton, J., Foo, C.S. and Cole, S.T. (2017) Structural studies of Mycobacterium tuberculosis DprE1 interacting with its inhibitors. Drug Discovery Today 22:526-533 »» Foo, C. S., Lechartier, B., Kolly, G.S., Boy-Rottger, S., Neres, J., Rybniker, J., Lupien, A., Sala, C., Piton, J. and Cole, S.T. (2016) Characterization of DprE1-Mediated Benzothiazinone Resistance in Mycobacterium tuberculosis. Antimicrobial Agents Chemother. 60: 6451-6459. »» Cole, S.T. (2016) Inhibiting Mycobacterium tuberculosis within and without. Philos Trans R Soc Lond B Biol Sci. 371: pii 20150506. »» Benjak, A., Uplekar, S., Zhang, M.,Piton, J., Cole, S.T. and Sala, C. (2016) Genomic and transcriptomic analysis of the streptomycin-dependent Mycobacterium tuberculosis strain 18b. BMC Genomics 17: 190. »» Avanzi, C., Del-Pozo, J., Benjak, A., Stevenson, K., Simpson, V.R., Busso, P., McLuckie, J., Loiseau, C., Lawton, C., Schoening, J., Shaw, D.J., Piton,J., Vera-Cabrera, L., Velarde-Felix, J.S., McDermott, F., Gordon, S.V., Cole, S.T. and Meredith, A.L. (2016) Red squirrels in the British Isles are infected with leprosy bacilli. Science 354: 744-747.

127

Fellay Lab Jacques Fellay - SNF Professor

Jacques Fellay is a medical scientist with expertise in infectious diseases and human genomics. He obtained an MD from the University of Lausanne and a PhD form University of Utrecht. Jacques Fellay joined the EPFL in April 2011 as an SNSF Professor; he is also a Group Leader at the Swiss Institute of Bioinformatics and a Visiting Physician at the Service of Infectious Diseases of the CHUV in Lausanne.

fellay-lab.epfl.ch

Introduction

Results Obtained

Research in the Fellay lab focuses on human genomics of infection and immunity. We explore the genetic roots of inter-individual differences in response to various infectious diseases, with a particular emphasis on genomic interactions between pathogens and their human hosts. At the crossroad between basic science and the clinical world, we are committed to translational genomic research, aiming at identifying, validating and bringing to clinical use genetic markers of susceptibility to infectious diseases.

During the two past years, our lab has focused its research on four synergistic areas.

We use a combination of genomic technologies, bioinformatic analyses and functional studies to understand the most severe clinical presentations of common infections (including diseases caused by respiratory viruses, Hepatitis B virus, HIV, group B Streptococcus, and others), and the impact of host genetic diversity on intra-host pathogen evolution. Methods include genomewide genotyping and association analysis, exome/genome sequencing and transcriptomics. We also collaborate with colleagues from the EPFL IC faculty to develop innovative solutions for genomic privacy, an essential trust-building component on to road toward genomic-based medicine.

Keywords Human genomics, infectious diseases, host-pathogen interactions, deepsequencing, translational genomics, genomic privacy, personalized medicine

We first used genome-wide genotyping and imputation, association analysis and in-depth dissection of signals present in the HLA region to delineate the impact of common human genetic variation on multiple phenotypes, including spontaneous HIV control (McLaren et al. 2015); immune activation and microbial translocation during chronic HIV infection (Perkins et al. 2015); and humoral response to common viruses (Hammer et al. 2015). Second, we investigated the influence of rare genetic variants on several infectious diseases using exome and RNA sequencing of carefully selected and thoroughly characterized clinical cases. The strategy has been applied to children suffering from severe respiratory symptoms due to common viruses; to liver transplant recipients who developed fulminant hepatitis upon infection with HBV; and to neonates with bacterial sepsis in the absence of any comorbidity (Asgari et al. 2016). Potentially causal genetic variants are validated genetically and then followed up functionally. A third line of research is the joint of human and viral genomes (described in Bartha et al. eLife 2013). We expanded this “genome-to-genome” strategy to integrate intra-host genetic diversity of chronic viruses, and to use it for bacterial pathogens. This pioneering work allowed us to start several academic and industrial collaborations. Finally, we also continued our work on genomic privacy in strong collaboration with the group of Prof. J.P. Hubaux (EPFL IC). In particular, we contributed to the first utilization of homomorphic encryption in the clinical setting, by running a pilot genomic study in collaboration with the seven outpatient clinics of the Swiss HIV Cohort Study. We demonstrated that it is feasible to ensure both patient privacy and usability of human genetic data in the context of HIV treatment (McLaren et al. 2016).

128

GHI - Global Health Institute

Team Members Postdoctoral Fellows

Christian Hammer Nimisha Chaturvedi Alessandro Borghesi Thomas Junier Samira Asgari PhD Students

Petar Scepanovic Christian Thorball Olivier Naret Master’s Students

Flavia Hodel

Administrative Assistants

Marisa Marciano Wynn

Five amino acid positions in the (A) HLA-B and (B) HLA-A proteins significantly associate with HIV viral load. They all line the HLA peptide-binding groove and explain the majority of the genome-wide association signal. (C) Effect on viral load of individual amino acid residues at each position.

Selected Publications »» McLaren, P.J., Coulonges, C., Bartha, I., Lenz, T.L., Deutsch, A.J., et al. (2015) Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load. PNAS 112(47):14658-14663. »» Bartha, I., Rausell, A., McLaren, P.J., Mohammadi, P., Tardaguila, M., et al. (2015) The Characteristics of Heterozygous Protein Truncating Variants in the Human Genome. PLoS Computational Biology 11(12):e1004647. »» Hammer, C., Begemann, M., McLaren, P.J., Bartha, I., Michel, A., et al. (2015) Amino acid variation in HLA class II proteins is a major determinant of humoral response to common viruses. American Journal of Human Genetics 97(5):738-743. »» Perkins, M., Bartha, I., Timmer, K., Liebner, J.C., Wollinsky, D., et al. (2015) The interplay between host genetic variation, viral replication and microbial translocation in untreated HIV-infected individuals. Journal of Infectious Diseases 212(4):578-584. »» Rusert, P., Kouyos, R.D., Kadelka, C., Ebner, H., Schanz, M., et al. (2016.) Determinants of HIV-1 broadly neutralizing antibody induction. Nature Medicine 22(11):1260-1267. »» Asgari, S., McLaren, P.J., Peake, J., Wong, M., Wong, R., et al. (2016). Exome sequencing reveals primary immunodeficiencies in children with community-acquired pseudomonas aeruginosa sepsis. Frontiers in Immunology 7:357. »» McLaren, P.J., Raisaro, J.L., Aouri, M., Rotger, M., Ayday, E., et al. (2016)Privacy-preserving genomic testing in the clinic - a model using HIV treatment. Genetics in Medicine 18(8):814-822.

129

Harris Lab Nicola Harris - Associate Professor

NNicola Harris was born and completed her PhD thesis in New Zealand. In 2002 she moved to ZĂźrich, Switzerland as a postdoctoral fellow in the lab of Hans Hengartner and the Nobel Laureate Rolf Zinkernagel. In July 2005 she joined the ETH Zurich as an Assistant Professor and in August 2009 she moved to the Global Health Institute, Faculty of Life Sciences, EPFL.

harris-lab.epfl.ch

Introduction

Results Obtained

The intestinal mucosa represents an extensive interface between the body and the external environment that is constantly exposed to environmental microorganisms. Amongst these intestinal bacteria are present in vast numbers (1012 per gram of intestinal contents) in all individuals at all times. Worms (helminths) can also establish chronic infections within our intestines and were present in a near ubiquitous manner throughout mammalian evolution. Today intestinal helminths still infect approximately 1/3 of the worldâ&#x20AC;&#x2122;s population, with the heaviest infections found in children living in poor communities within developing countries.

Type 2 immunity and protection against helminths: In the past few years we have expanded on our findings that immune antibodies limit helminth infection by showing that these small proteins function by activating immune cells called phagocytes (or macrophages) to attach to and paralyze these large multicellular parasites. We also identified the antibody isotypes and host receptors involved in this response and found a very surprisingly role for antibodies normally associated with bacterial but not helminth infection. We then expanded on these studies to show that antibodies directed against helminths also functioned to activate the macrophages to release soluble factors that promoted wound repair. Lastly we investigated the factors regulating antibody production and uncovered a role type 2 immune responses in promoting the remodelling of lymphoid organs to allow new B cell rich follicles to form which support antibody production. This remodelling involved a previously unknown interaction between B cells and stromal cells within the lymphoid tissues.

Our work aims to investigate how type 2 immunity limits the number of helminths able to establish long-term infection in the intestine and how it also promotes wound repair following the migration of helminth larvae through tissues. We are also actively investigating how low burdens of intestinal helminths can actually improve health by limiting the development of chronic inflammatory disease (allergy and autoimmunity) and protecting against excessive weight gain (obesity). With regard to this latter aim we are performing detailed studies of how helminth infection impacts on bacterial communities within the intestine to modulate both the species present and their production of health promoting metabolites.

Keywords Intestinal helminths, intestinal bacteria, type 2 immunity, allergy, obesity

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Helminth-bacterial interactions and the modulation of allergy: In a separate project we investigated whether helminths impact on the rich and complex community of bacteria within the intestine. We were able to demonstrate that helminth infection altered intestinal bacterial communities to promote the production of small metabolites, called short chain fatty acids (SCFA) which promoted the expansion of a specialized subset of immune cells that functioned to limit inflammation and reduce the severity of allergy asthma. This work uncovered a previously unrecognized role for the microbiota in helminth-induced modulation of host immunity and identified one of the molecular pathways involved in this regulation. Such insight should prove useful for the design of preventative and therapeutic treatment of allergies using microbial compounds. We are now expanding this work to include studies of obesity.

GHI - Global Health Institute

Team Members Postdoctoral Fellows

Tiffany Bouchery Lalit Kumer Dubey Mati Moyet PhD Students

Luc Lebon Alexis Rapin Kathleen Shah Beatrice Volpe Technicians

Manuel Kulagin Audry Chuat Administrative Assistants

Dagmara Dylong

Inflamed lymph node: The picture shows the draining lymph node of an animal with (right panel) or without (left panel) intestinal helminthes. Green areas show follicles containing B cells that produce antibodies and protect the animals against further infection. Red areas show adjacent T cells.

Selected Publications »» Harris, N. (2016) Immunology: The enigmatic tuft cell in immunity. Science 351:1264-1265. »» Kumar Dubey, L., Lebon, L., Mosconi, I., Ying Yang, C., Scandella, E., Ludewig, B., Luther, S. and Harris, N.L. (2016) Lymphotoxin-dependent B 1 cell-FRC crosstalk promotes de novo follicle formation and antibody production following intestinal helminth infection. Cell Reports 15:1527-1541. »» Zaiss, M., Rapin, A., Lebon, L., Dubey, L.K., Mosconi, I., Sarter, K., Piersigili, A., Menin, L., Walker, A. W., Rougemont, J., Paerewijck, O., Geldhof, P., McCoy, K.D., Macpherons, A.J., Croese, J., Giacomin, P.R., Loukas, A., Junt, T., Marsland, B.J. and Harris, N.L. (2015) The intestinal microbiota contributes to the ability of helminths to modulate allergic inflammation. Immunity 43:998–1010. »» Harris, N. (2015) Immunology: Chronic effects of acute infections. Nature 526:509-510. »» Mosconi, I., Dubey, L.K., Volpe, B., Esser-Von Bieren, J., Zaiss, M.M., Lebon, L., Massacand, J.C. and Harris, N. (2015) Parasite proximity drives the expansion of regulatory T cells in Peyer’s Patches following intestinal helminth infection. Infection and Immunity 83: 3657-3665. »» Esser-von Bieren, J., Volpe, B., Sutherland, D.B., Bürgi, J., Verbeek, J.S., Marsland, B.J., Urban, J.F. and Harris, N. (2015) Immune antibodies and helminth products drive CXCR2-dependent macrophage-myofibroblast crosstalk to promote intestinal repair. PLoS Pathogens 11:e31004778. »» Esser-von Bieren, J., Volpe, B., Kulagin, M., Sutherland, D.B., Guiet, R., Seitz, A., Marsland, B.J., Verbeek, J.S., and Harris, N.L. (2015) Antibody-mediated trapping of helminth larvae requires CD11b and Fcγ receptor I. J. Immunol. 194(3):1154-1163.

131

Lemaitre Lab Bruno Lemaitre - Full Professor - Director of the Doctoral Program in Molecular Life Sciences (EDMS)

Bruno Lemaitre obtained his PhD in 1992 with Dario Coen at the University Pierre and Marie Curie (Paris) on the P element transposition in Drosophila. Next, he joined the laboratory of Jules Hoffmann (Strasbourg France) as a research associate where he began the genetic dissection of the Drosophila antimicrobial response. In 1998, he started his own laboratory on Drosophila immunity at the Centre Génétique Moléculaire (Gif-sur-Yvette, France). In 2007, he was appointed professor at EPFL.

lemaitrelab.epfl.ch

Introduction

Results Obtained

Our group uses Drosophila and a range of genetic tools to study physiology at the organismal level. The three main axes of our research are:

Our group uses Drosophila as a model to study physiological processes at the organismal level. We currently have three main axes of research focusing on:

1. Drosophila immunity 2. Drosophila-Spiroplasma interaction 3. Drosophila gut function (including mucosal immunology, epithelium renewal, and metabolism)

Drosophila innate immunity We are interested in the molecular mechanisms underlying phagocytosis, melanization, and encapsulation, three poorly characterized insect immune defense modules. Using single or combined mutations, we analyzed the individual function of three prophenoloxidases, enzymes involved in the melanization reaction. While a specific function can be assigned to each of the prophenoloxidases, knocking out two out of the three genes is required to abolish melanization. An ambitious project to systematically delete all the immunity-related genes is currently in progress.

Our research provides insights into basic biological phenomenon, which are often conserved in humans. They also increase our knowledge about physiology in insects, some of which are vectors of human and plant diseases as well as crop pests.

Keywords Innate immunity, gut homeostasis, host-pathogen interactions, Drosophila, Symbiosis

The Drosophila-Spiroplasma interaction Virtually every insect species harbors facultative bacterial endosymbionts (e.g. Wolbachia etc.) that are transmitted in females to their offspring. In spite of the growing interest in endosymbiosis, very little is known about the molecular mechanisms underlying most endosymbiont-insect interactions. Our laboratory analyses the interaction between Drosophila and its endosymbiont Spiroplasma poulsonii. We have recently shown showed that the growth of Spiroplasma is not controlled by the immune system but by the availability of lipid. This dependence on lipid couples Spiroplasma growth to the nutritional state of its host. In 2015, we also provided the first genome of an endosymbiotic Spiroplasma: S. poulsonii. The digestive tract: an interactive barrier Apart from its central role in digesting and absorbing nutrients, the inner surface of the digestive tract also serves as the first line of defense against a wide variety of pathogens. Using an integrated approach, we are studying the mechanisms that make the gut an efficient and interactive barrier. We have recently characterized the role of the transcription factor Sox21a in intestinal stem cell differentiation, and articulate how a differentiation defect can lead to tumor formation (See Figure). In 2014, we described a new role for the TGFß signaling in the regulation of sugar homeostasis and digestive enzyme expression.

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Team Members Postdoctoral Fellows

Anna Dostalova Igor Iatsenko Juan Paredes Elodie Ramond Samuel Rommelaere Zongzhao Zhai Toshiyuki Harumoto Xiaoxue Li PhD Students

Jan Dudzic Gonzalo Arraez Technicians

Jean-Philippe Boquete Fanny Schüpfer Christophe Remondeulaz Administrative Assistants

Véronique Dijkstra

Intestinal progenitor tumor in the adult Drosophila midgut. A confocal section of progenitor tumor in the adult midgut of a Sox21a mutant fly. Nuclei are stained in blue, visceral muscle surrounding the intestine and brush border of enterocytes are in red, and the tracheal system in green (From Zhao 2015).

Selected Publications »» »» »» »» »» »»

Zhai, Z., Kondo, S., Ha, N., Boquete, J.P., Brunner, M., Ueda, R. and Lemaitre, B. (2015) Accumulation of differentiating intestinal stem cell progenies drives tumorigenesis. Nat Commun. 6:10219. Chakrabarti, S., Dudzic, J.P., Li, X., Collas, E.J., Boquete, J.P. and Lemaitre, B. (2016) Remote control of intestinal stem cell activity by haemocytes in Drosophila. PLoS Genet. 12(5): e1006089. Ramond, E., Maclachlan, C., Clerc-Rosset, S., Knott, G.W. and Lemaitre, B. (2016) Cell division by longitudinal scission in the insect endosymbiont Spiroplasma poulsonii. MBio. 7(4) pii: e00881-16. Paredes, J.C., Herren, J.K., Schüpfer, F. and Lemaitre, B. (2016) The role of lipid competition for endosymbiont-mediated protection against parasitoid wasps in Drosophila. MBio. 7(4) pii: e01006-16. Neyen, C., Runchel, C., Schüpfer, F., Meier, P. and Lemaitre, B. (2016) The regulatory isoform rPGRP-LC induces immune resolution via endosomal degradation of receptors. Nat Immunol. 17(10):1150-1158. Iatsenko, I., Kondo, S., Mengin-Lecreulx, D. and Lemaitre, B. (2016) PGRP-SD, an extracellular pattern-recognition receptor, enhances peptidoglycan-mediated activation of the Drosophila Imd pathway. Immunity 45(5):1013-1023. »» Lemaitre, B. (2016) Connecting the obesity and the narcissism epidemics. Med Hypotheses 95:10-19.

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McKinney Lab John McKinney - Full Professor - Director of the Doctoral Program in Biotechnology & Bioengineering (EDBB)

Prof. McKinney received his PhD from The Rockefeller University in 1994 for studies on eukaryotic cell cycle regulation. His postdoctoral studies at the Albert Einstein College of Medicine were focused on tuberculosis (1995-1998). Prof. McKinney headed the Laboratory of Infection Biology at Rockefeller University from 1999-2007. Since 2007, Prof. McKinney heads the Laboratory of Microbiology and Microsystems at EPFL. He is also the Section Director for Education in Life Sciences and Technology at EPFL.

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Introduction

Results Obtained

Research in the McKinney lab is focused on understanding the mechanistic basis of microbial individuality, defined as cell-to-cell phenotypic variation that is not attributable to genetic or environmental differences. A deeper understanding of this phenomenon could lead to new strategies to eliminate subpopulations of bacteria that are refractory to antimicrobial therapy and host immunity. Our interdisciplinary research program comprises equal parts microbiology and microengineering. In particular, we design, develop, and apply new microfabricated tools for single-cell microbiology, combined with advanced imaging techniques based on optical and atomic force microscopy. All of our studies are focused at the single-cell level. Areas of biology that we study include: bacterial cell growth and division; bacterial metabolism; bacterial infection and immune evasion; bacterial antibiotic persistence and resistance; bacterial gene expression and phenotypic adaptation to stressful and fluctuating environments.

Genetically identical cells display metastable non-genetic variation in growth rates, gene expression, stress resistance, and other quantitative phenotypes. This phenotypic heterogeneity is critical for bacterial persistence in fluctuating environments because it ensures that some individuals will survive potentially lethal stresses that would otherwise extinguish the population. Our research focuses on the pathogenic organism Mycobacterium tuberculosis and uropathogenic Escherichia coli. We use time-lapse optical and atomic force microscopy and custom-made microdevices to study the real-time dynamics of bacterial behavior at the single-cell level.

Keywords Microbiology, microengineering, microfluidics, microbial microscopy

individuality,

In 2016 we reported that the carbon flux in mycobacteria is regulated by a rheostat-like mechanism (Murima et al. 2016 Nature Commun 7: 12527). We showed that this metabolite mediated allosteric regulatory circuit is responsible for maintaining a balance between energy production and precursor biosynthesis and thus represents a novel target for chemotherapy. In 2016 we reported the development of a microfluidic platform, InfectChip, to visualize host-microbe interactions and the different stages of infection at the single-cell level (Delince et al. 2016 Lab Chip 16: 3276-3285). We demonstrated the utility of this approach by using Dictyostelium discoideum as the host and Klebsiella pneumoniae and Mycobacterium marinum as model pathogens. In 2016 we conducted several studies to study the impact of novel antituberculosis pre-clinical compounds on Mycobacterium tuberculosis using our microfluidic microscopy approach (Martinez-Hoyos et al., 2016 EBioMedicine 8: 291-301; Batt et al., 2015 ACS Infect Dis 1: 615-626). These studies are not only useful for elucidating mode of action of the compounds but often are crucial for making Go/ No-Go decisions in terms of compound progression.

GHI - Global Health Institute

Team Members Senior Scientist

Neeraj Dhar

Postdoctoral Fellows

Alex Eskandarian Viveck Thacker Chiara Toniolo PhD Students

Matthieu Delincé Katrin Schneider Kunal Sharma Thomas Simonet Joëlle Ven Amanda Verpoorte Gaëlle Thurre Technicians

François Signorino-Gelo Schematic view of the InfectChip. The coverslip is patterned with thousands of chambers made of SU8. The snapshots on the right show timlapse images of Dictyostelium discoideum infected with fluorescent Mycobacterium marinum (red). From: Delince et al., (2016) Lab Chip 16: 3276-3285.

Administrative Assistants

Suzanne Balharry

Selected Publications »» Murima, P., Zimmermann, M., Chopra, T., Pojet, F., Fonti, G., Dal Peraro, M., Alonso, S., Sauer, U., Pethe, K. and McKinney, J.D. (2016) A rheostat mechanism governs the bifurcation of carbon flux in mycobacteria. Nature Commun 7: 12527. »» Tischler, A.D., Leistikow, R.L., Ramakrishnan, P., Voskuil, M.I. and McKinney, J.D. (2016) Mycobacterium tuberculosis phosphate uptake system component PstA2 is not required for gene regulation or virulence. PLoS One 11(8): e0161467. »» Delincé, M.J., Bureau, J.B., López-Jiménez, A.T., Cosson, P., Soldati, T. and McKinney, J.D. (2016) A microfluidic cell-trapping device for single-cell tracking of host-microbe interactions. Lab Chip 16(17): 3276-3285. »» Ramakrishnan, P., Aagesen, A., McKinney, J.D. and Tischler, A. (2016) Mycobacterium tuberculosis resists stress by regulating PE19 expression. Infect Immun 84(3): 735-746. »» Martínez-Hoyos, M., Perez-Herran, E., Gulten, G., Encinas, L., Álvarez-Gómez, D., Alvarez, E., Ferrer-Bazaga, S., García-Pérez, A., Ortega, F., Angulo-Barturen, I., Rullas-Trincado, J., Blanco Ruano, D., Torres, P., Castañeda, P., Huss, S., Fernández Menéndez, R., González Del Valle, S., Ballell, L., Barros, D., Modha, S., Dhar, N., Signorino-Gelo, F., McKinney, J.D., García-Bustos, J.F., Lavandera, J.L., Sacchettini, J.C., Jimenez, M.S., Martín-Casabona, N., Castro-Pichel, J., Mendoza-Losana, A. (2016) Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor. EBioMedicine 8: 291-301. »» Batt, S.M., Izquierdo, M.C., Pichel, J.C., Stubbs, C.J., Del Peral, L.V.G, Pérez-Herrán, E., Dhar, N., Mouzon, B., Rees, M., Hutchinson, J.P., Young, R.J., McKinney, J.D., Barros, D., Ballell, L., Besra, G.S. and Argyrou, A. (2015) Whole cell target engagement identifies novel inhibitors of Mycobacterium tuberculosis decaprenylphosphoryl-beta-D-ribose oxidase. ACS Infect Dis 1(12): 615-626. »» Rullas, J., Dhar, N., McKinney, J.D., García-Pérez, A., Lelievre, J., Diacon, A.H., Hugonnet, J.E., Arthur, M., Angulo-Barturen, I., Barros-Aguirre, S. and Ballell, L. (2015) Combinations of beta-lactam antibiotics currently in clinical trials are efficacious in a DHP-1-deficient mice model of tuberculosis infection. Antimicrob Agents Chemother 59(8): 4997-4999.

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Salathé Lab Marcel Salathé - Associate Professor

Marcel Salathé is a digital epidemiologist working at the interface of population biology, computational sciences / engineering, and the social sciences. He received his PhD from ETH Zürich, and then went to Stanford University as a postdoc before becoming Assistant Professor at Penn States’ Center for Infectious Disease Dynamics. In August 2015, he returned to Switzerland as Associate Professor at EPFL.

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Introduction

Results Obtained

The Digital Epidemiology Lab is mainly dedicated to the production and analysis of new streams of digital data (big data) in order to improve public health, both locally and internationally. The group works on a variety of projects relating to human health or agricultural crops, and takes advantage of the latest technology to understand, describe or predict epidemics. One of its major projects, “PlantVillage”, is one of the largest libraries worldwide in terms of scientific knowledge on diseases of edible plants. It already lists 154 varieties and more than 1,800 diseases and continues to grow. “PlantVillage” is also a platform for dialogue and exchange among the best specialists and growers worldwide. Since last November, more than 50,000 images of healthy and infected plants were published and made freely accessible to allow experts in machine learning the development of algorithms able to immediately identify crop diseases. Our own group has applied deep learning models to reach an accuracy of over 99%. We have also recently developed an open data competition platform called crowdai.org.

Having arrived at EPFL in August 2015, most of the results obtained in 2015 were still flowing from research done at Penn State. The main findings related to pharmacovigilance, where we could show that Twitter can be used to identify adverse effects on HIV drug treatment, a finding that was published in the same year. Arriving at EPFL, I’ve spent the rest of the year setting up my lab at Campus Biotech in Geneva. We have started building a deep learning platform for the PlantVillage plant disease data, and have also begun the development of the open data challenge platform crowdAI.org. In addition, we’ve set up collaborative projects with the University Hospitals Zurich and Geneva, where we have started to studies measuring contact networks using wireless sensors. In 2016, we published our first paper on deep learning using the PlantVillage open dataset, demonstrating for the first time that plant diseases can be accurately diagnosed using artificial intelligence. We have run multiple challenges on the crowdAI platform, and have launched openfood.ch, the largest open food data base in Switzerland.

Keywords Digital epidemiology, health, disease, big data, machine learning, algorithms, AI, wireless sensors

GHI - Global Health Institute

Team Members Research Staff

Christopher Burger PhD Students

Gianrocco Lazzari Sharada Mohanty Martin Müller Technicians

Yannis Jaquet Sean Carroll Boris Conforty Trainee

Servan Grüniger Alberto Hernandez Administrative Assistants

Marina Secat

Visualization of activations in the initial layers of an AlexNet Deep Learning architecture demonstrating that a model has learnt to efficiently activate against diseased spots on an example leaf infected with Apple Cedar Rust.

Selected Publications »» »» »» »» »» »» »»

Vayena, E., Salathé, M., Madoff, L.C. and Brownstein, J.S. (2015) Ethical challenges of big data in public health. PLOS Computational Biology 11:e1003904. Althaus, C.L. and Salathé, M. (2015) Measles vaccination coverage and cases among vaccinated persons. Emerging Infectious Diseases 21:1480-1481. Adrover, C., Bodnar, T., Huang, Z., Telenti, A. and Salathé, M. (2015) Identifying adverse effects of HIV drug treatment and associated sentiments using Twitter. JMIR Public Health and Surveillance 1:e7 Sun, X., Lu, Z., Zhang, X., Salathé, M and Cao, G. (2015) Targeted vaccination based on a wireless sensor system. Pervasive Computing and Communications (PerCom) Mohanty, S.P., Hughes, D.P. and Salathé, M. (2016) Using deep learning for image-based plant disease detection. Frontiers in Plant Science 7:1419. Salathé M. (2016) Digital pharmacovigilance and disease surveillance: combining traditional and big-data systems for better public health. Journal of Infectious Diseases 214: S399-S403. Wang, Z., Bauch, C.T., Bhattacharyya,S., d’Onofrio, A., Manfredi,P., Perc,M., et al. (2016) Statistical physics of vaccination. Physics Reports 664: 1-113.

137

Trono Lab Didier Trono - Full Professor

After obtaining an M.D. from the University of Geneva and completing clinical training in pathology, internal medicine and infectious diseases in Geneva and at Massachusetts General Hospital, Didier Trono started a scientific career at the Whitehead Institute of MIT. In 1990, he joined the Salk Institute in San Diego to launch a center for AIDS research. Prof. Trono moved back to Europe seven years later, before taking the reins of the newly created EPFL School of Life Sciences, which he directed from 2004 to 2012. His research has long gravitated around interactions between viruses and their hosts and the development of tools for gene therapy. This led him to epigenetics, the current focus of his labâ&#x20AC;&#x2122;s investigation.

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Introduction

Results Obtained

Our laboratory has had a long-standing interest for interactions between viruses and their hosts. This led us in the past to study the biology of pathogens such as human immunodeficiency virus and hepatitis B virus, and to develop virus-based delivery systems for human gene therapy. Over the last twelve years, our research has shifted towards the field of epigenetics, to explore the impact of transposable elements and their controllers on transcriptional networks governing human biology. We have notably devoted much attention to the 350 KRAB-containing zinc finger proteins (KRAB-ZFPs) and their cofactor KAP1, which evolved during the last 400 million years from silencers of mobile genetic elements to master regulators of human development, physiology and evolution.

Transposable elements (TEs) may account for up to two-thirds of the human genome, and as genomic threats they are subjected to epigenetic control mechanisms engaged from the earliest stages of embryonic development. We previously determined that an important component of this process is the sequence-specific recognition of TEs by KRAB-containing zinc finger proteins (KRAB-ZFPs), a large family of tetrapod-restricted transcription factors that act by recruiting inducers of heterochromatin formation and DNA methylation. We further demonstrated that KRAB-ZFPs and their cofactor KAP1 exert a marked influence on the transcription dynamics of embryonic stem cells via their docking of repressor complexes at TE-contained regulatory sequences. It is generally held that, beyond this early embryonic period, TEs become permanently silenced, and that the evolutionary selection of KRAB-ZFPs and other TE controllers is the result of a simple evolutionary arms race between the host and these genetics invaders. Our analysis of the transcriptional activity of transposable elements in various developmental stages, tissues and cancers invalidates this dual assumption and demonstrates instead the potential of KRAB-ZFPs and their targeted transposon-based regulatory sequences as regulators of species-specific transcriptional networks governing human development and physiology. This field holds great promises to uncover new biomarkers and therapeutic targets for oncology and also opens new perspectives to explore human speciation.

Keywords Transposable elements, KRAB-ZFPs, epigenetics, stem cells, development, evolution

GHI - Global Health Institute

Team Members Post Doctoral Fellows

Marco Cassano Alberto De Iaco Marc Friedli Michaël Imbeault Suk Min Jang Julien Pontis Laia Simó Riudalbas Carmen Unzu Staff Scientist

Priscilla Turelli PhD Students

Natali Castro Diaz Andrea Coluccio Gabriela Ecco Pierre-Yves Helleboid Alexandra Iouranova Annamaria Kauzlaric Flavia Marzetta Technicians KZFPs and transposable elements interactions are foundations for species-specific transcriptional networks regulation. The complex interactions network between KZFPs (in grey) and TE families (in colors) are represented. Some KZFP / TE relationships are very exclusive (at the edge of the network), while some KZFPs recognize multiple families of TEs (for example SINEs and ERVs).

Selected Publications

Sandra Offner Charlène Raclot Sonia Verp Bioinformaticians

Evarist Planet Julien Duc Delphine Grun

Administrative Assistants

»» Ecco, G., Cassano, M., Kauzlaric, A., Duc, J., Coluccio, A., Offner, S., Imbeault, M., Rowe, H.M., Turelli, P. & Trono, D. Transposable Elements and Their KRAB-ZFP Controllers Regulate Gene Expression in Adult Tissues. Dev Cell 36, 611-23 (2016). »» Theunissen, T.W., Friedli, M., He, Y., Planet, E., O’Neil, R.C., Markoulaki, S., Pontis, J., Wang, H., Iouranova, A., Imbeault, M., Duc, J., Cohen, M.A., Wert, K.J., Castanon, R., Zhang, Z., Huang, Y., Nery, J.R., Drotar, J., Lungjangwa, T., Trono, D., Ecker, J.R. & Jaenisch, R. Molecular Criteria for Defining the Naive Human Pluripotent State. Cell Stem Cell 19, 502-515 (2016). »» Ecco, G., Rowe, H.M. & Trono, D. A Large-Scale Functional Screen to Identify Epigenetic Repressors of Retrotransposon Expression. Methods Mol Biol 1400, 403-17 (2016). »» Trono, D. Transposable Elements, Polydactyl Proteins, and the Genesis of Human-Specific Transcription Networks. Cold Spring Harb Symp Quant Biol 80, 281-8 (2015). »» Friedli, M. and Trono, D. (2015). The Developmental Control of Transposable Elements and the Evolution of Higher Species. Annu Rev Cell Dev Biol 31, 429-51 (2015). »» Singh, K., Cassano, M., Planet, E., Sebastian, S., Jang, S.M., Sohi, G., Faralli, H., Choi, J., Youn, H.D., Dilworth, F.J. & Trono, D. A KAP1 phosphorylation switch controls MyoD function during skeletal muscle differentiation. Genes Dev 29, 513-25 (2015). »» Castro-Diaz, N., Friedli, M. and Trono, D. Drawing a fine line on endogenous retroelement activity. Mob Genet Elements. 5:1-6 (2015).

Julia Prébandier Séverine Reynard

139

Van der Goot Lab F. Gisou van der Goot - Full Professor - Dean of the School of Life Sciences

Gisou van der Goot studied engineering at the Ecole Centrale de Paris, then did a PhD in Molecular Biophysics at the Nuclear Energy Research Center, Saclay, France, followed by a postdoc at the European Molecular Biology Laboratory (EMBL) in Heidelberg. She started her own group in 1994 in the department of Biochemistry, University of Geneva, became Associate professor at the Faculty of Medicine (Univ. Geneva) in 2001 and Full Professor at the EPFL in 2006, where she cofounded the Global Health Institute. In 2014, she was appointed Dean of the School of Life Sciences.

Introduction

Results Obtained

The general interest of our laboratory is to understand how biological membranes compartmentalize space, in 3D but also 2D, how shape is used to specify function, how transmission of information across membranes can be mediated. These overarching questions are addressed through the following main focuses:

Anthrax toxin receptors Through the study of biopsies from Hyaline Fibromatosis patients and of CMG2 knock out mice, combined with in vitro and tissue culture experiments, we found that CMG2 is a receptor for the extracellular matrix protein Collagen VI. CMG2 controls the extracellular levels of collagen VI. It does so by internalizing collagen VI into cells and targeting it for degradation in lysosomes. Upon loss of CMG2 function, collagen VI accumulates in the extracellular environment. Accumulation can be dramatic and lead to tissue damage and disease. CMG2 also informs the cell of the presence of collagen VI in the extracellular environment. Binding of collagen VI leads to remodelling of the actin cytoskeleton through mechanisms that we are currently investigating.

1. To understand how mammalian cells are compartmentalized, how compartmentalization of specific membranes is achieved and how this is related to function. We are particularly interested in the architecture of the endoplasmic reticulum and how palmitoylation, a uniquely reversible lipidation of proteins, regulates organelle structure and function by targeting key proteins. 2. To understand the physiological and pathological roles of the anthrax toxin receptors, TEM8 and CMG2. These two single spanning membrane proteins that are well known to enable intoxication by anthrax but poorly understood with respect to their role in communicating with the extracellular matrix. They are also palmitoylated and represent a useful model system to study this post-translational modification. 3. To unravel the molecular mechanisms responsible for Hyaline Fibromatosis and GAPO syndromes. These two rare genetic diseases are the result of mutations in the anthrax toxin receptors.

Keywords Palmitoylation, DHHC, TEM8, CMG2, anthrax toxin, endoplasmic reticulum, calnexin.

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S-palmitoylation This is the only reversible lipid modification. As phosphorylation and ubiquitination, it allows the control of protein function, conformation or localization in a switch like manner. To reach mechanistic understanding of palmitoylation, we choose to combine experimental kinetic investigation of protein palmitoylation-depalmitoylation and the consequences thereof on protein stability, localization and function with mathematical modelling. In close collaboration with the laboratory of Vassily Hatzimanikatis (EPFL, Basic Sciences) this approach was successfully applied to the ER chaperone calnexin, providing unprecedented understanding of the dynamics of the modification. This approach was extended to the palmitoyltransferase of calnexin, the DHHC6 enzyme. As the first evidence for palmitoylation cascades, we found that DHHC6 can be modified on 3 sites by an upstream DHHC enzyme. Palmitoylation is controls DHHC6 localization, stability and function. Datadriven mathematical modelling reveals a highly dynamic palmitoylation system that controls the abundance and function of this key ER palmitoyltransferase. As a community tool, we generated the SwissPalm knowledgebase which not only provides relevant information and tools regarding palmitoylation but most importantly allows the analyses of all palmitoyl-proteomes studies reported in the literature.

GHI - Global Health Institute

Team Members Senior Researcher

Laurence Abrami

Post Doctoral Fellows

Mathieu Blanc Oksana Sergeeva Maria Eugenia Zaballa Sarah Friebe Patrick Sandoz Olha Novokhatska PhD Students

Mustafa Demir Numa Piot Technicians

A: Structure of anthrax toxin receptor 2 or CMG2 (taken from The dark sides of capillary morphogenesis gene 2. Deuquet J, Lausch E, Superti-Furga A, van der Goot FG. EMBO J. 2012 Jan 4;31(1):3-13. doi: 10.1038/emboj.2011.442.) B: Schematic illustration of the complexity of palmitoyation networks, in particular in the endoplasmic reticulum

Sylvia Ho Béatrice Kunz Tiffany Thebault, Thomas Jenny Administrative Assistants

Geneviève Rossier

Selected Publications »» Blanc, M., David, F., Abrami, L., Migliozzi, D., Armand, F., Bürgi, J. and van der Goot, F.G. (2015) SwissPalm: Protein palmitoylation database. F1000Research 4:261. »» Dallavilla, T. #, Abrami, L. #, Sandoz, P.A., Savoglidis, G., Hatzimanikatis, V*. and van der Goot, F.G.* (2016) Model-driven understanding of palmitoylation dynamics: regulated acylation of the endoplasmic reticulum chaperone calnexin. PLoS Computational Biol. 12:e1004774. »» Bischofberger, M, Iacovache, I., Boss, D., Naef, F., van der Goot, F.G.* and Molina, N. * (2016) Revealing assembly of a pore-forming complex using single-cell kinetic analysis and modeling. Biophysical J. 110:15741581. »» Iacovache, I., De Carlo, S., Cirauqui,, N., Dal Peraro,, M., van der Goot, F.G. and*, Zuber,, B.* (2016) Cryo-EM structure of aerolysin variants reveals a novel protein fold and the pore formation process. Nature Com. 7:12062. »» Bürgi, J., Xue, B., Uversky, V.N. and van der Goot, F.G. (2016) Intrinsic disorder in transmembrane proteins: Roles in signaling and topology prediction. PLoS One 11:e0158594. »» Perrody, E., Abrami, L., Feldman, M., Kunz, B., Urbe, S. and van der Goot, F.G. (2016) Ubiquitin-dependent folding of the Wnt signaling coreceptor LRP6. eLife. 5. pii: e19083. »» Bürgi, J. Kunz, B., Abrami,, L., Deuquet, J., Piersigilli, A., Scholl-Bürgi, S., Lausch, E., Unger, S., Superti-Furga, A., Bonaldo,, P. and van der Goot, F.G. (2017) CMG2/ANTXR2 is a receptor for collagen VI and controls its extracellular levels. Nature Com. (in press). # Co-first author * Co-senior corresponding author

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ISREC

Swiss Institute for Experimental Cancer Research The Swiss Institute for Experimental Cancer Research (ISREC) has continued its contributions to the School of Life Sciences at EPFL, via cutting-edge research, mentoring young scientists, and classroom teaching. In addition, ISREC is playing a key role in the new Swiss Cancer Center Lausanne, a joint venture with the University of Lausanne and its Hospital and Medical Center (CHUV). This new cancer center, announced in January 2013, has a mission statement to become the first comprehensive cancer center is Switzerland, as defined by depth and breadth in basic and translational cancer research, in clinical research and clinical trials of new therapies, and excellent care of cancer patients. ISREC, with 15 faculty research groups focused on cancer research or fundamental cell and developmental biology, brings exceptional strength and talent to this new cancer center. ISREC has been centrally involved in community-building initiatives for the SCCL, including a series of annual faculty-only and faculty plus staff retreats, held in the spring and fall, respectively. Both retreats - initiated in 2013 and continued annually henceforth under the excellent stewardship of Etienne Meylan (ISREC, SV, EPFL) and Olivier Michielin (CHUV, UNIL) – have proved successful at building bridges across the multiple sites in Lausanne that house cancer-related faculty. The Lola and John Grace Distinguished Lectures in Cancer Research – sponsored by the Grace family – bring in eminent cancer scientists for a once-monthly lecture at EPFL that is televised to the CHUV and Biopole/Epalinges sites of the SCCL. In addition, ISREC sponsors a monthly faculty-only research presentation, and a weekly informal seminar series for ISREC students and postdocs. Douglas Hanahan - Director

Denis Duboule was recently elected to the prestigious College de France, established in Paris in 1530, a society consisting of 52 members whose endeavors span the pursuit and public dissemination of knowledge across the spectrum of academic disciplines. Michele de Palma and Oliver Hantschel were awarded highly competitive ERC Consolidator Grants. On the occasion of the EPFL graduation ceremony - the Magistrale 2016 - Etienne Meylan received the EPFL Life Sciences Teaching Prize, ‘For excellence of his teaching judged from the last 3 years’. http://sv.epfl.ch/ISREC

143

Brisken Lab Cathrin Brisken - Associate Professor

Cathrin Brisken received her MD and her PhD degree in Biophysics from the Georg August University of Göttingen, Germany. She completed her postdoctoral work in cancer biology with Dr. R.A. Weinberg at the Whitehead Institute of Biomedical Research in Cambridge, MA, USA. She previously held appointments at the Cancer Center of the Massachusetts General Hospital, Harvard Medical School, Boston and the Swiss Institute for Experimental Cancer Research (ISREC). Dr. Brisken is member of the International Breast Cancer Study Group (IBCSG) Biological Protocol Working Group. She served as Dean of EPFL Doctoral School (more than 2000 PhD students in 18 PhD programs), as member of the Hinterzartener Kreis, the oncology think-tank associated with the German Science Foundation, and numerous Swiss, European, and AACR committees. She co-founded the International Cancer Prevention Institute and is member of the AACRWomen in Cancer Research Council (2016-2019).

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Introduction

Results Obtained

Research in Dr. Brisken’s laboratory focuses on the cellular and molecular underpinnings of estrogen and progesterone receptor signaling in the breast and the respective roles of these hormones and hormonally active compounds in carcinogenesis. The aim is to understand how recurrent exposures to endogenous and exogenous hormones contribute to breast carcinogenesis in order to better prevent and treat the disease. The laboratory has pioneered in vivo approaches to genetically dissect the role of the reproductive hormones in driving mouse mammary gland development and shown how they control intercellular communication. Dr. Brisken’s group has developed ex vivo and humanized mouse models using patient samples to study hormone action in human tissues in normal settings and during disease progression.

Progesterone and Wnt4 control mammary stem cells via myoepithelial crosstalk Ovarian hormones increase breast cancer risk by poorly understoood mechanisms. We reveal that progesterone receptor (PR) signaling controls mammary epithelial stem cells through Wnt-4. Wnt-4 is secreted by PR positive luminal cells and activates canonical wnt signaling in basal cells.

Keywords Hormones, mammary gland development, breast carcinogenesis, paracrine signaling, estrogen, progesterone, RANKL, Wnt-4, stem cells, preclinical xenograft models

A preclinical model for ERα positive (ER+) breast cancer Ninety percent of new drugs in oncology fail, partly because the preclinical models used to test them are not adequate. Breast cancer is the leading cause of cancer-related death among women worldwide and we lack in vivo models for the ER+ subtypes, which represent more than 75% of all cases. We show that ER+ tumor cells can be successfully established as xenografts when injected into the milk ducts of immunocompromised mice. Traditional grafting into subcutaneous fat induces TGFβ/SLUG signaling and basal differentiation and prevents in vivo growth. Intraductally, SLUG is suppressed and ER+ tumor cells grow like their clinical counterparts. Disease progression with invasion and metastasis can now be studied in a physiologic endocrine milieu. The in vivo function of the secreted metalloproteinases ADAMTS18 We generated Adamts18-deficient mice and demonstrated a 100% penetrant eye defect resulting from leakage of lens material through the lens capsule. Adamts18 is also required for bronchiolar branching and vaginal opening. Thus, the orphan protease is essential in the development of distinct tissues and the new mouse strain is likely to be useful for investigating ADAMTS18 function in human disease, particularly in the contexts of infertility and carcinogenesis.

ISREC - Swiss Institute for Experimental Cancer Research

Team Members Postdoctoral Fellows

Georgios Sflomos Stéphanie Cagnet (until mid 2016) Csaba Lazlo PhD Students

Dalya Ataca Rachel Jeitziner Valentina Scabia Marie Shamseddin Lab Manager

Ayyakkannu Ayyanan Technicians

Laura Battista Administrative Assistants

Magali Frainier Tissue section from an intraductal xenograft’s hormone receptor positive breast cancer, stained for fibrillar collagen networks.

Selected Publications »» Ataca, D., Caikovski M., Piersigilli, A., Moulin, A., Benarafa, C.; Earp, S.E., Guri, Y., Kostic, C., Arsenivic, Y., Soininen, R., Apte, S.S., Brisken, C. (2016) Adamts18 deletion results in distinct developmental defects and provides a model for congenital disorders of lens, lung, and female reproductive tract development. Biol Open. 2016 Nov 15; 5(11):1585-1594. »» Sflomos, G., Dormoy, V., T. Metsalu, T., Jeitziner, R., Battista, L., Scabia, V., Raffoul, W., Delaloye, J.-F., Treboux, A., Vilo,J., Fiche, M., Ayyanan, A., Brisken C. (2016) A robust preclinical model for ERα positive breast cancer points to the mammary epithelial microenvironment as critical determinant of luminal phenotype and hormone response. Cancer Cell, 29(3): 407-422 »» Procopio, MG., Laszlo, C., Al Labban, D., Kim, D., Bordignon, P., Jo, SH., Goruppi, S., Menietti, E., Ostano, P., Ala, U., Provero, P., Hoetzenecker, W., Neel, V., Kilarski, W., Swartz, M., Brisken C, Lefort, K., Dotto, G. P. (2015) Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation. Nature Cell Biol 17(9):1193-204. »» Dobrolecki LE, Airhart SD, Alferez DG, Aparicio S, Behbod F, Bentires-Alj M, Brisken C, Bult CJ, Cai S, Clarke RB, Dowst H, Ellis MJ, Gonzalez-Suarez E, Iggo RD, Kabos P, Li S, Lindeman GJ, Marangoni E, McCoy A, Meric-Bernstam F, Piwnica-Worms H, Poupon MF, Reis-Filho J, Sartorius CA, Scabia V, Sflomos G, Tu Y, Vaillant F, Visvader JE, Welm A, Wicha MS, Lewis MT. Patient-derived xenograft (PDX) models in basic and translational breast cancer research. Cancer Metastasis Rev. 2016 Dec; 35(4): 547-573 »» Brisken C., Hess, K., Jeitziner, R. (2015) Progesterone and overlooked endocrine pathways in breast cancer pathogenesis. Endocrinology, 156(10):3442-50. »» Brisken C., Ataca, D., (2015) Endocrine hormones and local signals during the development of the mouse mammary gland. Wiley Interdiscip Rev Dev Biol. 4(3):181-95. »» Sflomos, G., Shamsheddin, M. , Brisken C. (2015) An ex vivo model to study hormone action in the human breast. J Vis Exp. (95): e52436

145

Constam Lab Daniel B. Constam - Associate Professor

Daniel Constam obtained his doctoral degree from ETH Zürich. After postdoctoral studies at Harvard University as an EMBO fellow, he became an ISREC group leader in 2000 and associate professor at the EPFL School of Life Sciences in 2007. His lab studies signaling pathways that direct stem cell differentiation in development and cancer.

constam-lab.epfl.ch

Introduction

Results Obtained

Using genetic and biochemical approaches, we investigate how proprotein convertase family and their substrates govern stem and progenitor cell renewal and differentiation in the mammalian embryo, and how cancer cells redeploy them for tumor progression. Such road maps of progenitor cell differentiation are important both for regenerative medicine and to find ways to reduce tumor aggressiveness. We have shown that proprotein convertases control TGFβrelated activities and other master regulators of early lineage differentiation. However, what determines the substrate specificities and paracrine range of action of these proteases during development and in cancer is unclear. To address this, we generated convertase gene deletions and high resolution live imaging probes that reveal when and where these enzymes are active in normal and cancerous cells and tissues.

The first lineage decision in mammalian embryos occurs at the morula stage when outer cells become polarized by asymmetric contacts and activate the transcription factor YAP to form trophectoderm. By contrast, symmetric contacts of the adhesion molecule E-cadherin in inner cells inhibit this pathway and maintain the pluripotency of the cells that will form all body parts.

Several cancer hallmarks are shared by heritable polycystic kidney diseases. In such patients, renal epithelial tubule cells or their progenitors are reprogrammed to form fluid-filled cysts as they fail to protrude functional primary cilia into the tubule lumen to sense urine flow and possibly other stimuli. We study the role of the RNA-binding protein Bicc1 in signal transduction pathways such as Wnt, PKA and mTOR that control cell growth, repair and metabolism upand/or downstream of primary cilia.

Keywords Protease imaging, mRNA silencing, stem cells, cancer, polycystic kidney diseases

146

Our PC7 gene knockout and live imaging showed that Furin and PC7 jointly initiate morula compaction at least in part by stimulating E-cadherin cleavage and stability, thus identifying the most upstream regulators of ICM formation known to date. However, a related convertase (Pace4) was activated a few hours later specifically in outer cells and significantly compensated for combined loss of Furin and PC7. Thus, during inner cell mass formation, E-cadherin precursor processing involves not only one but as many as three functionally overlapping proprotein convertases that are dynamically regulated. Ongoing work addresses whether other substrates rely on fewer PC family members for cleavage due to differential trafficking, and whether their processing in specific subcompartments would be a viable cancer drug target. Mutations in Bicc1 instigate cysts in kidney and pancreas. Our candidate search for the first direct targets identified AC6 and PKIα mRNAs that affect cAMP signaling. However, why cAMP accumulates in polycystic kidney disease patients with ciliary defects is unclear. To elucidate how Bicc1 enables mRNA silencing, we modeled the structure of its SAM domain. In this model, the SAM organizes Bicc1 as a helical polymer with RNA binding sites arrayed at the surface. In line with this prediction, the bpk mutant Bicc1 allele and point mutations blocking SAM polymerization abolished the localization and silencing of associated reporter mRNA in cytoplasmic Bicc1 foci (Fig. 1). Whether Bicc1 polymerization is regulated by cilia or vice versa is under investigation.

ISREC - Swiss Institute for Experimental Cancer Research

Team Members Postdoctoral Fellows

Simon Fortier Benjamin Rothé PhD Students

Teresa Didonna Olivier Dubey Lucia Leal-Esteban Pierpaolo Ginefra Administrative Assistants & Technicians

Manuela Isenschmid Virginie Kokocinski Séverine Urfer Nancy Thompson

In LTL-stained cyst-lining cells of bpk mutant polycystic mouse kidneys (*), isoform A of Bicc1 is not polymerized by its SAM domain in cytoplasmic foci (A-E). Enrichment of Bicc1 (pink) and bound mRNA (yellow) in foci is also inhibited if SAM polymerization is blocked by point mutation (mutD, C-H).

Selected Publications »» Bessonnard, S., Mesnard, D. and Constam, D.B. (2015) PC7 and the related proteases Furin and Pace4 regulate E-cadherin function during blastocyst formation. J. Cell Biol. 210(7): 1185-1197. »» Ellis, P., Burbridge, S., Soubes, S., Ohyama, K., Ben-Haim, N., Chen, C., Dale, K., Shen, M.M., Constam, D. and Placzek, M. (2015) ProNodal acts via FGFR3 to govern duration of Shh expression in the prechordal mesoderm. Development 142(22): 3821-3832. »» Lemaire, L. A., Goulley, J., Kim, Y. H., Carat, S., Jacquemin, P., Rougemont, J., Constam, D.B. and Grapin-Botton, A. (2015) Bicaudal C1 promotes pancreatic NEUROG3+ endocrine progenitor differentiation and ductal morphogenesis. Development 142(5): 858-870. »» Piazzon, N., Bernet, F., Guihard, L., Leonhard, W. N., Urfer, S., Firsov, D., Chehade, H., Vogt, B., Piergiovanni, S., Peters, D. J., Bonny, O. and Constam, D.B. (2015) Urine Fetuin-A is a biomarker of autosomal dominant polycystic kidney disease progression. J. Trans. Med. 13(1): 103. »» Rothe, B., Leal-Esteban, L., Bernet, F., Urfer, S., Doerr, N., Weimbs, T., Iwaszkiewicz, J. and Constam, D.B. (2015) Bicc1 polymerization regulates the localization and silencing of bound mRNA. Mol. Cell. Biol. 35(19): 3339-3353. »» Minocha, S., Bessonnard, S., Sung, T.L., Moret, C., Constam, D.B., and Herr, W. (2016) Epiblast-specific loss of HCF-1 leads to failure in anterior-posterior axis specification. Dev. Biol. 418: 75-88.

147

De Palma Lab Michele De Palma - Tenure-Track Assistant Professor

Miki De Palma graduated in Biology (1999) and obtained a PhD degree in cell biotechnologies (2004) from the University of Torino Medical School, Italy, with a thesis on the regulation of tumor angiogenesis by bone-marrowderived cells. He performed post-doctoral training (20052008) at the Telethon Institute for Gene Therapy in Milan, where he developed strategies for engineering monocytes and reprogramming them into antitumoral immune cells. He was appointed group leader at the San Raffaele Institute, Milan, in 2008 (tenured in 2011), and joined ISREC/EPFL in 2012. He serves on the advisory boards of several international journals, including Science Translational Medicine and Cell Reports.

148

depalma-lab.epfl.ch

Introduction

Results Obtained

Our lab has contributed to elucidating the pro-angiogenic functions of monocytes/macrophages in mouse models of cancer, as well as the molecular and functional heterogeneity of macrophages in both experimental and human tumors. We have also characterized VEGF-independent modes of tumor angiogenesis, and illustrated the therapeutic opportunities afforded by inhibiting angiopoietin signaling in de novo models of metastatic cancer. Currently, we employ genetic cancer models and cell-engineering strategies, largely based on lentiviral gene transfer, to dissect the interactions among macrophages, blood vessels and T cells in tumors, primarily by focusing on angiogenic signaling, immune checkpoints, microRNA regulation, and secreted exosomes. By tackling these processes, we aim to reprogram the immunosuppressive tumor microenvironment to a form that facilitates the deployment of anti-tumor immunity and enhances the efficacy of anticancer therapies.

In one recent study, we identified a mechanism regulating the immunosuppressive functions of macrophages in tumors. Tumor-associated macrophages (TAMs) largely express an alternatively activated (or M2) phenotype, which entails immunosuppressive and tumor-promoting capabilities. Reprogramming TAMs toward a classically activated (M1) phenotype may thwart tumor-associated immunosuppression and unleash anti-tumor immunity. We found that conditional deletion of the microRNA (miRNA)-processing enzyme DICER in macrophages prompts M1-like TAM programming, which is characterized by hyperactive interferon (IFN)-γ/STAT1 signaling. This rewiring abated the immunosuppressive capacity of TAMs and fostered the recruitment of activated cytotoxic T lymphocytes (CTLs) to the tumors. CTL-derived IFN-γ exacerbated M1 polarization of Dicer1-deficient TAMs and inhibited tumor growth. Remarkably, we found that DICER deficiency in TAMs negated the anti-tumoral effects of macrophage depletion by anti-CSF1R antibodies, and enabled complete tumor eradication by PD-1 checkpoint blockade or CD40 agonistic antibodies. Finally, we showed that the genetic rescue of Let-7 miRNA activity in Dicer1-deficient TAMs was sufficient to partly restore their M2-like phenotype and decrease tumor-infiltrating CTLs. These findings indicate that DICER/Let-7 activity opposes IFN-γ-induced, immunostimulatory M1-like TAM activation, with potential therapeutic implications.

Current research topics include: 1. Engineered dendritic cell vaccines for cancer immunotherapy; 2. microRNA regulation of macrophage activation in tumors; 3. Anti-angiogenesis as a tumor-conditioning strategy for improving cancer immunotherapy; 4. Mechanisms of tumor resistance to antiangiogenic therapy; 5. Tumor-derived exosomes and cancer progression.

Keywords Cancer, macrophage, angiogenesis, microRNA, exosome, immunotherapy, lentiviral vector.

ISREC - Swiss Institute for Experimental Cancer Research

Team Members Postdoctoral Fellows

Mario Leonardo Squadrito Martina Scmittnaegel Ioanna Keklikoglou Florent Duval Chiara Cianciaruso PhD Students

Caroline Baer Ece Kadioglu Technicians

Celine Wyse Danielle Thompson Antonino Cassará Axel Bellotti Administrative Assistants

Soledad Andany

The figure shows specific labeling of tumor-associated macrophages (TAMs; green) in mTmG mice, which express GFP upon Cre-mediated recombination. The Lyz2Cre transgene was used to induce macrophage-specific GFP activation. The Lyz2Cre transgene was also used to conditionally delete Dicer in TAMs (see publication Baer et al., Nat Cell Biol., 2016).

Selected Publications »» Baer, C., Squadrito, M.L., Laoui, D., Thompson, D., Hansen, S.K., Kiialainen, A., Hoves, S., Ries, C.H., Ooi, C.-H. and De Palma, M. (2016) Suppression of microRNA activity amplifies IFN-γ-induced macrophage activation and promotes anti-tumor immunity. Nat Cell Biol. 18(7): 790–802. »» Cianciaruso, C., Phelps, E.A., Pasquier, M., [...], Swartz, M.A., De Palma, M., Hubbell, J.A., Baekkeskov, S. (2016) Primary human and rat β-cells release the intracellular autoantigens GAD65, IA-2, and proinsulin in exosomes together with cytokine-induced enhancers of immunity. Diabetes 66(2):460-473. »» He, H., Mack, J.J., Güç, E., Warren, C.M., Squadrito, M.L., Kilarski, W.W., Baer, C., Freshman, R.D., McDonald, A.I., Ziyad, S., Swartz, M.A., De Palma, M. and Iruela-Arispe ML. (2016) Perivascular macrophages limit permeability. Arterioscler Thromb Vasc Biol. 36(11):2203-2212. »» Wallerius, M., Wallmann, T., Bartish, M., […], De Palma, M., Ostman, A., Andersson J. and Rolny, C. (2016). Guidance molecule SEMA3A restricts tumor growth by differentially regulating the proliferation of tumor-associated macrophages. Cancer Res. 76(11):3166-3178. »» Galletti, G., Scielzo, C., Barbaglio, F., […], De Palma, M., Caligaris-Cappio, F. and Bertilaccio, M.T.S. (2016) Targeting macrophages sensitizes chronic lymphocytic leukemia to apoptosis and inhibits disease progression. Cell Rep. 14(7):1748-1760. »» Ferri, F., Parcelier, A., Petit, V., [...], De Palma, M., Davidson, I., Rousselet, G. and Romeo, P.H. (2015) TRIM33 switches off Ifnb1 gene transcription during the late phase of macrophage activation. Nat Commun. 6:8900. »» Hughes, R., Qian, B.-Z., Muthana, M., […], Joyce, J.A., De Palma, M., Pollard, J.W. and Lewis, C.E. (2015) Perivascular M2 macrophages stimulate tumor relapse after chemotherapy. Cancer Res. 75(17):3479-3491.

149

Duboule Lab Denis Duboule - Full Professor

Denis Duboule earned his PhD in Biology in 1984. He is currently Professor of Developmental genetics and genomics at the EPFL and at the department of Genetics and Evolution of the University of Geneva’. Duboule has a longstanding interest in the function and regulation of Hox genes, a family of genes responsible for the organization and evolution of animal body plans. He is an elected member of several academies such as the National Academy of Sciences USA and the Royal Society and has received many awards, amongst which the Louis-Jeantet Prize for Medicine.

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duboule-lab.epfl.ch

Introduction

Results Obtained

Our laboratory has started operating at EPFL during 2007. Its major aim is to study principles of mammalian embryological development by using the recent tools of functional genomics. A special focus is given to those similarities and differences that exist between the embryological development of vertebrates (to whom mammals belong) and those of other animals (invertebrates), from whom vertebrates derive. To achieve this task, we use the developing mouse embryo in vivo as an experimental system, and try and apply the methodology developed following the sequencing of complex genomes. Our major aim is the understanding of the regulation of a critical family of transcription factors during the construction of the animal body plan, referred to as architect genes (the Hox gene family). These genes have a special interest in the study of both our ontogenesis (our development as individuals) and our phylogeny (our origin as a group of individuals) and the detailed understanding of their regulations and functions will be an important step in our understanding of our own histories. More recently, in collaboration with the Martinez-Arias (Cambridge) and Lutolf (EPFL) laboratories, we have started a new research program using in vitro grown organoids as models of mouse embryos.

Over the past two years, progresses have been made in several lines of research. Importantly, by using biochemical, genetic and epigenetic approaches, we have finally obtained a fair understanding of the collinear mechanism at work during limb development, a project that started in 1989 with the discovery of this intriguing phenomenon. We deciphered the chromatin structure around the HoxA and HoxD gene clusters and reported that they both had evolved related topologically associating domains (TADs) regulatory organization, likely implying that such a structure was already present in an ancestor animal that only had one gene cluster. During 2015, we have terminated a series of experiments whose aim was to determine which mechanism implements the transition between the regulation from one such TAD to the other, and we demonstrated that the Hox13 proteins themselves are involved in this important switch either by repressing the telomeric, or by activating the centromeric regulation. These opposite effects of the same proteins explain how these two regulations are exclusive from another and hence how the transition between the forearm and the hands is organized, with the mesopodial articulation (the wrist) in between. In the same context, we have shown how regulations in this system could be hi-jacked to serve another purpose in the course of evolution, as illustrated by the necessary function of these genes during the emergence of the mammary glands.

Keywords Embryos, development, evolution, transcription, epigenetic regulation, Hox gene clusters, enhancers, chromatin.

In parallel with these molecular studies, we have well progressed in our projects to try and better visualize the spatial organization of these genetic loci, as well as their long-range contacts with other genomic loci, either in expressing tissues, or in tissues where these genes are silent. In the former case, we set up a collaboration with the Sulyana Manley laboratory from the school of physics at EPFL, to try and picture the gene cluster by using STORM microscopy at very high resolution, in comparison with either SIM or more ‘classical’ FISH technology.

ISREC - Swiss Institute for Experimental Cancer Research

Team Members Postdoctoral Fellows

Pierre Fabre Nayuta Yakushiji Christopher Bolt Lucille Delisle PhD Students

Fabrice Darbellay Rita Amândio Technicians

Elisabeth Brönimann-Joye Trainees

Tripartite interactions between Hoxd13 and regulatory islands. A: 3D DNA-FISH Hoxd13 and two regulatory islands. B: Quantifications showing variations in the distribution of physical distances between Hoxd13 and island II or island IV, or island II and island IV. c: Heatmap showing the distribution of tripartite interactions including at least Hoxd13.

Ben Mormann, Fullbright fellow Athimed El Taher, stage Master Célia Bochaton, stage Master Hosted Ambizione Fellow

Anamaria Necsulea

Administrative Assistants

Gordana Favre

Selected Publications »» Amândio, A.R., Necsulea, A., Joye, E., Mascrez, B. and Duboule, D. (2016) Hotair is dispensible for mouse development. PLoS Genet. 12(12):e1006232 »» Schep, R., Necsulea, A., Rodríguez-Carballo, E., Guerreiro, I., Andrey, G., Nguyen Huynh, T.H., Marcet, V., Zákány, J., Duboule, D. and Beccari, L. (2016) Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape. Proc Natl Acad Sci USA 113(48):E7720-E7729. »» Guerreiro, I., Gitto, S., Novoa, A., Codourey, J., Nguyen Huynh, T.H., Gonzalez, F., Milinkovitch, M.C., Mallo, M. and Duboule, D. (2016) Reorganisation of Hoxd regulatory landscapes during the evolution of a snake-like body plan. Elife 5. pii: e16087. »» Beccari, L., Yakushiji-Kaminatsui, N., Woltering, J.M., Necsulea, A., Lonfat, N., Rodríguez-Carballo, E., Mascrez, B., Yamamoto, S., Kuroiwa, A. and Duboule D. (2016) A role for HOX13 proteins in the regulatory switch between TADs at the HoxD locus. Genes Dev. 30(10):1172-1186. »» Darbellay, F. and Duboule, D. (2016) Topological domains, metagenes, and the emergence of pleiotropic regulations at Hox loci. Curr Top Dev Biol. 116:299-314. »» Fabre, P.J, Benke, A., Manley, S. and Duboule, D. (2015) Visualizing the HoxD Gene Cluster at the Nanoscale Level. Cold Spring Harb Symp Quant Biol. 80:9-16. »» Fabre, P.J., Benke, A., Joye, E., Nguyen Huynh, T.H., Manley, S. and Duboule D. (2015) Nanoscale spatial organization of the HoxD gene cluster in distinct transcriptional states. Proc Natl Acad Sci USA 112(45):13964-13969. »» Woltering, J.M. and Duboule, D. (2015) Tetrapod axial evolution and developmental constraints; Empirical underpinning by a mouse model. Mech Dev. 138 Pt 2:64-72. »» Lonfat, N. and Duboule, D. (2015) Structure, function and evolution of topologically associating domains (TADs) at HOX loci. FEBS Lett. 589(20 Pt A):2869-2876. »» Vieux-Rochas, M., Fabre, P.J., Leleu, M., Duboule, D. and Noordermeer, D. (2015) Clustering of mammalian Hox genes with other H3K27me3 targets within an active nuclear domain. Proc Natl Acad Sci USA. 112(15):4672-4677.

151

Gönczy Lab Pierre Gönczy - Full Professor

Pierre Göncyz obtained his PhD from The Rockefeller University (New York City, USA) in 1995. Thereafter, he conducted postdoctoral work at the EMBL (Heidelberg, Germany), before starting his laboratory in Lausanne in 2000 at ISREC, joining EPFL in 2005.

gonczy-lab.epfl.ch

Introduction

Results Obtained

We are interested in understanding fundamental cell division processes and focus on two in particular: centriole assembly and asymmetric division. To uncover the underlying mechanisms, we use a combination of genetic, functional genomic, biochemical, proteomic and cell biological approaches, primarily in C. elegans embryos and human cells.

We pursued our multidisciplinary research program to gain insights notably into the mechanisms of centriole assembly, as well as of centrosome positioning, in particular during asymmetric division. Two studies illustrating our efforts are highlighted below.

Centriole formation: Centrioles are evolutionarily conserved organelles essential for the assembly of cilia, flagella, and centrosomes, and which are characterized by a 9-fold radial symmetry of microtubules. We and others identified five proteins required for centriole formation in C. elegans, which are likewise crucial in other organisms. In collaboration with the Steinmetz laboratory, we discovered that one of these protein families (SAS-6 proteins) forms 9-fold symmetric rings at the root of the 9-fold symmetry of centrioles. Asymmetric cell division: Asymmetric division is crucial for generating diversity during development and stem cell lineages, and relies notably on proper positioning of the mitotic spindle. We and others showed that spindle positioning requires an evolutionary conserved ternary complex, which anchors the minus end directed motor protein complex dynein at the cell cortex. There, dynein is thought to generate pulling forces on astral microtubules that emanate from the spindle poles, thus positioning the mitotic spindle.

Keywords Cell biology, developmental biology, mitosis, centriole assembly, spindle positioning, C. elegans, human cells.

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Persistence of paternal centrioles The two gametes contribute differently to the zygote at fertilization. Apart from the genetic material, the oocyte contributes the bulk of cytoplasmic constituents, whereas in most animal species the sperm contributes two centrioles. How long such paternally contributed centrioles persist in the developing embryo was not known in any system. We set out to track the fate of paternally contributed centriolar components in C. elegans embryos. Our analysis revealed that several evolutionarily conserved centriolar components exhibit exceptional persistence over many cell cycles in the embryo. These findings raise the intriguing possibility that centrioles could act as information carrier, and that paternal centrioles may contribute information to the zygote. See Balestra et al.; 2015. Centrosome separation The two centrosomes present at the onset of mitosis must separate accurately to ensure proper bipolar spindle assembly. The minus-end directed motor dynein plays a key role in centrosome separation, but the underlying mechanisms remained elusive. We addressed these questions in the one-cell C. elegans embryo using a combination of 3D time-lapse microscopy and computational modeling. Our analysis revealed that centrosome separation is powered by the joint action of dynein at the nuclear envelope and at the cell cortex. We demonstrated that dynein at the cell cortex acts as a crosslinker that transmits polarized actomyosin cortical flows initiated by the centrosomes earlier in the cell cycle. This novel mechanism elegantly couples the early events of cell polarization with centrosome separation, thus ensuring faithful cell division. See also De Simone et al.; 2016.

ISREC - Swiss Institute for Experimental Cancer Research

Team Members Postdoctoral Fellows

Niccolò Banterle George Hatzopoulos Kerstin Klinkert Marie Pierron Jian Qiu Benita Wolf PhD Students

Radek Jankele Melina Scholze Veronika Villimova Technicians

Coralie Busso Isabelle Fluckiger Computer simulation of centrosome separation in C. elegans embryo. Sperm (blue disk) and oocyte (dark green disk) pronuclei are shown. The two centrosomes (small green disks) nucleate microtubules (white lines). Dynein motors at the surface of pronuclei (blue points) or the cell cortex (red points) bind microtubules, exert force on them, and thus separate centrosomes.

Administrative Assistants

Nicole De Montmollin

Selected Publications »» Graciotti M., Fang Z., Johnsson K. and Gönczy, P. (2016) Chemical genetic screen identified natural products that modulate centriole number. Chembiochem 17: 2063-2074. »» Sharma A., Aher A., Dynes N.J., Frey D., Katrukha E.A., Jaussi R., Grigoriev I., Croisier M., Kammerer R.A., Akhmanova A., Gönczy P. and Steinmetz M.O. (2016) Centriolar CPAP/SAS-4 imparts slow processive microtubule growth. Dev Cell 37: 362-376. »» De Simone A., Nédélec F. and Gönczy P. (2016) Dynein transmits polarized actomyosin cortical flows to promote centrosome separation. Cell Rep 14: 2250-2262. »» Gönczy, P. (2015) Centrosomes and cancer: revisiting a long-standing relationship. Nat Rev Cancer 15(11): 639-52. »» Neves, A., Busso, C. and Gönczy, P. (2015) Cellular hallmarks reveal restricted aerobic metabolism at thermal limits. Elife 4: e04810. »» Balestra, F.R., von Tobel, L. and Gönczy, P. (2015) Paternally contributed centrioles exhibit exceptional persistence in C. elegans embryos. Cell Res 25: 642-644. »» Blanchoud, S., Busso, C., Naef, F. and Gönczy, P. (2015) Quantitative analysis and modeling probes polarity establishment in C. elegans embryos. Biophysical J 108: 799-809.

153

Hanahan Lab Douglas Hanahan - Full Professor - Director of Swiss Institute of Experimental Cancer Research (ISREC)

Douglas Hanahan, born in Seattle, Washington, USA, received a bachelor’s degree in Physics from MIT (1976), and a Ph.D. in Biophysics from Harvard (1983). He worked at Cold Spring Harbor Laboratory in New York (1978-88) initially as a graduate student and then as a group leader. From 1988-2010 he was on the faculty of the Department of Biochemistry & Biophysics at UCSF in San Francisco. He has been elected to the American Academy of Arts & Sciences (2007), the Institute of Medicine (USA) (2008), the US National Academy of Science (2009), and EMBO (2010). In 2011, Hanahan received an honorary degree from the University of Dundee (UK).

154

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Introduction

Results Obtained

The Hanahan group investigates tumor development and progression using genetically engineered mouse models of cancer that recapitulate important characteristics of human cancers, with strategic goals to elucidate pathogenic mechanisms underlying multi-step tumorigenesis and malignant progression, and to develop new therapeutic strategies based on knowledge of mechanism for translation toward clinical trials aiming to improve the treatment of human cancers. Currently the lab focuses on melanoma, glioblastoma, and pancreatic, breast, and cervical cancers. Topics include mechanistic studies on acquired capabilities – hallmarks of cancer – including the capabilities for ‘invasion and metastasis’ and ‘evading immune destruction’. A crosscutting theme is the role of the heterotypic tumor microenvironment and the accessory cells that collaborate with cancer cells to manifest malignant disease. In addition, the lab is studying mechanisms of adaptive resistance to therapies targeting these and other hallmark capabilities, which represent fascinating perturbations into corrupted regulatory systems, and offer potential avenues to circumvent such drug resistance with combinatorial therapies.

The lab has made exciting progress on multiple fronts during 2015/16. We have, for example: • Reported that glioblastoma brain cancers are hypersensitive to drugs that elevate the cellular recycling system called autophagy to levels that cause cell death, impairing tumor progression, and that such autophagyassociated cell death can be instigated by repurposing two classes of clinically approved drugs, originally developed to be anti-depressants or anti-coagulants, which are now appreciated to hyper-stimulate autophagy (Shchors et al, Cancer Cell, 2015). • Extended this concept, where in on-going studies we have found that these autophagy-inducing drugs can be combined with anti-angiogenic therapy, producing added benefit, exemplifying a conceptual strategy of co-targeting distinct hallmarks of cancer, aiming to limit adaptive resistance to cancer therapies (unpublished). • Reported that pancreatic neuroendocrine tumors can be defined as two molecular subtypes, of which one is preferentially associated with metastasis (Sadanandam et al, 2015, and unpublished). • Described a new form of adaptive resistance to anti-angiogenic therapy - metabolic symbiosis - whereby cancer cells, faced with vascular insufficiency, adopt compartmentalized metabolic states to share limited supplies of blood-borne glucose, with one instead utilizing as fuel lactate that is produced by the other’s metabolism of glucose (Allen et al Cell Reports, 2016). • Investigated mechanisms of resistance to cancer immunotherapy, using a mouse model of cervical carcinoma induced by the HPV16 oncogenes, wherein multiple micro-environmental barriers to infiltration and killing by cytotoxic T cells are implicated. In the context of a Sinergia grant and two pharma collaborations, we are characterizing the immune barriers and testing mechanism-based therapies in logical combinations, seeking to break down the barriers and unleash efficacious immunotherapy (unpublished).

Keywords Cancer mechanisms & therapeutic targeting, mouse models of cancer; tumor microenvironment.

ISREC - Swiss Institute for Experimental Cancer Research

Team Members Postdoctoral Fellows

Krisztian Homicsko Iacovos Michael Courtney Thomas Stephan Wullschleger Qian (Sophia) Zeng PhD Students

Gabriele Galliverti (joint M. Swartz) Julie Scotton Sadegh Saghafina Technical Staff

Sylvie André Balfast Mei-Wen Peng Bruno Torchia Sebastien Lamy Lab Manager Metabolic symbiosis induced by anti-angiogenic therapy. Vascular regression elicits reorganization of tumors into a hypoxic compartment that is glycolytic and a normoxic compartment that imports and metabolizes lactate. Inhibition of mTOR disrupts this symbiosis (Allen et al., Cell Reports 2016).

Ehud Drori

Visiting Students

Agata Mlynska

Administrative Assistants

Diane Cevat Dorothée Demeester

Selected Publications »» Shchors, K. Massaras, A. and Hanahan, D. (2015) Dual targeting of the autophagic regulatory circuitry in gliomas with repurposed drugs elicits cell-lethal rates of autophagy and therapeutic benefit. Cancer Cell 28: 456-471. »» Sadanandam, A., Wullschleger, S., Lyssiotis, C., Grötzinger, C., Barbi, S., Bersani, S., Körner, J., Wafy, I., Mafficini, A., Lawlor, R.T., Asara, J., Bläker, H., Cantley, L.C., Wiedenmann, B., Aldo Scarpa, S. and Hanahan, D. (2015) Pancreatic neuroendocrine tumors: cross-species analysis reveals molecular subtypes with distinctive metastatic, developmental, and metabolic characteristics. Cancer Discovery 5: 1296-1313. »» Hanahan, D. and Weinberg, R.A. (2016) The hallmarks of cancer: Perspectives for cancer medicine. In “The Oxford Textbook of Oncology, 3rd edition”, eds. Kerr, D., Haller, D., Van De Velde, C., Baumann, M, & Saijo, N.; Oxford University Press, Oxford, UK. »» Hanahan, D. and Weinberg, R.A. (2016) Biological Hallmarks of Cancer. In “Holland-Frei Cancer Medicine, Ninth Edition”, eds. Bast Jr., R.C., Croce, C.M., Hait, W., Hong, W.K., Kufe, D.W., Pollock, R.E., Weichselbaum, R.R., & Holland, J.F.; John Wiley & Sons, Hoboken, USA. »» Allen, E., Mieville, P., Warren, C.M., Li, L., Peng, M.-W., and Hanahan, D. (2016) Metabolic symbiosis enables adaptive resistance to anti-angiogenic therapy that is dependent on mTOR signaling. Cell Reports 15: 1144-1460.

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Hantschel Lab Douglas Hanahan - Tenure-Track Assistant Professor - ISREC Foundation Chair for Translational Oncology

Oliver Hantschel studied biochemistry in Regensburg and New York, received his PhD in 2004 from EMBL Heidelberg and did postdoctoral work at the Center for Molecular Medicine in Vienna. In 2010, he obtained his Venia Docendi (Habilitation) in Experimental Haematology from the Medical University of Vienna and joined EPFL in 2011.

Introduction

Results Obtained

Protein kinases are strongly involved in oncogenesis. The inhibition of aberrantly activated kinases is considered to be beneficial for cancer treatment. Since 2001, 30 inhibitors of a few oncogenic driver kinases in haematological and solid tumors have entered clinical practice. Despite remarkable clinical responses that could be achieved in selected diseases, most kinase inhibitors merely improve progression-free survival, but not overall survival, which is due to various mechanisms of evasive and adaptive resistance. Moreover, it is difficult to develop highly selective kinase inhibitors, as there are more than 500 kinases in humans with a conserved structure. Therefore, side effects caused by the inhibition of off-target kinases may limit its clinical utility. The Hantschel lab studies oncogenic kinase signaling by using interdisciplinary approaches at the interface of biochemistry, proteomics, chemical biology and protein engineering with the aim to identify innovative ways for therapeutic intervention.

Despite the success of ATP-competitive kinase inhibitors, the development of secondary drug resistance severely blunted initial clinical responses in most cases. In addition, only few human protein kinases have been targeted with the required degree of specificity by inhibitors targeting the ATP binding pocket of the protein kinase domain. An alternative strategy is the identification and targeting of sites other than the ATP binding pocket that are critical for kinase activity and that may down-modulate oncogenicity. This may provide an alternative handle to provide more specific kinase inhibitors, as the targeted site would be unique to only a few kinases and could decrease the overall incidence of drug resistance. We have demonstrated that the SH2 domain of the cytoplasmic tyrosine kinases oncoproteins ABL and FES acts as an allosteric activator, which is critical for high kinase activation and oncogenicity.

Main research avenues include: • Structure-function analysis of protein kinases • Targeting of intracellular protein-protein interactions and posttranslational modifications with engineered high-affinity protein antagonists • Analysis of oncogenic signaling networks using interaction- and phospho-proteomics. • Mechanism-of-action and specificity studies of kinase inhibitors

Keywords Leukemia, kinase inhibitors, protein engineering, phosphorylation, proteomics.

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Based on the promising results we have embarked on a systematic survey of most classes of cytoplasmic tyrosine kinases for allosteric activation that may be mediated by their modular protein interaction domains, e.g. SH2 and SH3 domains (see Figure). Using both quantitative in vitro enzymological assays with purified kinases (from bacterial, insect cell and mammalian expression systems), structure-function analysis as well as models in cancer cells, we have mapped such novel allosteric interactions and currently study their molecular mechanism-of-action. This provides the rationale for the functional testing of these interactions in cancer models with the prospect of their targeting with engineered protein inhibitors (monobodies) and small molecule chemical inhibitors. Our work provides important insight into the regulation of a large class of therapeutically important protein kinases, may identify additional targetable sites and provide the framework for future cancer drug development efforts.

ISREC - Swiss Institute for Experimental Cancer Research

Team Members Postdoctoral Fellows

Tim Kükenshöner Allan Lamontanara Gregory Mann Sina Reckel Timothy Reichart PhD Students

Daniel Duarte Grégory La Sala Nadine Schmit Research Technician

Sandrine Georgeon Apprentice

Sara Pereira In cytoplasmic tyrosine kinases (CTKs), protein interaction domains (PID) are involved in autoinhibition. Upon oncogenic activation, PIDs contribute to allosteric activation of CTKs and increase substrate recruitment. Engineered proteins or drugs can be used to disrupt allosteric activation.

Administrative Assistants

Christine Skaletzka

Selected Publications »» Wojcik, J., Lamontanara, A.J., Grabe, G., Koide, A., Akin, L., Gerig, B., Hantschel, O. and Koide, S. (2016) High-affinity monobody inhibitors directed to the SH2-kinase interface of Bcr-Abl. J. Biol. Chem. 291(16):8836-8847. »» Maxson, J.E., Abel, M.L., Wang, J., Deng, X., Reckel, S., Luty, S.B., Sun, H., Gorenstein, J., Hughes, S., Bottomly, D., Wilmot, B., McWeeney, S.K., Radich, J., Hantschel, O., Middleton, R.E., Gray, N.S., Druker, B.J. and Tyner, J.W. (2016) Identification and characterization of tyrosine kinase nonreceptor 2 mutations in leukemia through integration of kinase inhibitor screening and genomic analysis. Cancer Res. 76(1): 127-138. »» Reckel, S. and Hantschel, O. (2015) Kinase regulation in Mycobacterium tuberculosis: variations on a theme. Structure 23(6): 975-976. »» Lorenz, S., Deng, P., Hantschel, O., Superti-Furga, G. and Kuriyan, J. (2015). Crystal structure of an SH2-kinase construct of c-Abl and effect of the SH2 domain on kinase activity. Biochem. J. 468(2): 283-291. »» Hantschel, O. (2015) Unexpected off-targets and paradoxical pathway activation by kinase inhibitors. ACS Chem. Biol. 10(1) : 234-245.

157

Huelsken Lab Joerg Huelsken - Associate Professor

Joerg Huelsken received his PhD in 1998 at the Humboldt University, Berlin, and did postdoctoral research at the Max-Delbrueck Center for Molecular Medicine, Berlin. He joined ISREC as an associate scientist and NCCR project leader in January 2003 and was nominated Associate Professor at the EPFL School of Life Sciences in 2011.

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Introduction

Results Obtained

Cancer stem cells (CSC) or tumor-initiating cells have been identified as subpopulation of tumor cells at the origin of cancer development and as a major driver for long-term tumor growth, tumor progression and metastasis. We are studying the biology of these cells with an emphasis on their interaction with other tumor cells and with the tumor stroma. In particular the role of cancer stem cells in the control of anti-tumor immune reactions has been a major topic of our research in recent years. Based on the principles we have learned from detailed analysis of pre-clinical tumor models, we are currently exploring several novel therapeutic options to interfere with these cells. We concentrate on breast and colon cancers for which we were able to show that eliminating cancer stem cells can cure disease even in advanced stages of cancer progression.

Most cancers, even in an advanced stage, resemble their tissue of origin indicating that tumor cells maintain parts of the normal differentiation program of their non-transformed ancestors. We now identified the homeobox transcription factor HoxA5 as an important inducer of intestinal epithelial differentiation. In colon cancer, HoxA5 is down-regulated during cancer progression, but when re-activated can induce loss of the cancer stem cell phenotype and can strikingly block-tumor growth and metastasis in vivo. HoxA5 is interconnected with the Wnt pathway in a negative feedback loop which ensures definitive bimodal fate decisions enforcing cells to halt cell cycling and exit the stem cell pool. Since HoxA5 expression can be triggered by retinoids, this may allow to treat colon cancer patients by Hox-mediated elimination of cancer stem cells.

Keywords Cancer stem cells, immunotherapy

metastatic

colonization,

differentiation

therapy,

Apart from generating all other tumor cells, we now find that cancer stem cells have an important function in controlling anti-tumor immune responses. For breast cancer, we have identified mechanisms which enable cancer stem cells to induce an immune suppressive microenvironment. This appears to be in particular important during metastatic seeding when a small number of cancer stem cells arrives in a new target organ and has to modify the stroma to become tumor-supportive. An important aspect of this ability of cancer stem cells is their immanent resistance to cell death which makes them withstand a number of hostile influences from the tumor stroma. We are working to decompose this immune suppressive activity in order to design targeted strategies for metastasis prevention which overcome these resistance mechanisms.

ISREC - Swiss Institute for Experimental Cancer Research

Team Members Postdoctoral Fellows

Laurent Beziaud PhD Students

Luisa Spisak Maxim Norkin Mathieu Girardin Nicolas Desbaillets Zuzana Tartarova Visiting Scientists

Jean-Paul Abbuehl Paloma Ordóñez Morán Technician

Pierre Dessen Administrative Assistants

Fanny Cavat

Cancer initiation in the intestinal epithelium of the pre-clinical cancer model APClox/lox, a frequently mutated tumor suppressor gene in human colorectal cancers, can be prevented by treatment with vitamin A (retinoic acid). This enforces differentiation of cancer stem cells preventing cancer growth.

Selected Publications »» Natalia Lugli, N., V.S. Dionellis, P. Ordonez-Moran, I. Kamileri, S.K. Sotiriou, J. Huelsken, T. Halazonetis (2017). Enhanced rate of acquisition of point mutations in mouse intestinal adenomas compared to normal tissue. Cell Reports, in press. »» Khurana, S., S. Schouteden, A. Santamaria-Martinez, J. Huelsken, A. Lacy-Hulbert, C. Verfaillie (2016). Outside-in integrin signaling regulates stemness and ageing of hematopoietic stem cells. Nature Commun 7:13500. »» Tatárová, Z., J.P. Abbuehl, S. Maerkl and J. Huelsken (2016). Microfluidic co-culture platform to quantify chemotaxis of primary stem cells. Lab Chip, 16:1934-45. »» Diderich, P., D. Bertoldo, P. Dessen, M. Khan, I. Pizzitola, W. Held, J. Huelsken, C. Heinis (2016). Phage selection of chemically stabilized α-helical peptide ligands. ACS Chem Biol, 11:1422-7. »» Bertoldo, D., M. Khan, P. Dessen, W. Held, J. Huelsken, C. Heinis (2016).Phage Selection of Peptide Macrocycles against β-Catenin to Interfere with Wnt Signaling. Chem Med Chem., 11:834-9. »» Ordóñez-Morán, P., Dafflon, C., Imajo, M., Nishida, E., Huelsken, J. (2015). HoxA5 counteracts stem cell traits by inhibiting Wnt signalling in colorectal cancer. Cancer Cell, 28:815-29. »» Chiacchiera, F. , Rossi, A., Jammula, S., Piunti, A., Scelfo, A., Ordóñez-Morán, P., Huelsken, J., Koseki, H., Pasini, D. (2015). Polycomb complex PRC1 preserves intestinal stem cell identity by sustaining Wnt/ßcatenin transcriptional activity. Cell Stem Cell 18:91-103.

159

Lingner Lab Joachim Lingner - Full Professor

Joachim Lingner received his PhD in 1989 from the Biocenter, University of Basel under the supervision of Walter Keller. He then pursued a Postdoc working with Thomas Cech at the Howard Hughes Medical Institute in Boulder, Colorado. In 1997, he became a group leader at ISREC and then was promoted to Senior group leader in 2002. Prof. Lingner became an Associate Professor at EPFL in 2005 and then a Full Professor in 2009. He has received many honors including the STARTfellowship from the Swiss National Science Foundation in 1997; Friedrich Miescher Prize from the Swiss Society of Biochemistry in 2002; EMBO member in 2005; ERC advanced investigator grant in 2008.

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Introduction

Results Obtained

Telomeres are nucleoprotein structures at the ends of eukaryotic chromosomes. They have crucial functions as tumor suppressors and they protect chromosome ends from degradation and rearrangements. Telomere length and chromatin defects cause telomeropathies, which are characterized by damage in highly proliferative tissues early in life. Telomeres also serve as cellular clocks. They shorten in normal human cells with every round of DNA replication due to the DNA end replication problem and the absence of telomerase. Short telomeres elicit a DNA damage response triggering a permanent cell cycle arrest termed cellular senescence. Thus, the replicative potential of primary human cells is limited. While cellular senescence may contribute to organismal aging, it is beneficial to restrain the growth of pre-cancerous lesions. During progression towards malignancy, senescence is overcome by mutations in cell cycle regulators such as p53 and pRB. Furthermore, cancer cells acquire mutations that reactivate the telomerase enzyme, which stabilizes telomere length. Through telomerase activation, cancer cells acquire an immortal phenotype representing a cancer hallmark. Our laboratory combines telomeric chromatin analysis by mass spectrometry, biochemistry and molecular genetics to study the function, the dynamics and maintenance of telomere structures in normal development and disease.

Oxidative damage of telomeres can promote cancer, cardiac failure, and muscular dystrophy. Specific mechanisms protecting telomeres from oxidative damage had not been described. In collaboration with Viesturs Simanis, we analyzed telomeric chromatin composition by QTIP (Nat Comm. 4, 2848 (2013); Methods 114, 28 (2017)) during the cell cycle and showed that the antioxidant enzyme peroxiredoxin 1 (PRDX1) is enriched at telomeres during S phase (Cell Reports 17, 3107 (2016)). Deletion of the PRDX1 gene leads to damage of telomeric DNA upon oxidative stress, revealing a protective function of PRDX1 against oxidative damage. We also found that oxidized nucleotide or DNA substrates cause premature chain termination when incorporated by telomerase. Thus, PRDX1 safeguards telomeres from oxygen radicals to counteract telomere damage and preserve telomeric DNA for elongation by telomerase. The telomeric shelterin protein TRF2 suppresses the DNA damage response (DDR) and this function has been attributed to its abilities to trigger t-loop formation or to prevent massive decompaction and loss of density of telomeric chromatin. In collaboration with the group of Suliana Manley, we applied stochastic optical reconstruction microscopy (STORM) to measure the sizes and shapes of functional human telomeres of different lengths and dysfunctional telomeres that elicit a DDR (Genes & Dev, in press). Telomeres have an ovoid appearance with considerable plasticity in shape. Depletion of TRF2, TRF1 or both affected the sizes of only a small subset of telomeres. Co-staining of telomeres with DDR markers further revealed that the majority of DDR-signaling telomeres retained a normal size. Thus DDR signaling at telomeres does not require decompaction. We propose that telomeres are monitored by the DDR-machinery in the absence of telomere expansion and that the DDR is triggered by changes at the molecular level in structure and protein composition.

Keywords Telomeres, TERRA long noncoding RNA, chromatin, cellular senescence, telomeropathies.

ISREC - Swiss Institute for Experimental Cancer Research

Team Members Postdoctoral Fellows

Eric Aeby Wareed Ahmed Reyes Babiano Marianna Feretzaki Galina Glousker Gérald Lossaint Sophie Redon PhD Students

Jana Majerska Anna-Sophia Reis Patricia Renck-Nunes Aleksandra Vancevska Technician

Thomas Lunardi Administrative Assistants

Nicole de Montmollin

Quantitative telomeric chromatin isolation protocol (QTIP). (a) Workflow of QTIP. (b) Effects of TRF2-depletion at telomeres. (c) Comparison of telomeric protein composition at long versus short telomeres. See Grolimund, Aeby et al., Nature Communications 4: 2848 (2013) for details.

Selected Publications »» »» »» »» »» »» »»

Aeby, E. and Lingner, J. (2015) ALT telomeres get together with nuclear receptors. Cell 160(5): 811-813. Azzalin, C.M. and Lingner, J. (2015) Telomere functions grounding on TERRA firma. Trends Cell Biol. 25(1): 29-36. *Aeby, E., *Ahmed, W., Redon, S., Simanis, V. and Lingner, J. (2016) Peroxiredoxin 1 protects telomeres from oxidative damage and preserves telomeric DNA for extension by telomerase. Cell Rep (17): 3107-3114. Lossaint, G. and Lingner, J. (2017) TZAP or not to zap telomeres. Science 355: 578-579. Feretzaki, M. and Lingner, J. (2017) A practical qPCR approach to detect TERRA, the elusive telomeric repeat-containing RNA. Methods 114: 39-45. Majerská, J., Redon, S. and Lingner, J. (2017) Quantitative telomeric chromatin isolation protocol for human cells. Methods 114: 28-38. *Vancesca, A., *Douglass, K.M., Pfeiffer, V., **Manley, S. and **Lingner, J. (2017) The telomeric DNA damage response occurs in the absence of chromatin decompaction. Genes & Dev, in press

161

Meylan Lab Etienne Meylan - Tenure-Track Assistant Professor - SNSF Professor

Etienne Meylan received a PhD in Life Sciences from the University of Lausanne in 2006. From 2007 to 2010, he was a postdoc at MIT, Cambridge USA. In 2011, he established his laboratory at ISREC as a SNSF Professor and since 2013 as Tenuretrack Assistant Professor. His laboratory focuses on the molecular mechanisms that contribute to the development of lung cancer..

Introduction

Results Obtained

In our laboratory, we study signalling pathways that regulate crucial aspects of tumor metabolism or immunology. Our efforts are currently focused on nonsmall cell lung cancer (NSCLC), the principal type of lung cancer, which is the leading cause of cancer related deaths worldwide in women and men.

In 2015 and 2016 we have continued our work on glucose transporter GLUT3, and have begun to investigate GLUT1 in NSCLC.Based on our previous findings of GLUT3 being a target gene of the epithelial-mesenchymal transition (EMT) transcription factor ZEB1, we decided to explore how EMT perturbation would affect GLUT3 expression and, by extension, glucose metabolism in NSCLC. To address these points, we used KrasLSL-G12D/WT; p53Flox/Flox mouse models of lung adenocarcinoma, where we increased or decreased the expression of an EMT transcription factor. Upon sacrifice, these lung tumors were isolated, and are currently under molecular and histopathological analysis. During our characterization of GLUT3 expression in tumor cells, we made the interesting observations that tumor cell lines from a rare pediatric liver cancer, hepatoblastoma, express GLUT3 to very high levels. This prompted us to interrogate how GLUT3 is regulated in tumor cells from this malignancy, and if knowledge can be gained about the metabolism of these tumors. Experiments with cultured cells as well as actual human tumor tissue samples are ongoing.

We use combinations of in vitro cellular systems, bioinformatics analyses and genetically-engineered mouse models of human cancer as well as human tissue specimens to accomplish our goal: to better understand how this malignancy develops and progresses to a fatal disease. An initial focus in our laboratory was to comprehend the molecular mechanisms explaining the regulation and function of a high affinity glucose transporter in NSCLC, GLUT3. Currently, we are expanding our research activities toward a more global understanding of pathways regulating the tumor environment. Hopefully, our projects will enable us to identify new vulnerabilities of this cancer, which could be amenable to future therapies to combat it. We have also developed a new line of research on hepatoblastoma, a rare childhood liver cancer where we identified GLUT3 expression being strongly elevated.

Keywords Lung cancer, mouse models, glucose metabolism, tumor immunology

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We have also continued our investigations of signalling pathways that impact lung tumor development, and highlighted two proteins, RIP4 and RANKL, which are both known to be potent activators of NF-kappaB signalling, a pathway promoting lung cancer development. Through genetic or pharmacologic-based experiments, we modified their expression or activity directly in vivo, to reveal their function in the development of NSCLC. The consequences of RIP4 or RANKL blockade on tumor cells and the immune microenvironment are currently being investigated. In parallel, we have elaborated a sophisticated methodology to extract and analyse in an unbiased manner the complex immune microenvironment of lung tumors from our mouse models. Hopefully, these analyses will provide new information about immune cell types causally linked to tumor progression.

ISREC - Swiss Institute for Experimental Cancer Research

Team Members Postdoctoral Fellows

Pierre-Benoit Ancey Julien Faget Jawahar Kopparam PhD Students

Caroline Contat Svenja Groeneveld Technician

Jessica Vazquez Silvia Sabatino (apprentice) Bioinformatician

Nadine Zangger

Masterâ&#x20AC;&#x2122;s Students

Bernard Moret

Administrative Assistants

Christine Skaletzka

General experimental setting: tumors are initiated by intratracheal virus-Cre, where a second gene or shRNA of interest can be added for study. Micro-CT reveals lung tumors a few months after initiation. At sacrifice, tumors are collected individually and prepared for multiple analyses.

163

Oricchio Lab Elisa Oricchio - Tenure-Track Assistant Professor - ISREC Foundation Chair for Translational Oncology

In November 2014, Elisa Oricchio was appointed as tenure track Assistant Professor at ISREC/EPFL. Prof. Oricchio graduated in Genetics with highest honor in 2004 and obtained a PhD in 2008 at the National Italian Institute of Health in Rome Italy. In Sept 2008, she joined the group of Dr. HG Wendel at Memorial Sloan Kettering (NY, USA) as a post-doc. Her research work focused on the genetics of Lymphoma exploring innovative therapeutic approaches.

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Introduction

Results Obtained

Research in Oricchio laboratory focuses on the genetics of lymphoma and its translation into new therapies. Lymphoma is a heterogeneous disease characterized by multiple genomic alterations. We combine genomic analyses of human tumors with functional in vivo studies using mosaic models of lymphomas to functionally annotate genes of interest. Moreover, we directly compare the impact of different genetic lesions on therapy response using highly controlled experimental systems that resemble the design of clinical trials in a physiological context. Our ultimate goal is to exploit our genetic and biological studies for the design of new therapeutic strategies.

The research activity in the lab focuses on the lymphoma biology and recently we started a new project on Primitive Neuro-Ectodermal Tumors. We have 3 main projects ongoing in the lab. Project 1. Identify novel therapeutic targets in Follicular and Diffuse Large B-cell lymphoma. We used an inducible CRISPR/Cas9 library targeting more than ~500 kinases to identify new essential targets in DLBCL lymphoma. We found that loss of specific kinases regulating B-cell receptor and mTOR signaling strongly impair B-cell proliferation. Moreover, we uncovered an unexpected synthetic lethal interaction between inhibition of B-cell receptor signaling and SRC- family kinases prompting the possibility to test new rational combination therapies. Project 2. Identify chromosomal structural changes dictate by epigenetic and copy number alterations. Follicular lymphoma development is driven by multiple genomic alterations, including frequently mutated epigenetic modifiers (e.g. EZH2) and several copy number changes. The EZH2 gain of function mutation Y641X increases the H3K27me3 levels altering the heterochromatin organization and blocking the expression of several genes. Now, we are defining how epigenetic changes influence tri-dimensional organization of the genome. To analyze the chromosomal structural organization, we are using highthroughput Chromosome Conformation Capture method (Hi-C). We recently completed Hi-C analysis in lymphoma cell lines and in our preliminary data, we identified that the expression of several genes is concordantly regulated within specific chromosomal domains and is epigenetically controlled. Project 3. Define epigenetic and metabolic alterations in Primitive NeuroEctodermal Tumors (PNET). We developed a new in vivo model to study PNET pathogenesis. Our model is based on primary human neural precursor originated from induced pluripotent stem cells (human-iPS). We reported that PNET are dependent on MYC activity and genetic MYC inhibition alters the expression of metabolic genes such as PKM2 and LDHA and blocks cell proliferation. Now, we are exploring metabolic and epigenetic changes associated with PNET development. We are analyzing public available DNA methylation profile in PNET patients and we obtained in vivo preliminary data of the metabolic changes associated with these tumors.

Keywords Cancer genetics, mouse models, therapy

ISREC - Swiss Institute for Experimental Cancer Research

Team Members Post doctoral

Sungalee Stephanie PhD Students

Battistello Elena Donaldson Maria Technician

Katanayeva Natalya Administrative Assistants

Demeester Dorothée

Design and analysis of a genome editing screen using Crispr to identify new therapeutic targets for lymphoma treatment.

Selected Publications »» Boice, M., Salloum, D., Mourcin, F., Sanghvi, V., Amin, R., Oricchio, E., Jiang, M., Mottok, A., Denis-Lagache, N., Ciriello, G., Tam, W., Teruya-Feldstein, J., de Stanchina, E., Chan, W.C., Malek, S.N., Ennishi, D., Brentjens, R.J., Gascoyne, R.D., Cogné, M., Tarte, K. and Wendel, H.G. (2016) Loss of the HVEM tumor suppressor in lymphoma and restoration by modified CAR-T cells. Cell 167(2): 405-418. »» Oricchio, E., Papapetrou, E.P., Lafaille, F., Ganat, Y.M., Kriks, S., Mark, W.H., Teruya-Feldstein, J., Huse, J.T., Reuter, V., Sadelain, M., Studer, L. and Wendel, H.G. (2014) A cell engineering strategy to enhance the safety of stem cell therapies. Cell Report 8: 1677-1685. »» Goldgur, Y., Susi, P., Karelehto, E., Sanmark, H., Lamminmäki, U., Oricchio, E., Wendel, H.G., Nikolov, D.B. and Himanen, J.P. (2014) Generation and characterization of a single-chain anti-EphA2 antibody. Growth Factors 32(6): 214-222. »» Oricchio, E., Ciriello, G., Schatz, J.H., Jiang, M., Heguy, A., Viale, A., de Stanchina, E., Teruya-Feldstein, J., Sander, C., Wayne, T., Seshan, V.E., Chaganti,,R.S.K. and Wendel, H.G. (2014) Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy. J Exp. Med. 211(7): 1379-1391.

165

Radtke Lab Freddy Radtke - Full Professor

Freddy Radtke graduated from the University of ZĂźrich in molecular biology 1994, a postdoctoral fellowship at Genentech Inc. USA 19951996 was followed by a postdoctoral position at ISREC Switzerland 1997-1999; Assistant Member of the Ludwig Institute for Cancer Research 1999-2004 promoted to Associate Member in 2004; joined ISREC as Senior Scientist in 2006, before joining EPFL in August 2006 as associate professor; promoted to full professor in 2012.

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Introduction

Results Obtained

Our group is interested in the molecular mechanisms controlling tissue selfrenewal, differentiation and cancer. The basic principle of self-renewing tissues is that they continuously produce cells from a stem cell reservoir that gives rise to proliferating transient amplifying cells, which subsequently differentiate and migrate to the correct compartment. These processes have to be tightly regulated to ensure life-long homeostasis. Developmental signaling pathways such as Notch and Wnt signaling have been shown to play important roles in regulating self-renewing tissues. Moreover, these pathways are often deregulated during tumorigenesis due to mutations in key elements involved in these pathways. Using mouse genetics we study the role of evolutionarily conserved signaling pathways under physiological and pathological situations to gain a better understanding of their role in cancer. In addition, the lab optimizes and validates potential drug development candidates that target developmental signaling pathways to assess their mode of action and their efficacy in pre-clinical cancer models and in primary human tumor samples. The goal is to develop these drug development candidates further for clinical proof of concept in human studies. Another aspect of our current research is to study the influence of inflammation for tumor progression.

Dicer1 imparts essential survival cues in Notch driven T-ALL via miR-21 mediated tumor suppressor Pdcd4 repression: The modulatory function of individual miRNAs in Notch driven T-ALLs has recently been established. Although pro-tumorigenic and tumor-suppressive miRNAs are implicated in disease onset in murine models of Notch-driven T cell leukemia, whether Dicer1-processed miRNAs are essential for Notchdriven T-ALL was unknown. We showed that Dicer1-processed miRs are essential at all stages of T-ALL development and maintenance. Lineage tracing experiments revealed that Dicer1 deficiency led to the induction of apoptosis in T-ALL cells whereas cell cycle progression remained unaltered. Through microarray-based miRNA profiling, we identified miR-21 as a previously unrecognized miRNA deregulated in both mouse and human T-ALL. We demonstrated that miR-21 regulates T-ALL cell survival via repression of the tumor suppressor Pdcd4.

Keywords Cancer, leukemia, stem cells, differentiation, immunity, notch, Wnt, preclinical drug development and trials.

Chronic inflammation imposes aberrant stem cell fate via mechanotransduction : Chronic inflammation is associated with a variety of pathological conditions in epithelial tissues, including cancer, metaplasia and aberrant wound healing. We have delineated the effect of chronic inflammation on epithelial stem cells using the corneal epithelium as a model tissue. We demonstrated that chronic inflammation indirectly regulates stem cell fate choice by altering the mechanical properties of the surrounding microenvironment. Subsequently, aberrant mechanotransduction in corneal epithelial stem/progenitor cells induces epidermal differentiation via elevated Î˛-catenin signaling. Corneal differentiation can be restored using small molecule inhibitors of mechanotransduction. Collectively, this study demonstrates that chronic inflammation and mechanotransduction are linked and act to elicit pathological responses in epithelial stem cells. This therefore establishes a new mechanism by which chronic inflammation can contribute to disease.

ISREC - Swiss Institute for Experimental Cancer Research

Team Members Senior Scientists & Post Doctoral

Ute Koch Markus Germann Rajwinder Lehal Alain Kfouri Charlotte Urech Nadine Zangger PhD Students

Mateusz Antoszewski Linlin Cao Delphine Harduin Technician

Christelle Dubey Pasqualina Magliano Marianne Nkosi Administrative Assistants

Catherine Pache The schematic depicts the essential function of Dicer1 mediated miRNA biogenesis for induction and maintenance of Notch-driven T cell acute lymphoblastic leukemia (T-ALL) as well as novel signaling axis involving miR-21 and the tumor suppressor Pdcd4 that is essential for survival of T-ALL cells.

Selected Publications »» Chennupati, V., Koch, U., Coutaz, M., Scarpellino, L., Tacchini-Cottier, F., Luther, S.A., Radtke, F., Zehn, D. and MacDonald, H.R. (2016) Notch signaling regulates the homeostasis of tissue-restricted innate-like T cells. J Immunol 197: 771.782. »» Gamrekelashvili, J., Giagnorio, R., Jussofie, J., Soehnlein, O., Duchene, J., Briseño, C.G., Ramasamy, S.K., Krishnasamy, K., Limbourg, A., Kapanadze, T., Ishifune, C., Hinkel, R., Radtke, F., Strobl, L.J., Zimber-Strobl, U., Napp, L.C., Bauersachs, J., Haller, H., Yasutomo, K., Kupatt, C., Murphy, K.M., Adams, R.H., Weber, C. and Limbourg, F.P. (2016) Regulation of monocyte cell fate by blood vessels mediated by Notch signaling. Nat Commun 7: 12597. »» Nowell, C,S., Odermatt, P,D., Azzolin, L., Hohnel, S., Wagner, E.F., Fantner, G.E., Lutolf, M.P., Barrandon, Y., Piccolo, S. and Radtke, F. (2016) Chronic inflammation imposes aberrant cell fate in regenerating epithelia via mechanotrunsdaction. Nature Cell Biology 18(2):168-180. »» Bernier-Latmani, J., Cisravvsky, C., Demir, C.S., Bruand, M., Jaquet, M., Davanture, S., Ragusa, S., Siegert, S., Dormond, O.l., Benedito, R., Radtke, F., Luther, S.A. and Petrova, T.V. (2015) DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport. J Clin Invest 125(12): 4572-4586. »» Urech-Varenne, C., Radtke, F*. and Heinis, C*. (2015) Phage selection of bycyclic peptide ligands of the Notch1 receptor. CheMedChem 10(10):1754-1761. »» Junker, F., Chabloz, A., Koch, U. and Radtke, F. (2015) Dicer1 imparts essential survival cues in Notch-driven T-ALL via miR-21-mediated tumor suppressor Pdcd4 repression. BLOOD 126(8): 993-1004. »» López-Arribillaga, E., Rodilla, V., Pellegrinet, L., Guiu, J., Iglesias, M., Roman, A.C., Gutarra, S., González, S., Muñoz-Cánoves, P., Fernández-Salguero, P., Radtke, F., Bigas, A. and Espinosa, L. (2015) Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch. Development 142(1): 41-50.

167

Simanis Lab Viesturs Simanis - Associate Professor

Viesturs Simanis studied Biochemistry at Imperial College, graduating with a First Class Honours Degree in 1980. He did his Ph.D. studies with Professor Sir David Lane, at Imperial College London (awarded 1984). He did his postdoctoral studies with Professor Sir Paul Nurse, at ICRF in London, and the Department of Microbiology in Oxford (1984 to 1988). He then moved to the Swiss Institute for Experimental Cancer Research in Lausanne (Switzerland), as a junior, then senior group leader (1988 to 2006). He was appointed Associate Professor at EPFL in 2006.

simanis-lab.epfl.ch

Introduction

Results Obtained

Cell division requires duplication of the genome followed by segregation of one copy to each daughter cell and cytokinesis. Errors in these events can result in cell death, or alter the cellâ&#x20AC;&#x2122;s behaviour, which can contribute to the development of diseases such as cancer. We use S. pombe model to study cytokinesis, the final event of the cell cycle. Our goal is to understand how cytokinesis is regulated and coordinated with other events in the cell cycle. In S. pombe a GTPase-regulated NDR-kinase signalling network known as the Septation Initiation Network (SIN) acts at multiple points during cytokinesis. Failure of SIN signalling results in the production of multinucleated cells that die, while inappropriate activation of the SIN promotes cytokinesis from any cell cycle stage. The SIN is considered to be the functional counterpart of the mammalian Hippo signalling pathway, which regulates growth and proliferation. The SIN also plays a role in meiosis, where is it essential for generating the spores/ gametes following completion of the two meiotic divisions. Our primary tools are forward and reverse genetics, combined with cell biology and biochemical analysis. Our goal is to identify regulators and targets of the SIN in mitosis and meiosis.

Association of SIN proteins with the spindle pole bodies (SPBs) during mitosis is important for SIN regulation. We used semi-automated image analysis (with the Unser lab, EPFL) to study SIN proteins localisation in wild-type and mutant cells. This analysis uncovered new facets of SIN regulation. First, the association of Cdc7p with the SPBs in early mitosis is asymmetric, favouring the new SPB. This requires Plo1p activity, and is unaffected by mutations that influence Cdc7p asymmetry in anaphase. Second, Cdc7p asymmetry in anaphase B is promoted by the 14-3-3 protein Rad24p, but delayed by the DYRK-family kinase Pom1p and the spindle assembly checkpoint. Finally, some SIN proteins show dynamic localisation patterns in early mitosis, which then become fixed in anaphase B. We are now investigating the molecular basis underlying the transition between the two states of the SIN.

Keywords Cytokinesis, cell division, meiosis, mitosis, signal transduction, yeast

In a companion study in collaboration with the Xenarios lab (SIB-UNIL), we adopted a Boolean modelling approach to describe the qualitative behaviour of the SIN and predict the behaviour of compound mutants that had not yet been constructed. Our extended Boolean model of the SIN comprised most SIN components and regulators as individual, experimentally malleable nodes. We used CDK activity levels as control nodes for the simulation of SIN related events in different stages of the cell cycle. The model was optimized using single knock-out experiments of known phenotypic effect as a training set, and was able to correctly predict a double knock-out test set. Moreover, the model made in silico predictions that have been validated in vivo, providing new insights into the regulation and hierarchical organization of the SIN. We also collaborated with the Lingner lab (EPFL SV) to study the protein composition of telomeres at different cell cycle stages. This study revealed that peroxiredoxin1 associates with telomeres maximally during S-phase and helps protect telomeres from oxidative damage.

168

ISREC - Swiss Institute for Experimental Cancer Research

Team Members Post Doctoral Fellows

Andrea Krapp

PhD Students

Claudia Melcarne Manuela Moraru (graduated Oct. 2016) Technician

Elena Cano del Rosario Administrative Assistants

Catherine Pache

The image of the SIN scaffold Cdc11p-GFP illustrates progress from interphase (single SPB) to mitosis as a kymograph. The vertical axis is time, the horizontal represents SPB position. The inter-SPB distance decreases as the nuclei move to the middle of the daughter cells after spindle disassembly. In wild-type cells, CAR contraction begins at maximal SPB separation. The three phases of mitosis are shown to the right of the image. The “early” and “late” states of the SIN are shown to the right of the image. The “early” state requires Plo1p activity, and is characterised by faint SIN protein signals and unstable association of Cdc7p and Sid1p with the SPBs. The “late” state does not require Plo1p, but depends upon Spg1p and Etd1p. It is characterised by asymmetric localisation of some SIN proteins. The gradient between them indicates the fact that the precise timing of the transition varies from cell to cell

Selected Publications »» Aeby, E., Ahmed, W., Redon, S., Simanis, V. and Lingner, J. (2016) Peroxiredoxin 1 protects telomeres from oxidative damage and preserves telomeric DNA for extension by telomerase. Cell Reports 17:3107 - 3114. »» Chasapi, A., Wachowicz, P., Niknejad, A., Collin, P., Krapp, A., Cano, E., Simanis, V. and Xenarios, I. (2015) An extended, Boolean model of the septation initiation network in S.Pombe provides insights into its regulation. PLoS One 10: e0134214. (co-corresponding author) »» Simanis, V. (2015) Pombe’s thirteen - control of fission yeast cell division by the septation initiation network. Journal of Cell Science 128: 1465-1474. »» Wachowicz, P., Chasapi, A., Krapp, A., Cano Del Rosario, E., Schmitter, D., Sage, D., Unser, M., Xenarios, I., Rougemont, J. and Simanis, V. (2015) Analysis of S. pombe SIN protein association to the SPB reveals two genetically separable states of the SIN. Journal of Cell Science 128: 741-754.

169

Bucher Lab Philipp Bucher - Group Leader

Philipp Bucher was first trained as a molecular biologist at the University of Zürich, and subsequently received his PhD in computational biology at the Weizmann Institute of Science in Israel. He then worked as a postdoctoral fellow with Sam Karlin at Stanford University before he moved to ISREC where he was promoted senior scientist in 2001.

bucher-lab.epfl.ch

Introduction

Results Obtained

New technologies allow for comprehensive characterization of the molecular changes that cause a healthy cell to become cancerous. These technologies produce vast amounts of data. We develop computational methods that will help to extract insights and knowledge from such data. Our main focus is on gene regulation. Transcription factors are key elements of regulatory circuits that control gene expression. We are interested in the molecular processes that guide transcription factors to their target sites, in a developmental stage- and tissue-specific manner, and we are studying these processes by using computational approaches in conjunction with highthroughput functional genomics data such as CAGE and ChIP-Seq data. We are further interested in the use of molecular profiling data for medical diagnosis. To this end we develop and test machine learning methods in the framework of open prediction challenges organized by the DREAM and sbv IMPROVER consortia. Besides research, our group develops and maintains bioinformatics databases and web servers. Our best known resource is the Eukaryotic Promoter Database EPD, created in 1986 and regularly updated since then. The ChIPseq server features web-based programs to access and analyze a large collection of public functional genomics data sets. The Signal Search Analysis (SSA) and PWMTools server offer DNA motif discovery and search tools. These three resources are tightly interlinked and together form a comprehensive web-based platform for gene regulatory regions analysis.

Research Building cell differentiation trees from ChIP-seq data. Following up on previous joint work with Bernard Moret’s group we successfully applied a new tree building algorithm to histone modification data from ENCODE. The novelty of this algorithms is that it can assign samples to internal nodes of a tree corresponding to the common progenitors of more differentiated cell types. Building transcription factor specificity models from high-throughput experimental data: We successfully adapted a computational pipeline originally developed for protein binding microarray (PBM) to be used with highthroughput data generated with SMiLE-seq (Selective Microfluidics-based Ligand Enrichment followed by sequencing) technology recently developed in Bart Deplancke’s lab. Promoter analysis: Making use of large volumes of recently published transcription start and nucleosome mapping data, we carried out a comparative study on the role of positioned nucleosomes in promoter regions in five model organisms. Our results show that the so-called +1 nucleosome plays an active role in transcription start site selection in those promoters that lack a core promoter element such as a TATA-box, initiator or DPE. Annotation of SNPs with regard to TF binding potential. We developed a computational pipeline to identify all common variants that change the predicted affinity of a transcription factor binding site in the human genome. The resulting catalogue will be used to interpret histone modification profiles from a GWAS study carried by the SysGenetiX consortium.

Keywords Computational genomics, epigenetics, molecular diagnostics and machine learning

170

Bioinformatics resources The Eukaryotic Promoter database EPDnew was extended to three new model organisms: Arabidopsis thaliana, Saccharomyces cerevisiae and Schizosaccharomyces pombe. Several new feature has been added to the ChIP-seq server, including an application that generates genomic feature correlation plots in form of heatmaps and allows export of the corresponding numerical data in a format appropriate for follow-up analyses by statistics software packages such as R.

ISREC - Swiss Institute for Experimental Cancer Research

Team Members Postdoctoral Fellows

Giovanna Ambrosini René Dreos Sunil Kumar Rouayda Cavin Périer PhD Students

Romain Groux Administrative Assistants

Sophie Barret

Input form and results page of the PWMScan server. Upper right: Input form. Center left: sequence logo of the position weight matrix entered. Bottom: results page with action buttons for saving the match list, for extracting surrounding DNA sequences or sending the results to another web application.

Selected Publications »» Dreos, R., Ambrosini, G., Périer Cavin, R. and Bucher P. (2015). The Eukaryotic Promoter Database: expansion of EPDnew and new promoter analysis tools. Nucleic Acids Res. 43(Database issue):D92-D96. »» Ambrosini. G., Dreos, R. and Bucher, P. (2015). Principles of ChIP-seq data analysis illustrated with examples. Genomics Comp. Biol. 1(1):e22.

171

172

Core Facilities & Technology Platforms

In its goal to offer maximal support to its students and scientists in their training and research capabilities, EPFL and its School of Life Sciences have made a significant investment over the past years to establish state-of-the-art technology platforms and core facilities. These facilities are directed and managed by dedicated teams of highly trained and experienced staff and are run on a fee-for-service basis. They offer training, access to technology, assistance with experimental design and high level data analysis, and collaborations. The platforms are also involved in the School’s undergraduate and graduate teaching programs. In addition, scientists from our School of Life Sciences closely collaborate with other services in the Lemanic region, including the ‘Center for Biomedical Imaging’ (http://www.cibm.ch) and the ‘Lausanne Genomics Technologies Facility’

(http://www.unil.ch/gtf/en/home.html)

The following pages describe the Life Sciences-related core facilities and technology platforms currently available at the EPFL School of Life Sciences.

173

Bioelectron Microscopy - BioEM

Introduction The Bio Electron Microscopy Facility provides life scientists at the EPFL and the lemanic area with a wide range of equipment and expertise for imaging biological samples with electrons. This expanding field offers biologists a multitude of methods for seeing structures at high resolution and these play an important role in understanding cell function. The facility is situated in the School of Life Science, and the Interdisciplinary Centre of Electron Microscopy. The laboratories are equipped to prepare any type of biological sample for imaging with either scanning or transmission electron microscopy. This includes cryo as well as ambient temperature methods. BioEM supports laboratories in various ways, from providing users with advice and training in the different techniques, to complete service whereby all aspects of experiments are undertaken by the facility staff. This includes, sample preparation, imaging, and image analysis. The specific techniques are standard transmission and scanning electron microscopy, and the associated sample preparation methods. However, the facility also offers the latest 3D imaging technology using either serial section TEM, or electron tomography, as well as block face scanning and focussed ion beam volume imaging.

Team Members During the early part of 2016, the facility installed a new block face scanning electron microscope. This is a high resolution scanning electron microscope that houses an ultramicrotome immediately below the electron beam. The technique allows thin sections to be sliced from a sample’s surface whilst it is being imaged and enables serial images through the sample to be collected automatically. Although this was first developed for imaging brain circuits, this microscope is now being used on a wide variety of samples.

Services and Technologies

Facility Head

Graham Knott Senior Scientists

Davide Demurtas Daniela Sahlender Scientific Assistant

Catherine Maclachlan Technical Assistants

The facility offers training and services in the following methods: • Transmission electron microscopy • Cryo transmission electron microscopy • Scanning electron microscopy • Focussed ion beam scanning electron microscopy • Correlated light and electron microscopy • Pre-embedding immunolabelling • Post-embedding immuno labelling • Single particle imaging and analysis • Cryo fixation with high pressure freezing • Standard chemical fixation methods including microwave

Selected Publications »» Sharma A, Aher A, Dynes NJ, Frey D, Katrukha EA, Jaussi R, Grigoriev I, Croisier M, Kammerer RA, Akhmanova A, Gönczy P, Steinmetz MO (2016) Centriolar CPAP/SAS-4 Imparts Slow Processive Microtubule Growth. Dev Cell 37:362–376 »» Ramond E, Maclachlan C, Clerc-Rosset S, Knott GW, Lemaitre B (2016) Cell Division by Longitudinal Scission in the Insect Endosymbiont Spiroplasma poulsonii. MBio 7:e00881-16 »» Kulkarni SS, Joffraud M, Boutant M, Ratajczak J, Gao AW, Maclachlan C, Hernandez-Alvarez MI, Raymond F, Metairon S, Descombes P, Houtkooper RH, Zorzano A, Cantó C (2016) Mfn1 Deficiency in the Liver Protects Against Diet-Induced Insulin Resistance and Enhances the Hypoglycemic Effect of Metformin. Diabetes 65:3552–3560.

Image: Image showing a 3D model of endoplasmic reticulum (green), mitochondria (red) and lipid droplets (blue) inside a cultured mammalian cell. This model was reconstructed from serial electron microscopy images taken with a focussed ion beam scanning electron microscope (reconstruction work by Marine Sanna Meyer, Vincent Berweiler and Catherine Maclachlan).

174

bioem.epfl.ch

Stéphanie Clerc-Rosset, Marie Croisier Jerome Blanc Administrative Assistant

Marie-France Radigois

Contact Graham Knott AI 0143, Station 19 CH-1015, Lausanne +41 (0)21 693 18 62 graham.knott@epfl.ch

Core Facilities & Technology Platforms

BioImaging & Optics - BIOP

biop.epfl.ch

Introduction

Services and Technologies

Team Members

The Bioimaging and Optics platform (BIOP) is providing access to state of the art light microscopes and even more important expertise to solve challenging (biological) questions with modern light-microscopy. A broad range of instruments ranging from simple wide-field imaging systems over standard point-scanning confocal microscopes up to a high-end 2-Photonexcitation microscope and microscopes which allow imaging below the diffraction limit (high/super resolution microscopes) are currently available. Scientists seeking access to the BIOP are trained on the instrument optimally matching their scientific questions. The competence in sample preparation and image acquisition is complemented with strong image processing skills and necessary computer power to perform image processing. The idea is to link the image analysis with the image acquisition as early as possible in order to guarantees optimal scientific results.

• • • • • •

Facility Head

•

Wide-field transmission and fluorescent microscopes Life cell imaging microscopes Single and multiple-beam confocal microscopes 2P microscope Fluorescence Lifetime Microscopy (FLIM) High resolution and super resolution microscopes (SIM, STROM, STED) Image Processing tools (commercially available and/or custom built)

Arne Seitz

Microscopy

Jose Artacho Luigi Bozzo Joao Firmino Thierry Laroche Image Processing

Olivier Burri Romain Guiet

Administrative Assistant

Maureen Hersperger

Contact Arne Seitz AI 0241, Station 15 CH-1015, Lausanne +41 (0)21 693 96 18 arne.seitz@epfl.ch

Selected Publications »» Sage D, Donati L, Soulez F, Fortun D, Schmit G, Seitz A, Guiet R, Vonesch C, Unser M. (2017) DeconvolutionLab2: An open-source software for deconvolution microscopy. Methods 15 115:28-41. »» Dudin O, Bendezú FO, Groux R, Laroche T, Seitz A, Martin SG. (2015) A formin-nucleated actin aster concentrates cell wall hydrolases for cell fusion in fission yeast. J Cell Biol. 208(7):897-911. »» Bretscher AJ, Honti V, Binggeli O, Burri O, Poidevin M, Kurucz É, Zsámboki J, Andó I, Lemaitre B. (2015) The Nimrod transmembrane receptor Eater is required for hemocyte attachment to the sessile compartment in Drosophila melanogaster. Biol Open. 4(3):355-63. »» Virginie Hamel, Paul Guichard, Mathias Fournier, Romain Guiet, Isabelle Flückiger, Arne Seitz, and Pierre Gönczy (2014) Correlative multicolor 3D SIM and STORM microscopy. Biomedical Optics Express 5(10): 3326-3336. »» Burri O., Guiet R., Seitz A. (2014) Development of freely available software tools from the perspective of a multi user core facility. Microscopy: advances in scientific research and education 2 (13): 978-84.

175

Bioinformatics & Biostatistics - BBCF

bbcf.epfl.ch

Introduction

Services and Technologies

Team Members

The Bioinformatics and Biostatistics Core Facility (BBCF) provides the EPFL and Lemanic institutions with extensive support in bioinformatics and biostatistics, from designing experiments to interpreting and visualizing complex data. Its main competences are in management and analysis of genomic data, mathematical modeling and statistical analysis of quantitative biological data. The facility works in close relationship with the Geneva and Lausanne Genomics platforms and complements their respective bioinformatics team with additional support for the analysis of large or complex data sets, for the implementation of data processing pipelines for new high-throughput technologies, and for the statistical planning in complex experimental designs. It also helps researchers with mining public databases, designing and setting up local databases, inferring mathematical models from experimental data and running simulations to validate a model. The facility acts as a point of contact between the experimental biologists and the research groups in bioinformatics and in basic sciences. It also makes the junction between the EPFL life science community and the various resources maintained by the Swiss Institute of Bioinformatics, in particular the Vital-IT high performance computing center.

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Facility Head

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Analysis of high-throughput sequencing data: http://htsstation.epfl.ch Management of genomics data http://biorepo.epfl.ch Software development for genomics and bioinformatics: https://github. com/bbcf and http://bbcftools.epfl.ch Building blocks for online genomic data manipulations: http://bioscript. epfl.ch/ Databases and tools for lipidomics: http://lipidomes.org Atlas of the Drosophila midgut: http://flygut.epfl.ch Database of PCR primers http://bbcftools.epfl.ch/getprime Database of palmitoylated proteins: http://swisspalm.epfl.ch

Selected Publications »» »» »» »»

Loviglio, M. N. et al. (2016) Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics. Genome Med 8:105. Styles, E. B. et al. (2016) Exploring Quantitative Yeast Phenomics with Single-Cell Analysis of DNA Damage Foci. Cell Syst 3:264–277.e10. Zeng, Y.-X., Mjøs, S. A., David, F. P. A. & Schmid, A. W. (2016) Extension of least squares spectral resolution algorithm to high-resolution lipidomics data. Anal. Chim. Acta 914:35–46. Zaiss, M. M. et al. (2015) The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation. Immunity 43:998–1010.

176

Jacques Rougemont Post Doctoral

Fabrice David Philippe Jacquet Marion Leleu Scientific Assistants

Sara Benmohammed Elena Cabello Elena Rosinskaya Administrative Assistant

Marie-France Radigois

Contact Jacques Rougemont AAB 025, Station 15 CH-1015, Lausanne +41 (0)21 693 95 73 jacques.rougemont@epfl.ch

Core Facilities & Technology Platforms

Biomolecular Screening - BSF

bsf.epfl.ch

Introduction

Team Members

The Biomolecular Screening Facility is a multidisciplinary platform created in 2006 at the EPFL for performing screens in life sciences-related projects. In the frame of the NCCR-Chemical Biology, the BSF is hosting ACCESS, Academic Chemical Screening Platform for Switzerland, that provides chemical diversity, screening facilities and know-how in chemical genetics for academics countrywide.

Facility Head

Gerardo Turcatti Scientists

Damiano Banfi Marc Chambon Fabien Kuttler

Services and Technologies • • • • • • • •

Access to instrumentation dedicated to microplates and cell culture facilities Chemical libraries of about 100’000 small molecules (BSF-ACCESS) Genome–wide siRNA collections Compound storage and management Compounds delivery to partners Assay development and validation for HTS Assay automation and statistical validations Pilot screenings

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Primary screening campaigns Hits confirmation Dose response assays Secondary screens High Content Screening. Phenotypic assays by Digital Holographic Imaging (label free) and Fluorescence Microscopy Image processing for high content screening read-outs Data management using in house developed Laboratory Implementation Management System (LIMS). Cheminformatics

Assistants

Nathalie Ballanfat Julien Bortoli Antoine Gibelin Jonathan Vesin Florian Monachon Postdoctoral

Benjamin Rappaz Administrative Assistant

Maureen Hersperger

Contact

Selected Publications »» Horvath, P.; Aulner, N.; Bickle, M.; Davies, A. M.; Nery, E. D.; Ebner, D.; Montoya, M. C.; Ostling, P.; Pietiainen, V.; Price, L. S.; Shorte, S. L.; Turcatti, G.; von Schantz, C.; Carragher, N. O., Screening out irrelevant cell-based models of disease. Nat Rev Drug Discov 2016, 15 (11), 751-769. »» Kirkpatrick, C. L.; Martins, D.; Redder, P.; Frandi, A.; Mignolet, J.; Chapalay, J. B.; Chambon, M.; Turcatti, G.; Viollier, P. H., Growth control switch by a DNA-damage-inducible toxin–antitoxin system in Caulobacter crescentus. Nature Microbiology 2016, 1, 16008. »» Graciotti, M.; Fang, Z.; Johnsson, K.; Gönczy, P., Chemical Genetic Screen Identifies Natural Products that Modulate Centriole Number. Chembiochem 2016, 17 (21), 2063-2074. »» Rappaz, B., Moon, I., Yi, F., Javidi, B., Marquet, P., and Turcatti, G. (2015) Automated multi-parameter measurement of cardiomyocytes dynamics with digital holographic microscopy, Optics Express 23, 13333-13347. »» Rappaz, B., Kuttler, F., Breton, B., and Turcatti, G. (2015) Digital Holographic Imaging for Label-Free Phenotypic Profiling, Cytotoxicity, and Chloride Channels Target Screening, in Label-Free Biosensor Methods in Drug Discovery (Fang, Y., Ed.), pp 307-325, Springer Science+Business Media New York. »» Scott, C. C., Vossio, S., Vacca, F., Snijder, B., Larios, J., Schaad, O., Guex, N., Kuznetsov, D., Martin, O., Chambon, M., Turcatti, G., Pelkmans, L., and Gruenberg, J. (2015). Wnt directs the endosomal flux of LDL-derived cholesterol and lipid droplet homeostasis, EMBO Rep. e201540081

Gerardo Turcatti AAB 0 03 Station 15 CH-1015, Lausanne +41 (0)21 693 96 66 gerardo.turcatti@epfl.ch

177

Flow Cytometry - FCCF

fccf.epfl.ch twitter: Cytometry_EPFL

Introduction Flow cytometry is a technology that simultaneously measures and then analyses multiple physical characteristics of single particles, usually cells, as they flow in a fluid stream through a beam of light. The properties measured include a particle’s relative size, relative granularity or internal complexity, and relative fluorescence intensity. Sorting allows us to capture and collect theses particles of interest for further analysis. The Flow Cytometry Core Facility (FCCF) is located in the faculty of Life Sciences (SV) at the Ecole Polytechnique Fédérale de Lausanne (EPFL) and part of a network of core facilities at he institute. FCCF mission is to provide to all investigators at EPFL and outside, comprehensive mass cytometry & flow cytometric analysis and sorting including instrumentation, technical and professional assistance, training and consultation.

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2 - Cyan ADP (Beckman Coulter) 3 laser benchtop analyser with 11 parameters. 1 - Galios (Beckman Coulter) is a 3-laser benchtop analyser with 12 parameters. 1 - Accuri C6 is a 2 laser benchtop analyser with 6 parameters and a plate reader 1 - AutoMACS Pro is a fully automated bench-top magnetic beads sorter that can be used to perform sterile bulk sorts. 1 – FACSAria (Becton Dickinson) 4-ways high-speed BLS-2 cell sorter, 5 lasers with 20 parameters and ACDU. 1 - MoFlo Astrios EQ (Beckman Coulter) 6-ways high-speed BLS-2 cell sorter, 4-laser with 19 parameters. 1 – CyTOF 2 (Fluidigm) Mass cytometry is a variation of flow cytometry in which antibodies are labeled with heavy metal ion tags rather than fluorochromes. Readout is by time-of-flight mass spectrometry.

The FCCF facility aims to keep on the cutting edge of cytometric technology and they are constantly updating hardware. They also introduce new techniques appropriate to users needs. All the staff for the facility are member from the ISAC society.

Researchers have the option, once trained, of performing their own acquisition/analysis or utilizing the expertise of the facility’s staff to run their samples with them

Equipment

Services

Currently the Flow Cytometry Core Facility is equipped with seven state of the art self-service benchtop analysers as well as two high-speed BLS2 cell sorters. The Core Facility also operates an automated immunomagnetic bead cell separator from Miltenyi Biotec MACS® Technology. This year, we complete our parc with the acquisition of a Mass cytometer, CyTOF 2.

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•

1 - LSRII (Becton Dickinson) 5 lasers benchtop analyser with 20 parameters. 1 - LSRII (Becton Dickinson) 4 lasers benchtop analyser with 15 parameters. 178

Cell sorting User training (machines and software) Flow Cytometry teaching Advice on experimental design Setup and optimization of flow cytometry protocols Expertise and advice include consultation on flow cytometry acquisition and data analysis Support, in reporting flow cytometry data for manuscript and grant applications

Team Members Facility Head

Miguel Garcia Cytometry Operators

Valérie Glutz Loïc Tauzin André Mozes

CyTOF specialist

Christoph Schwärzler Administrative Assistant

Maureen Hersperger

Contact Miguel Garcia AI 0147, Station 15 CH-1015, Lausanne +41 (0)21 693 09 01 miguel.garcia@epfl.ch

Core Facilities & Technology Platforms

Gene Expression Core Facility - GECF gecf.epfl.ch

Introduction

Team Members

The GECF provides a set of tools for the functional and quantitative analysis of genome expression. First, we offer a next-generation sequencing service, enabling transcriptome analyses (RNA-seq), epigenetic analyses (Chip-seq), chromosomal structure analyses (Hi-C) as well as whole genome sequencing, amongst others. For that, we can prepare diverse types of libraries, starting from a wide variety of samples including nucleic acids derived from single-cells or from clinical specimen (FFPE samples for instance). Moreover, we provide access to a panel of sensitive instruments and techniques for nucleic acid quantitation, from standard qPCR analyses to microfluidics-based high-throughput technologies. Our liquid handling robotized station greatly facilitates the set-up of large qPCR runs. We can also perform quality control of nucleic acids by profile analysis owing to one of our capillary- or gel-based instruments.

Lastly, we enable manipulation of the cellular gene expression program by providing human and murine genome-wide collections of ORFs, either in Gateway plasmids ready for transfer into expression vectors, or already inserted into lentiviral vectors. Handling these collections is facilitated by our liquid handling robot that can perform on-demand high-throughput manipulation such as plasmid DNA extraction (also available for user projects unrelated to our collections). Importantly, for all these tools we provide support for the experimental design, troubleshooting and data analysis. Users can also get trained in order to operate the instruments autonomously. Finally, because new technologies constantly emerge, we are eager to discuss means to further improve and develop our services.

Facility Head

Bastien Mangeat Scientific Assistant

Joséphine Uldry (until 30.09.2016) Laboratory Assistant

Mélanie Thobor

Administrative Assistant

Marie-France Radigois

Contact Bastien Mangeat SV 1841, Station 19 CH-1015, Lausanne +41 (0)21 693 71 13 bastien.mangeat@epfl.ch

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Histology - HCF & Comparative Pathology hcf.epfl.ch

Introduction Histology involves the use of a set of techniques to examine the morphology, architecture and composition of tissues. The tissue samples are processed for the study of structures seen under the microscope, also called microscopic anatomy, as opposed to gross anatomy which involves structures that can be observed with the naked eye. The histology core facility is a competence pole which provides expertise in those analyses as well as routine work for researchers. All the techniques would be nothing without the expertise of a specialist in veterinarian pathology helping researchers analyzing their slides.

Services and Technologies

On one hand, the facility assists researchers in the setting up and optimizing of histological approaches specific for each scientific project. Members of the SV faculty can be trained on the available instruments like microtomes or cryostats and have then access to them for their own experiments. On the other hand technicians of the facility perform work for researchers: • Tissue processing to frozen, paraffin or resin sections • Histological stains like the standard Hematoxyline and eosin and special stains like Sirius red among others both manually or automated (Prisma from Sakura) • Setup and optimization of immunohistochemistry and immunofluorescence protocols manually as well as automated (Ventana Discovery xT)

Team Members • •

Detection of mRNA and miRNA using cold probes on the Discovery xT from Roche-Ventana or using RNAscope kits from ACDbio. Tests of newly available techniques or useful published methods.

Pathology service Pathology support is provided by a specialist that underwent formal postgraduate training in veterinary anatomic pathology officially acknowledged by board certification of specialty. The pathologist is trained to diagnose, describe and interpret morphologic macro- and microscopic lesions within organs and tissues. Appropriate interpretation implies proper recognition of tissue abnormalities and sound knowledge of pathologic processes of diseases that manifest as morphologic changes as well as of the experimental design and settings. The service provides the following activities: • Consulting, at the study design level for issues related to pathology investigation • Morphologic phenotyping, whole body or organ targeted for genetically engineered animals • Analysis of histological specimens • Support, in reporting pathology data for manuscript submission and grant application • Diagnostics. Post mortem examination of diseased animals within the colony.

Selected Publications »» Zaiss MM, Rapin A, Lebon L, Dubey LK, Mosconi I, Sarter K, Piersigilli A, Menin L, Walker AW, Rougemont J, Paerewijck O, Geldhof P, McCoy KD, Macpherson AJ, Croese J, Giacomin PR, Loukas A, Junt T, Marsland BJ, Harris NL. (2015) The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation. Immunity 43(5):998-1010. »» Trachet B, Fraga-Silva RA, Piersigilli A, Segers P, Stergiopulos N.(2015) Dissecting abdominal aortic aneurysm in Angiotensin II-infused mice: the importance of imaging. Curr Pharm Des. 21(28):4049-60. »» Trachet B, Fraga-Silva RA, Piersigilli A, Tedgui A, Sordet-Dessimoz J, Astolfo A, Van der Donckt C, Modregger P, Stampanoni MF, Segers P, Stergiopulos N. (2015) Dissecting abdominal aortic aneurysm in Ang II-infused mice: suprarenal branch ruptures and apparent luminal dilatation. Cardiovasc Res.105(2):213-22. »» Trachet B, Piersigilli A, Fraga-Silva RA, Aslanidou L, Sordet-Dessimoz J, Astolfo A, Stampanoni MF, Segers P, Stergiopulos N. (2016) Ascending Aortic Aneurysm in Angiotensin II-Infused Mice: Formation, Progression, and the Role of Focal Dissections. Arterioscler Thromb Vasc Biol. 36(4):673-81.

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Facility Head

Jessica Sordet-Dessimoz Collaborators

Gian-Filippo Mancini Nathalie Müller Agnès Hautier Vanessa Mack Comparative Pathologists

Alessandra Piersigilli Nadine Stokar

Administrative Assistant

Maureen Hersperger

Contact Jessica Sordet-Dessimoz AI 0342, Station 19 CH-1015 Lausanne Phone: +41 21 693 09 62 info.hcf@epfl.ch

Core Facilities & Technology Platforms

Proteomics - PCF-PTP pcf-ptp.epfl.ch

Introduction

In the last 10 years mass spectrometry has become an invaluable tool in the arsenal of techniques offered to the biologist to study the expressed and active part of the genome named proteome and the lipidome. The rapid evolution of the technique has been tightly bound to the continuous increase in performance of mass spectrometers. Nowadays it is possible to get quantitative information about thousands of proteins and hundreds of lipids in one experiment. Researchers can begin to think more globally. But there is still room for very detailed studies on single proteins especially those modified by post-translational modifications. The EPFL Proteomics Core Facility is a technological platform that has been created to address these needs and help researchers in using these techniques.

Services and Technologies Instrumentation The PCF-PTP laboratory is currently equipped with sample preparation and fractionation devices (HPLC, FPLC, pI) and mass spectrometers coupled to liquid chromatography (4 Orbitraps, 3 QQQ LC-ESI-MS/MS) and 1 MALDI-TOF/TOF instrument. A mass cytometry instrument (CyTOF 2) jointly operated with the Flow Cytometry platform (PTCF) completes the instrument base.

The bioinformatics analysis pipeline includes Mascot, Xtandem! SEQUEST and Peaks servers for matching MS data with protein sequence databases and data post-treatment tools like Maxquant, Perseus, Proteome Discoverer, Skyline and Scaffold for protein validation and pipelining of quantitative studies. Services The PCF-PTP has implemented several complementary workflows for protein and recently introduced lipid analysis and offers an increasing palette of services... • Protein/Peptide Molecular Weight Measurements by Mass Spectrometry. • Mass Spectrometry based Protein/Peptide Identification from Gel or Solution. • Protein Relative Quantification by SILAC or Label-free Quantitative Analysis on collaborative basis. ... contributes also to collaborative based services requiring heavy involvement of both parties like: • Accurate protein quantification by SRM-MRM. • Localization and quantification of PTM’s other than phosphorylation. • Lipid mixtures profiling and targeted quantification. ... entertains tight collaboration with other proteomics facilities (UNILPAF, UNIL-CHUV-Metabo, UNIGE-PCF, UNIBE) and with computer science and bioinformatics research centers (Vital-IT, SIB, etc..).

Team Members Facility Head

Marc Moniatte Scientific Collaborators

Diego Chiappe (Proteomics) Florence Armand (Bioinformatics) Adrian Schmid (Proteomics) Research Assistants

Romain Hamelin (Proteomics) Jonathan Paz-Montoya (Lipidomics) Lisa Pilet Administrative Assistant

Maureen Hersperger

Contact Marc Moniatte AI 0149, Station 15 CH-1015, Lausanne +41 (0)21 693 17 53 marc.moniatte@epfl.ch

Selected Publications »» Reckel S, Hamelin R, Georgeon S, Armand F, Jolliet Q, Chiappe D, Moniatte M, Hantschel O. »» Differential signaling networks of Bcr-Abl p210 and p190 kinases in leukemia cells defined by functional proteomics. Leukemia. 2017 Jan 23. doi: 10.1038/leu.2017.36. »» Cianciaruso C, Phelps EA, Pasquier M, Hamelin R, Demurtas D, Ahmed MA, Piemonti L, Hirosue S, Swartz MA, De Palma M, Hubbell JA, Baekkeskov S. Primary Human and Rat Beta Cells Release the Intracellular Autoantigens GAD65, IA-2 and Proinsulin in Exosomes Together with Cytokine-Induced Enhancers of Immunity. Diabetes. 2016 Nov 21. pii: db160671. [Epub ahead of print] »» Rudinskiy N, Fuerer C, Demurtas D, Zamorano S, De Piano C, Herrmann AG, Spires-jones TL, Oeckl P, Otto M, Frosch MP, Moniatte M, Hyman, BT, Schmid, AW. Amyloid-beta oligomerization is associated with the generation of a typical peptide fragment fingerprint. Alzheimers Dement. 2016 Sep;12(9):996-1013. doi: 10.1016/j.jalz.2016.03.011. Epub 2016 Apr 26. »» Monteil DT, Juvet V, Paz J, Moniatte M, Baldi L, Hacker DL, Wurm FM. A comparison of orbitally-shaken and stirred-tank bioreactors: pH modulation and bioreactor type affect CHO cell growth and protein glycosylation. Biotechnol Prog. 2016 Sep;32(5):1174-1180. doi: 10.1002/btpr.2328. Epub 2016 Aug 11.

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Protein Crystallography - PCRYCF pcrycf.epfl.ch

Introduction

Services and Technologies

Team Members

The Protein Crystallography Core Facility provides instrumentation and expertise at every stage of the structure determination process for noncrystallography groups who are interested in solving the structures of their favorite macromolecule.

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Facility Head

Expertise and advice include consultation on protein purification, crystallization, and crystal optimization, as well as assistance with X-ray crystal screening, data collection, data processing and structure determination and analysis. X-ray crystallography is the primary method for determining three-dimensional structures of biological macromolecules, and is therefore an essential tool, which should be available to a broad range of researchers. Nowadays, it is possible for a non-crystallographer to access this technology thanks to automation and a variety of commercially available kits as well as to the friendlier and more intuitive programs that have been developed in recent years. With personalized advice, training, and follow-up, users are in the optimal environment to manage their crystallization screens, and to solve, refine and analyze the structures of their favorite proteins.

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Advice on larger-scale protein expression and purification, if required. Set-up of crystallization screens using commercial and facility-made conditions. Optimization of crystals. Data collection of quality crystals at facility x-ray source and synchrotrons. Data processing using popular packages such as XDS and Mosflm. Structure determination using molecular replacement and MAD techniques. Structure refinement, fitting and analysis using ccp4i and Phenix software. Deposition of structures in the protein database. Preparation of images for publication using PyMol software

Florence Pojer Technical Staff

Aline Reynaud Jean Philippe Gaudry Administrative Assistant

Manuelle Mary

Contact

Selected Publications »» Rybniker J, Vocat A, Sala C, Busso P, Pojer F, Benjak A, Cole S. Lansoprazole is an antituberculous prodrug targeting cytochrome bc1 (2015). Nat Commun. 9;6:7659. »» Korotkova N, Piton J, Wagner JM, Boy-Röttger S, Japaridze A, Evans TJ, Cole S, Pojer F, Korotkov KV. Structure of EspB, a secreted substrate of the ESX-1 secretion system of Mycobacterium tuberculosis (2015). J Struct Biol. 191(2): 236-44. »» Makarov V, Lechartier B, Zhang M, Neres J, van der Sar AM, Raadsen SA, Hartkoorn RC, Ryabova OB, Vocat A, Decosterd LA, Widmer N, Buclin T, Bitter W, Andries K, Pojer F, Dyson PJ, Cole S. Towards a new combination therapy for tuberculosis with next generation benzothiazinones (2014). EMBO Mol 6(3):372-83 »» Chen S, Bertoldo D, Angelini A, Pojer F, Heinis C. Peptide Ligands Stabilized by Small Molecules (2014). Angew Chem 53(6):1602-6 »» Hartkoorn RC, Pojer F, Read JA, Gingell H, Neres J, Horlacher OP, Altmann KH, Cole S. Pyridomycin bridges the NADH- and substrate-binding pockets of the enoyl reductase InhA (2014). Nat Chem Biol. 10(2):96-8

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Florence Pojer Office: AI 2147 CH-1015 Lausanne Phone: +41 21 693 1976 Florence.pojer@epfl.ch

Core Facilities & Technology Platforms

Protein Expression Technology - PTEP pecf.epfl.ch

Introduction

Services and Technologies

Team Members

The objective of the PECF is to provide recombinant proteins, rapidly and at low cost, to EPFL researchers. Both cultivated mammalian cells and E. coli are used as production hosts. One of our main activities is recombinant protein production by transient transfection of Chinese hamster ovary (CHO) or human embryo kidney (HEK293) cells in suspension at volumetric scales from 5 mL to 10 L. We also produce proteins from existing recombinant cell lines developed by our clients. This may involve adapting the cell line to serum-free suspension culture. In this case, cultures at volumetric scales up to 10 L are used. For protein production in mammalian cells, we have a number of expression vectors available. We produce monoclonal antibodies by scale-up of existing hybridoma cell lines. When using E. coli as a host for protein production, the scales of operation range up to 20 L. For all the types of production mentioned, the PECF has non-instrumented bioreactors available for use. After production, we also provide services in protein recovery, mainly by affinity chromatography of proteins secreted from mammalian cells (antibodies and Fc- and his-tagged proteins) and GST- and his-tagged proteins produced in E. coli. For protein production in mammalian cells, we have a number of expression vectors available.

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Facility Head

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Large-scale transient transfection for recombinant protein in mammalian cells Scale-up of existing cell lines for recombinant protein production Scale-up of existing hybridoma cell lines for monoclonal antibody production Recombinant protein production in E. coli Affinity protein purification Provision of vectors for protein production in mammalian cells

David Hacker Laboratory Assistant

Ione Gutscher Technicians

Laurence Durrer Soraya Quinche Administrative Assistant

Marie-France Radigois

Contact David Hacker CH B1 423, Station 6 CH-1015, Lausanne +41 (0)21 693 18 78 david.hacker@epfl.ch

Selected Publications »» Balasubramanian S, Rajendra Y, Baldi L, Hacker DL, Wurm FM.2016. Comparison of three transposons for the generation of highly productive recombinant CHO cell pools and cell lines. Biotechnol Bioeng. 113(6):1234-43. »» Hacker DL, Balasubramanian S. 2016. Recombinant protein production from stable mammalian cell lines and pools. Curr Opin Struct Biol. 38:129-36. »» Monteil DT, Juvet V, Paz J, Moniatte M, Baldi L, Hacker DL, Wurm FM. 2016. A comparison of orbitally-shaken and stirred-tank bioreactors: pH modulation and bioreactor type affect CHO cell growth and protein glycosylation. Biotechnol Prog. 32(5):1174-1180. »» Balasubramanian S, Wurm FM, Hacker DL.2016. Multigene expression in stable CHO cell pools generated with the piggyBac transposon system. Biotechnol Prog. 32(5):1308-1317. »» Monteil DT, Shen X, Tontodonati G, Baldi L, Hacker DL, Wurm FM.2016. Disposable orbitally shaken TubeSpin bioreactor 600 for Sf9 cell cultivation in suspension. Anal Biochem. 505:26-8.

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tcf.epfl.ch

Centre of PhenoGenomics Transgenic - CPG-TCF Introduction

Services and Technologies

Team Members

Genetic manipulation of rodents through the generation of transgenic animals is a procedure of primary importance for biomedical research, either to address fundamental questions or to develop preclinical models of human diseases. We offer a centralized resource with various technologies for the generation of transgenic animals including pronuclear injection of DNA, lentiviral vector injection in the mouse oocyte and embryonic stem cells injection into the blastocyst. We are using CRISPR/Cas9 technology directly into mouse embryos to generate precise genomic edits into specific loci. We are also a general support in both vector design and lentiviral vector production and titration, as our expertise in lentiviral vectors has become of general interest for many other applications than transgenesis. An important variable that affects the results of mouse studies is the sanitary status of the animals. Taking advantage of our expertise in embryo manipulation we also propose the sanitary cleaning of mouse transgenic lines by embryo transfer as a routine service. This procedure allows cleaning and hosting of a wide range of mouse lines in the EPFL animal husbandry. For long-term preservation of mouse line of particular interest, we now propose cryopreservation by sperm freezing and recovery by in vitro fertilization (IVF).

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Facility Head

Pronuclear injection: plasmids and BACs. Lentiviral vector mediated transgenesis. ES cells microinjection into blastocysts. Lentiviral vectors production/titration. Vectorology. Cleaning of established mouse lines by embryo transfer. Cryopreservation of mouse lines by sperm freezing. In vitro fertilization assay (IVF)

Selected Publications »» Ecco, G., Cassano, M., Kauzlaric, A., Duc, J., Coluccio, A., Offner, S., Imbeault, M., Rowe, H.M., Turelli, P., Trono, D. (2016) Transposable Elements and Their KRAB-ZFP Controllers Regulate Gene Expression in Adult Tissues. Dev Cell. 36(6):611-23. »» Ordóñez-Morán, P., Dafflon, C., Imajo, M., Nishida, E., Huelsken, J. (2015) HOXA5 Counteracts Stem Cell Traits by Inhibiting Wnt Signaling in Colorectal Cancer. Cancer Cell. 28(6):815-29. »» Gubelmann, C., Schwalie, P.C., Raghav, S.K., Röder, E., Delessa, T., Kiehlmann, E., Waszak, S.M., Corsinotti, A., Udin, G., Holcombe, W., Rudofsky, G., Trono, D., Wolfrum, C., Deplancke, B. (2014) Identification of the transcription factor ZEB1 as a central component of the adipogenic gene regulatory network. Elife, e03346. »» Lonfat, N., Montavon, T., Darbellay, F., Gitto, S., Duboule, D. (2014) Convergent evolution of complex regulatory landscapes and pleiotropy at Hox loci. Science;346(6212):1004-6.

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Isabelle Barde Collaborators

Dalil Ait-Bara Michelle Blom Sandra Offner (50%) Sonia Verp (50%)

Contact Isabelle Barde Office: SV 1842 CH-1015 Lausanne Phone: +41 21 693 17 02 isabelle.barde@epfl.ch

Core Facilities & Technology Platforms

Center of PhenoGenomics Phenotyping - CPG-UDP Introduction

Services and Technologies

Team Members

The development of genetic tools for the manipulation of the mouse genome has led to the creation of numerous and sophisticated mouse models. The in-depth characterization of the phenotype of these mouse lines is crucial to decipher the roles of the genes of interest. The Phenotyping Unit is composed of highly interactive service platforms including clinical chemistry laboratory, metabolic and behavior exploration platform. We offer different types of support to the users of the platform, going from general support and training to full completion of tests and analysis. The UDP is part of the animal facility barrier unit, and encompasses a working area constituted of housing, testing and analysis rooms. The mouse models are housed in individual ventilated cages and maintained at a conventional sanitary status.

The UDP provides a range of state-of-the-art equipment that has been chosen to ensure a high level of flexibility for the tests that can be performed. Additionally, most of experiments can be run by fully programmable and automated interfaces and thus the impact of experimental interventions by the researcher over the experimental period is reduced.

Facility Head

We offer tests in the different scientific fields mentioned in the opposite figure. A series of tests can be combined in a pipeline in order to answer questions related to a given topic such as neurodegenerative diseases or obesity and diabetes. In addition, the in-vivo imaging platform allows monitoring of disease progress in oncology by the assessment of tumor development, progression, metastasis, and response to therapy in models of cancer. Imaging modalities include high resolution CT scan, ultrasound and optical imaging (in-vivo bioluminescence or fluorescence) improving cancer research by allowing longitudinal and non-invasive assessment.

Xavier Warot - CPG Raphaël Doenlen - UDP Project Manager

Roy Combe

Collaborators

Arnaud Bichat Cristina Cartoni Sébastien Lamy (until Sept. 2016) / Giacomo Diaceri Adeline Langla Elodie Schneider Céline Waldvogel Camille Aebischer Sybil Bron Christine Di Natale-Pehm Cindy Bula (until Mar. 2016) / Maude Zahno

Contact Xavier Warot - CPG Head +41 (0)21 693 18 69 xavier.warot@epfl.ch

Selected Publications »» Williams EG, Wu Y, Jha P, Dubuis S, Blattmann P, Argmann CA, Houten SM, Amariuta T, Wolski W, Zamboni N, Aebersold R, Auwerx J. (2016). Systems proteomics of liver mitochondria function. Science. Jun 10;352(6291). »» Ryu D, Mouchiroud L, Andreux PA, Katsyuba E, Moullan N, Nicolet-Dit-Félix AA, Williams EG, Jha P, Lo Sasso G, Huzard D, Aebischer P, Sandi C, Rinsch C, Auwerx J. (2016). Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nature Med. Aug;22(8):879-88 »» Padovani R, Lehnert T, Cettour-Rose P, Doenlen R, Auwerx J, Gijs MA. »» (2016). Miniaturized implantable sensors for in vivo localized temperature measurements in mice during cold exposure. Biomed Microdevices. 18(1):1. »» Trachet, B., Fraga-Silva, R.A., Piersigilli, A., Tedgui, A., Sordet-Dessimoz, J., Astolfo, A., Van der Donckt, C., Modregger, P., Stampanoni, M.F., Segers, P. and Stergiopulos, N. (2015). Dissecting abdominal aortic aneurysm in Ang IIinfused mice: suprarenal branch ruptures and apparent luminal dilatation. Cardiovasc Res. 105(2):213-22.

Raphaël Doenlen - UDP Head +41 (0)21 693 09 53 raphael.doenlen@epfl.ch

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Editor: Laurence Mauro Many thanks to Friedrich Beermann, Lucia Baldi, Dietrich Reinhard, Sacha Sidjanski, Harald Hirling and Roland Chabloz at the Repro for their help and support!

12th edition 2015/2016 Produced and edited by the EPFL School of Life Sciences Printed at the EPFL “Atelier de Reprographie”

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