2011 IBI Institute Annual Report

EPFL School of Life Sciences - 2011 Annual Report

Table Of Contents

INTRO

Main Scientific Events..................................................................................................................6 Public-Oriented Events................................................................................................................6 Honors-Awards-Announcements.................................................................................................7 Undergraduate Studies.................................................................................................................8 Graduate Studies.........................................................................................................................8 School of Life Sciences at a Glance.............................................................................................9 Congratulations to our PhD Grads!............................................................................................10

Core Facilities & Technology Platforms............................................................................13 Bioelectron Microscopy.............................................................................................................14 BioImaging & Optics.................................................................................................................15 Bioinformatics & Biostatistics.....................................................................................................16 Biomolecular Screening.............................................................................................................17 Flow Cytometry ........................................................................................................................18 Histology ..................................................................................................................................19 Proteomics.................................................................................................................................20 Protein Crystallography..............................................................................................................21 Protein Expression.....................................................................................................................22 Transgenic ................................................................................................................................23 Phenotyping Unit.......................................................................................................................24

BMI - Brain Mind Institute...............................................................................................27 Aebischer Lab............................................................................................................................28 Blanke Lab.................................................................................................................................30 Fraering Lab...............................................................................................................................32 Gerstner Lab..............................................................................................................................34 Hadjikhani Group......................................................................................................................36 Herzog Lab................................................................................................................................38 Lashuel Lab...............................................................................................................................40 Luthi-Carter Lab . ................................................................................................................42 Magistretti Lab...........................................................................................................................44 Markram Lab.............................................................................................................................46 Moore Lab.................................................................................................................................48 Petersen Lab..............................................................................................................................50 Sandi Lab...................................................................................................................................52 Schneggenburger Lab................................................................................................................54 Blue Brain Project......................................................................................................................56

IBI - Institute of Bioengineering.......................................................................................59 Auwerx - Schoonjans Lab..........................................................................................................60 Barrandon Lab...........................................................................................................................62 Dal Peraro Lab...........................................................................................................................64 Deplancke Lab..........................................................................................................................66 Hubbell Lab...............................................................................................................................68 Lutolf Lab..................................................................................................................................70 Naef Lab....................................................................................................................................72 Swartz Lab.................................................................................................................................74 Wurm Lab.................................................................................................................................76

Co-affiliated Research Groups.........................................................................................78 Aminian Lab..............................................................................................................................78 Fantner Lab . .............................................................................................................................79 Guiducci Lab.............................................................................................................................80

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EPFL School of Life Sciences - 2011 Annual Report

Hatzimanikatis Lab....................................................................................................................81 Ijspeert Lab................................................................................................................................82 Johnsson Lab.............................................................................................................................83 Jolles-Haeberli Lab ...................................................................................................................84 Lacour Lab ...............................................................................................................................85 Maerkl Lab ...............................................................................................................................86 Mermod Lab..............................................................................................................................87 Millán Lab ................................................................................................................................88 Pioletti Lab ...............................................................................................................................89 Psaltis Lab ................................................................................................................................90 Radenovic Lab . ........................................................................................................................91 Roke Lab ..................................................................................................................................92 Stergiopulos Lab .......................................................................................................................93 Van de Ville Lab . ......................................................................................................................94 Van den Bergh Lab ...................................................................................................................95

GHI - Global Health Institute..........................................................................................97 Blokesch Lab.............................................................................................................................98 Cole Lab..................................................................................................................................100 Doerig Lab...............................................................................................................................102 Fellay Lab................................................................................................................................104 Harris Lab................................................................................................................................106 Lemaitre Lab............................................................................................................................108 McKinney Lab.........................................................................................................................110 Trono Lab................................................................................................................................112 Van der Goot Lab....................................................................................................................114

ISREC - Swiss Institute for Experimental Cancer Research......................................117 Aguet Lab................................................................................................................................118 Beard Lab................................................................................................................................120 Brisken Lab..............................................................................................................................122 Constam Lab............................................................................................................................124 De Palma Lab..........................................................................................................................126 Duboule Lab............................................................................................................................128 Gönczy Lab.............................................................................................................................130 Grapin-Botton Lab...................................................................................................................132 Hanahan Lab...........................................................................................................................134 Hantschel Lab..........................................................................................................................136 Huelsken Lab .........................................................................................................................138 Kühn Lab.................................................................................................................................140 Lingner Lab..............................................................................................................................142 Meylan Lab..............................................................................................................................144 Radtke Lab...............................................................................................................................146 Simanis Lab.............................................................................................................................148 Bucher Group..........................................................................................................................150

Other Professors............................................................................................................152 Knowles...................................................................................................................................153 Molinari Group........................................................................................................................154 Rainer Group...........................................................................................................................156 Schorderet Group....................................................................................................................158 Tanner.....................................................................................................................................160

Introduction

Welcome To Our New Collaborators!............................................................................161

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EPFL School of Life Sciences - 2011 Annual Report

Preamble Whether paving the way to personalized medicine or meeting our planet’s environmental challenges, trans-disciplinary approaches will be the key to research and education in the life sciences. It is with a true pioneering spirit that our school is geared to train a new breed of engineers/scientists endowed with quantitative and integrative skills. In accordance with this objective, our close to fifty research groups push for holistic approaches that span a range of disciplines from functional genomics to high-tech bio-engineering, and from computer neurosciences to structural modeling.

A bachelor degree (Life Sciences and Technology), two masters degrees (Life Sciences and Technology; Bioengineering), and three Ph.D. programs (Biotechnology and Bioengineering; Neurosciences; Molecular Life Sciences), constitute the educational arms of our school, hosting some six hundred students from all geographic and scientific horizons. Our first classes of Engineers in Life Sciences and Technology are now in the greater world.

In 2011, our faculty further increased its team of ERC grant recipients to a total of 12 (9 seniors, 4 juniors), launched the Center for Neuroprosthetics in association with the School of Engineering, held its first SV Research Day for the wider EPFL community, and established very productive interactions with its new neighbor, the Nestlé Institute for Health Sciences.

These are exciting times to be at the EPFL School of Life Sciences!

Didier Trono, M.D. Professor & Dean of the School of Life Sciences Ecole Polytechnique Fédérale de Lausanne (Switzerland)

Introduction

http://sv.epfl.ch

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EPFL School of Life Sciences - 2011 Annual Report

Main Scientific Events

INTRO

March 14th - 15th: A Symposium on Stress, the Social Brain and Psychopathology was organized by Prof. Sandi (BMI) which brought together international leading scientists to discuss work done on human and animal models. The meeting was attended by over 100 participants.

May 2nd - 3rd: Experts from India and Switzerland were brought together for a Indo-Swiss Symposium on Infectious Diseases hosted by the GHI. India and Switzerland share many common interests in the fields of science and medicine and both countries have exceptional expertise in the areas of HIV/AIDS, malaria and tuberculosis, human diseases of global importance.

May 30th: A one day symposium was organized by the GHI called GMS 2011 “Gut Microbiota in Health and Disease”.

Areas such as microbial communities (ecology, metabolism) and mucosal immunology were presented and discussed by young international experts in the field.

July 4th to August 26th: The 2011 International Summer Research Program for undergraduate students welcomed 26 high potential future researchers from all over the world. They joined the SV labs and learned cutting edge research techniques while investigating scientific questions relevant to today’s world.

September 7th - 10th: The annual Life Sciences Symposium was hosted by ISREC, on the theme “Hallmarks and Horizons of Cancer”, with a world-class roster of speakers. The symposium was a resounding success, with well over 600 applicants.

The 2011 Debiopharm Life Sciences Award was given to Professor Stefano Piccolo, from the University of Padua, Italy.

Public-Oriented Events March: The SV labs welcomed 10 enthusiastic high school students from all corners of Switzerland under the framework of La Science Appelle les Jeunes! (Schweizer Jugend forscht!) These students experienced first-hand lab work and completed and presented a mini-project. http://fr.sjf.ch/index.cfm March: The undergraduate (or Bachelor-Master) teaching section in Life Sciences and Technologies participated in the EPFL Prospective Students Days and welcomed more than 150 high school and “Lycées” students from the French speaking areas of Switzerland and France. The same event took place for Swiss Italian and Swiss German speaking high school students in November. More information : http://ssv.epfl.ch/gymnasiens June 8th: The first SV Research Day was held with the theme of “Towards Personalised Medicine”. Non-bio EPFL scientists were cordially invited to attend.

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EPFL School of Life Sciences - 2011 Annual Report

Honors-Awards-Announcements February: The EPFL, has joined with AstraZeneca, Sanofi-Aventis, the Universities of Pavia, Uppsala and Cambridge, and 19 other research groups from 13 different countries, to form the More Medicines for Tuberculosis (MM4TB) consortium, which aims to develop new drugs for successful and shorter treatment of Tuberculosis (TB). This consortium is led by TB expert Professor Stewart Cole (GHI).

March: On World Tuberculosis Day (24 March 2011), Dr Neeraj Dhar, senior scientist within the research group of Prof.

John McKinney (GHI) received the “2011 Swiss TB Award” from the Swiss Foundation for Tuberculosis Research.

March: Prof. Melody A. Swartz (IBI), Head of the Laboratory of Lymphatic and Cancer Bioengineering, together with Prof.

Stephanie Hugues, Department of Pathology and Immunology at the University of Geneva won one of the 2011 Leenaards Foundation’s Scientific Prizes for their project on an emerging therapeutic approach to destroy cancer cells by activating the body’s immune system.

April: Tej Tadi, PhD student in Prof. Olaf Blanke’s lab (BMI), was awarded two prizes: the “Lausanne Entrepreneurship Region” PERL Prize for his start-up “MindMaze” and one of EPFL’s prestigious PhD prizes, the Chorofas Award.

April: PhD student Alireza Roshan Ghias from the Laboratory of Biomechanical Orthopedics (Director Prof. Dominique Pioletti, IBI), was awarded the Swiss Bone Mineral Society’s President Award for an outstanding publication (European Cell and Materials) in 2010.

May: Douglas Hanahan (ISREC) was awarded an honorary degree from the University of Dundee, Scotland, UK. September: Denis Duboule (ISREC) received the Annual Prize of the Fondation pour Genève and the EPFL Polysphere Prize for teaching in Life Sciences.

September: Etienne Meylan (ISREC) was honored with a Debiopharm Group Junior Life Sciences Award.

October: Congratulations to Prof. Carl Petersen (BMI) for his European Research Council (ERC) Advanced Grant.

October: Patrick Aebischer (BMI) has received a Dr. Honoris Causa from the Ecole Polytechnique of the University of Montreal.

October: Henning Sprekeler, PostDoc from Prof. Gerstner’s Computational Neuroscience Lab (BMI), received the very prestigious Berstein Award that will allow him to start his own research group in Germany.

October: José del R. Millán (IBI) received the IEEE Nobert Wiener Award for “seminal and pioneering contributions to non-invasive brain-computer interfaces, in particular brain-controlled robots, wheelchairs and prostheses”, at the IEEE International Conference on Systems, Man, and Cybernetics.

November: Harvard Medical School and Ecole Polytechnique Fédérale de Lausanne (EPFL) launched a Joint Program to “Improve Quality of Life for People With Neurological Disabilities” joining forces to combine neuroscience and engineering in order to alleviate human suffering caused by such neurological disabilities as paralysis and deafness. Collaboration on six pioneering neuroengineering projects was made possible by a grant from the Bertarelli Foundation.

Introduction

November: The Zonta Award was presented to Stéphanie Lacour (IBI) for her work on creating an electronic artificial skin which could help repair nerves that have been severed due to a serious accident.

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EPFL School of Life Sciences - 2011 Annual Report

Undergraduate Studies

INTRO

The Life Sciences curriculum aims to educate a new generation of engineers who can master the technical and scientific skills needed for studying life processes and developing the biomedical technologies of tomorrow. This educational program, established under the direction of Prof. William F. Pralong, M. D., is unique in Switzerland and Europe.

Bachelor’s Program (3 years)

The first two years provide basic courses followed throughout the EPFL, such as analysis, linear algebra, physics, chemistry (general and organic), statistics and numerical methods. Specific courses in Life Sciences begin with biochemistry, cellular, molecular biology, biophysics, computer sciences, and biothermodynamics. In the first two years, life sciences courses make up less than 20% of the total academic load.

In the third year, engineering courses (signals and systems, electronic and electrical systems) and typical life sciences courses such as genetics and genomics, immunology, developmental biology, bio-computing, systems biology via the study of human physiology are integrated. Physiology also gives the opportunity to integrate the engineering and biological knowledge acquired up to this point. During this year, the students also fine tune their training by choosing some specific credits to better prepare themselves for one of the orientations offered in our masters’ programs. This includes a bachelor project either in bioengineering, in bio-computing, in biomedical technologies, in neurosciences, or in molecular medicine.

Master’s Programs (2 years)

The Master’s in Life Science and Technology includes several orientations. Among these are neurosciences, molecular medicine, and bio-computing. Each orientation is made up of 30 credits of optional courses selected under the supervision of a mentor. Students aiming to focus their training on interdisciplinary subjects will have the possibilities to choose different minors such as bio-computing, computing neurosciences and neuroprosthetics.

The Master’s in Bioengineering is organized in collaboration with STI, and provides classical courses in bioengineering; in addition students can chose different possible orientations through the choice of a minor such as biomedical technologies (STI), biotechnology(SB), bio-computing (I&C), or neuroprosthetics. Each minor requires taking 30 specific credits chosen under the guidance of a mentor. The minors, as indicated, are organized within the different schools at EPFL. Both degree programs share some common basic curriculum that aims to provide students with the knowledge of the modern technologies used in the life sciences such as imaging, bio-computing and optical systems applied to biology, etc.... In addition, courses in management, economics, applied laws and ethics for the life sciences are offered. A large portion of the master’s program (60 credits) can be dedicated to laboratory work and projects. http://ssv.epfl.ch/

Graduate Studies

All three graduate programs comprise a combination of coursework, laboratory-based research, in-house seminars, and national or international conferences. Highly qualified applicants worldwide are chosen twice a year through a competitive selection procedure.

The Doctoral Program in Biotechnology and Bioengineering aims at providing doctoral students with the education

necessary to be leaders in the fast-growing industrial and academic biotechnology and bioengineering sectors, i.e. a depth of knowledge and competence in their specific research area as well as a breadth of knowledge in biology, bioengineering and biotechnology. These program themes include: genomics and proteomics, biomolecular engineering and biomaterials, stem cell biotechnology, cell and process engineering, biochemical engineering, orthopaedic engineering, biomechanics, mechanobiology, cell biophysics, computational biology, biomedical imaging as well as molecular, cell and tissue engineering. http://phd.epfl.ch/edbb

The Doctoral Program in Neuroscience provides its students with training from the genetic to the behavioural level including molecular, cellular, cognitive, and computational neuroscience. Students enroll in the highly dynamic and interdisciplinary environment of the BMI-EPFL of the SV. The program is further strengthened by research and training opportunities in collaboration with the Universities of Lausanne and Geneva. ‘http://phd.epfl.ch/edne The Doctoral Program in Molecular Life Sciences is a joint program between the Swiss Institute for Experimental Cancer Research (ISREC-EPFL) and the Global Health Institute (GHI-EPFL). The program provides training and research opportunities to highly motivated doctoral students in key areas of modern biology. http://phd.epfl.ch/edms/en

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EPFL School of Life Sciences - 2011 Annual Report

INTRO

Congratulations to our PhD Grads!

Mr. Alessandro Wataru Amici

EDBB

Prof. Yann Barrandon

The Role of LEKTI in Fate Determination of Keratinocyte Stem Cells

Ms. Julie Deuquet Ariosa

EDBB

Prof. Gisou van der Goot

Molecular mechanisms underlying Hyaline Fibromatosis Syndrome

Ms. Elena Aritonovska

EDMS

Prof. Joachim Lingner

Insight into the Regulation of Telomerase Access to Telomeres by Shelterin Proteins

Mr Maxime Baud*

EDNE

Prof. P. Magistretti/ Dr J.-M. Petit

The Impact of Sleep Fragmentation on Sleep Homeostasis, Brain and Peripheral Energy Metabolism and Spatial Learning

Ms. Alexandra Bezler

EDMS

Prof. Pierre Gönczy

Mutual Inhibition Between the Anaphase-promoting Complex and the Spindle Assembly Checkpoint in C. Elegans Embryos

Mr. Jorge Castro

EDNE

Prof. Carmen Sandi

Psychobiological Vulnerability to Stress: Behavioral Traits and Neurobiological Mechanisms

Mr. Philippe Coune

EDNE

Prof. P. Aebischer/ Dr B.Schneider

Alpha-Synuclein Effects at the ER-to-Golgi Level and Potential Biomarkers in Rat Models of the Early Phase of Parkinson's Disease

Mr. Sebastian Dieguez

EDNE

Prof. Olaf Blanke

Bodily Ownership: Tactile, Visual and Motor Mechanisms

Ms. Anja Dietze

EDMS

Prof. Daniel Constam

Role of Nodal Processing in Pluripotent Progenitors

Mr. Thomas d'Eysmond

EDBB

Prof. Felix Naef

On the Precision of Circadian Oscillators

Mr. Rodrigo Manuel Gonzalez EDBB

Prof. Gisou van der Goot Cellular Responses to Bacterial Pore-Forming Toxins

Ms. Chiara Greggio

EDMS

Definition of in Vitro Microenvironments to Prof. Anne Grapin-Botton Characterize and Control Pancreatic Progenitor Expansion and Differentiation

Ms. Anna Claire Groner

EDBB

Prof. Didier Trono

Studies on KRAB/KAP1-mediated long-range repression and its potential as a tool

Ms. Yunyun Han

EDNE

Prof. Ralf Schneggenburger

RIM Determines Ca2+ Channel Density and Vesicle Docking at the Presynaptic Active Zone

Mr. Lukas Heydrich*

EDNE

Prof. Olaf Blanke

Turning Body and Self Inside Out: Extero- and Interoceptive Signal Integration in Temporo-Parietal and Insular Cortex

Ms. Jemila Houacine

EDNE

Prof. Patrick Fraering

The Gamma-Secretase-Mediated Proteolytic Processing of APP C-Terminal Fragments as a Therapeutic Target for Alzheimer's Disease

Ms. Mircea Ioan Iacovache

EDBB

Prof. Gisou van der Goot

Folding and Structure of the Pore Forming Toxin Aerolysin

Mr Asif Jan

EDNE

Prof. H.Markram/ Dr F.Schürmann

A Pipeline Based Approach for Experimental Neuroscience Data Management

Ms. Ana Jovicic

EDNE

Prof. Ruth Luthi-Carter

Unique Cell-Type-Specific Distributions and Functions of Brain MicroRNAs

Ms. Susanna Eveliina Kallioinen

EDMS

Prof. Daniel Constam

Activin Signalling in Human Melanoma Cells

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EPFL School of Life Sciences - 2011 Annual Report

Mr. Georges Khazen

EDNE

Prof. Henry Markram

Predictive Engineering the Membrane Composition of Neocortical Neurons

Mr. Stephane Kontos

EDBB

Prof. Jeffrey Hubbell

Engineering erythrocyte affinity for improved pharmacokinetics and immune tolerogenesis

Ms. Kristen Lorentz

EDBB

Prof. Jeffrey Hubbell

Biofunctional Scaffold Design for Soft Tissue Regeneration

Ms. Alexandra Magold

EDNE

Prof. Patrick Fraering

Gamma-Secretase Dependent Gene Expression: A Potential New Focus of Alzheimer's Disease Research

Mr. Nicolas Marcille

EDNE

Prof. Wulfram Gerstner

Models of Evidence Integration in Rapid Decision Making Processes

Mr. Mikaël Martino

EDBB

Prof. Jeffrey Hubbell

Engineering of Signaling Microenvironments with Fibronectin Fragments to Enhance Tissue Regeneration

Mr. Lionel Ambroise Micol*

EDBB

Prof. Jeffrey Hubbell

Hydrogels for Urinary Tract Tissue Engineering

Mr. Richard Naud

EDNE

Prof. Wulfram Gerstner

The Dynamics of Adapting Neurons

Mr. Luca Pellegrinet

EDMS

Prof. Freddy Radtke

The Intestinal Epithelium: Role of Notch Signaling

Ms. Emilda Pino

EDNE

Prof. P. Aebischer/ Dr B. Schneider

Role of the FoxO3a Transcription Factor in alphasynuclein Induced Neurodegeneration

Mr. Rubin Berek Pisarek

EDBB

Prof. Jeffrey Hubbell

New/Surface-Modified Biocompatible Polymer for ICD Lead Insulation

Ms. Caroline Poisson

EDMS

Prof. Freddy Radtke

The Microenvironment and the Cell Differentiation Status Influence the Outcome of Notch-Induced Malignancy

Ms. Carolyn Yong Pullin

EDBB

Prof. Melody Swartz

In Vitro Lymphatic Endothelial Morphogenesis: Molecular vs. Biophysical Regulation

Mr. Ranjan Rajnish

EDNE

Prof. Henry Markram

Mr. Lehal Rajwinder

EDMS

Prof. Freddy Radtke

Mr. Srikanth Ramaswamy

EDNE

Prof. Henry Markram/ Dr S. Hill

Emergent Properties of in silico Synaptic Transmission in a Model of the Rat Neocortical Column

Mr. Guillaume Rey

EDMS

Prof. Felix Naef

On the Relationship Between Protein-DNA Interactions and Circadian Gene Expression in Mouse Liver

Mr. Tej Tadi

EDNE

Prof. Olaf Blanke

Neural Mechanisms of the Embodied Self Merging Virtual Reality and Electrical Neuroimaging

Ms. Kalyani Thyagarajan

EDMS

Prof. Pierre Gönczy

Asymmetric Spindle Positioning and Intracellular Trafficking in C. elegans Embryos

Ms. Stéphanie Tissot

EDBB

Prof. Florian Wurm

OrbShake Bioreactors for Mammalian Cell Cultures: Engineering and Scale-up

Mr. Norbert Wiedemann

EDMS

Prof. Michel Aguet

Role of BcI9 and BcI9I in Homeostasis, Regeneration and Tumorigenesis of the Gastrointestinal Epithelium

Engineering Neuron Models: from Ion Channels to Electrical Behavior Identification and Preclinical Validation of Novel Inhibitors of the Notch Pathway

*MD-PhD" UNIL-EPFL joint degrees EDMS - Molecular Life sciences

Introduction

EDBB - Biotechnology and Bioengineering EDNE - Neuroscience

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EPFL School of Life Sciences - 2011 Annual Report

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://unil.ch/dafl).

Core Facilities & Technology Platforms

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

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CORE

EPFL School of Life Sciences - 2011 Annual Report

Bioelectron Microscopy - Bio-EM http://cime.epfl.ch/bio-em

Team Members Facility Head Graham Knott

Postdoctoral researchers Natalya Korogod Bohumil Maco Scientists Davide Demurtas Corrado Cali Technicians Marie Croisier Stéphanie Rosset

Introduction

The Bio Electron Microscopy Facility (BioEM) is located in the Faculty of Life Science (SV), and also in the Interdisciplinary Centre of Electron Microscopy (CIME). It provides both services and training to researchers at the EPFL who need to image their biological samples at high resolution.

This begins with specific sample preparation techniques, carried out in the preparation laboratories, and then a range of different imaging approaches using either scanning or transmission electron microscopes. These machines are specially suited to biological samples and during 2011, the facility expanded its range of imaging technology with the acquisition of two new transmission electron microscopes; one for ambient temperature imaging, and the other for imaging frozen samples. Other additions during the past year also include the installation of a new high-pressure freezer for instantaneously freezing living material.

Services and Technologies • Transmission electron microscopy • Cryo transmission electron microscopy • Scanning electron microscopy • Focussed ion beam scanning electron microscopy • Correlated light and electron microscopy • Resin embedding • Semithin sectioning • Ultrathin sectioning • Serial sectioning • Cryosectioning and immunolabelling • Pre-embedding immuno labelling • Negative staining • Critical point drying • High pressure freezing • Plunge freezing • Low temperatureand, freeze substitution embedding

Selected Publications

Knott, Graham, Stéphanie Rosset, and Marco Cantoni. «Focussed Ion Beam Milling and Scanning Electron Microscopy of Brain Tissue.» Journal of visualized experiments : JoVE , no. 53 (2011) Lucchi, A, K Smith, R Achanta, G Knott, and P Fua. «Supervoxel-Based Segmentation of Mitochondria in EM Image Stacks with Learned Shape Features.» IEEE transactions on medical imaging (2011) Straehle, C N, U Köthe, G Knott, and F A Hamprecht. «Carving: Scalable Interactive Segmentation of Neural Volume Electron Microscopy Images.» Med Image Comput Comput Assist Interv 14, no. Pt 1 (2011): 653-60.

Kreshuk, Anna, Christoph N Straehle, Christoph Sommer, Ullrich Koethe, Marco Cantoni, Graham Knott, and Fred A Hamprecht. «Automated Detection and Segmentation of Synaptic Contacts in Nearly Isotropic Serial Electron Microscopy Images.» PloS one 6, no. 10 (2011).

Cantoni, M. Genoud, C., Hébert, C., Knott, GW. (2010). Large volume, isotropic, 3D imaging of cell structure on the nanometer scale. Microscopy and Analysis 24 (4).

Contact Information: Graham Knott Station 19, EPFL CH-1015 Lausanne Tel: +41 (0) 21 693 1862 graham.knott@epfl.ch

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EPFL School of Life Sciences - 2011 Annual Report

BioImaging & Optics - PT-BIOP http://biop.epfl.ch/

Team Members Facility Head Arne Seitz

Collaborators José Artacho Olivier Burri Mathias Fournier Romain Guiet Thierry Laroche

The Bioimaging and Optics platform (PT-BIOP) is located in the faculty of Life Science (SV) at the Ecole Polytechnique Fédérale de Lausanne (EPFL) and is part of a network of core facilities at the institute. The general idea of the platform is to provide state of the art light microscopes and even more importantly, expertise to solve challenging (biological) questions with modern light-microscopy. Currently a broad range of instruments ranging from simple wide-field imaging systems over standard point-scanning confocal microscopes up to a high-end 2-Photon-excitation microscope are available in the facility.

Scientists who want to make use of the available equipment are trained by the PT-BIOP staff so that they can use the instruments independently or under the supervision of the staff. Additionally there is a strong competence and necessary computer power to perform image processing. The idea is to link the image analysis with the image acquisition as early as possible as only this approach guarantees optimal scientific results. The microscopes and the image analysis capabilities can be used by scientists of the faculty and the EPFL but are also available to scientist coming from outside the EPFL.

Services and Technologies • Wide-field transmission and fluorescent microscopes • Life cell imaging microscopes

Selected Publications

Bélanger M, Yang J, Petit JM, Laroche T, Magistretti PJ, Allaman I. Role of the glyoxalase system in astrocyte-mediated neuroprotection. J Neurosci. (2011) 31(50):18338-52.

Terjung, S., Walter, T., Seitz, A., Neumann, B., Pepperkok, R., and Ellenberg, J. (2010) High-throughput microscopy using live mammalian cells, (2010) Cold Spring Harbor Protocols, pdb top84.

Maurel, D., Banala, S., Laroche, T., and Johnsson, K. (2010) Photoactivatable and photoconvertible fluorescent probes for protein labeling, ACS Chem Biol 5, 507-516.

Kobel, S., Limacher, M., Gobaa, S., Laroche, T., and Lutolf, M. P. (2009) Micropatterning of hydrogels by soft embossing, Langmuir 25, 8774-8779.

Lefort S., Tomm C., Floyd Sarria J.C., Petersen C.C. (2009) The excitatory neuronal network of the C2 barrel column in mouse primary somstosensory cortex, Neuron 61, 301-316.

Emmenlauer, M., Ronneberger, O., Ponti, A., Schwarb, P., Griffa, A., Filippi, A., Nitschke, R., Driever, W., and Burkhardt, H. (2009) XuvTools: free, fast and reliable stitching of large 3D datasets, J Microsc 233, 42-60.

Contact Information: Arne Seitz AI 0240 Station 19, EPFL CH-1015 Lausanne Tel: +41 (0) 21 693 9618 Fax: +41 (0) 21 693 9585 arne.seitz@epfl.ch

Core Facilities & Technology Platforms

Introduction

• Single and multiple-beam confocal microscopes • 2P microscope • High resolution and super resolution microscope (will be available in 2012) • Image Processing tools (commercially available and/or custom built)

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EPFL School of Life Sciences - 2011 Annual Report

Bioinformatics & Biostatistics- BBCF http://bbcf.epfl.ch

Team Members Facility Head Jacques Rougemont Post doctoral Solenne Carat Fabrice David Julia di Iulio Gregory Lefebvre Marion Leleu Scientific assistants Julien Delafontaine Yohan Jarosz Bara’ah Khubieh Frederick Ross Lucas Sinclair Administrative Assistant Sophie Barret

Introduction and Services and Technologies

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 development of data management pipelines for new high-throughput technologies (e.g. high-density arrays, high-throughput sequencers) and for the statistical planning in complex experimental designs. It also helps researchers in the areas of 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, and in particular the Vital-IT high performance computing center.

Selected Publications

Ayyanan, A., Laribi, O., Schuepbach-Mallepell, S., Schrick, C., Gutierrez, M., Tanos, T., Lefebvre, G., et al. (2011). Perinatal exposure to bisphenol a increases adult mammary gland progesterone response and cell number. Molecular Endocrinology, 25(11), 1915–1923.

Huber, A., French, S. L., Tekotte, H., Yerlikaya, S., Stahl, M., Perepelkina, M. P., Tyers, M., et al. (2011). Sch9 regulates ribosome biogenesis via Stb3, Dot6 and Tod6 and the histone deacetylase complex RPD3L. The EMBO journal, 30(15), 3052–3064.

Rey, G., Cesbron, F., Rougemont, J., Reinke, H., Brunner, M., & Naef, F. (2011).

Genome-wide and phase-specific DNA-binding rhythms of BMAL1 control circadian output functions in mouse liver. PLoS Biology, 9(2), e1000595.

Leleu, M., Lefebvre, G., & Rougemont, J. (2010). Processing and analyzing ChIP-seq data: from short reads to regulatory interactions. Briefings In Functional Genomics, 9(5-6), 466–476.

Preti, M., Ribeyre, C., Pascali, C., Bosio, M. C., Cortelazzi, B., Rougemont, J., Guarnera, E., et al. (2010). The telomere-binding protein Tbf1 demarcates snoRNA gene promoters in Saccharomyces cerevisiae. Molecular Cell, 38(4), 614–620.

Rowe, H. M., Jakobsson, J., Mesnard, D., Rougemont, J., Reynard, S., Aktas, T., Maillard, P. V., et al. (2010). KAP1 controls endogenous retroviruses in embryonic stem cells. Nature, 463(7278), 237–240.

Contact Information: Dr. Jacques Rougemont Station 15, CH-1015, Lausanne +41 (0)21 693 9573 jacques.rougemont@epfl.ch

Noordermeer, D., Leleu, M., Splinter, E., Rougemont, J., de Laat, W., & Duboule, D. (2011). The dynamic architecture of Hox gene clusters. Science, 334(6053), 222–225.

Truman, R. W., Singh, P., Sharma, R., Busso, P., Rougemont, J., Paniz-Mondolfi, A., Kapopoulou, A., et al. (2011). Probable zoonotic leprosy in the southern United States. The New England Journal of Medicine, 364(17), 1626–1633.

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EPFL for all material published in this report info.sv@epfl.ch

EPFL School of Life Sciences - 2011 Annual Report

Biomolecular Screening - BSF http://bsf.epfl.ch/

Team Members Facility Head Gerardo Turcatti

Scientists Damiano Banfi Marc Chambon Ruud van Deursen Assistants Nathalie Ballanfat Manuel Bueno Miquel Busquets Julien Mena

The BSF provides access to EPFL, NCCR-Chemical Biology and SystemsX.ch researchers to the infrastructure, expertise and collections of molecules required for performing medium to high throughput molecular screening assays. In the frame of the NCCR-Chemical Biology, the BSF leads the project ACCESS with the main mission to become the platform for Academic Chemical Screens in Switzerland.

In addition, the BSF is pursuing an innovative and focused research program with industrial partners in screening or drug discovery-linked areas.

Most of the incoming projects are related to chemical biology, systems biology or disease-oriented research in particular in the areas of cancer, infectious diseases and neurobiology. Our multidisciplinary laboratory provides scientists with adequate screening instrumentation, state-of-the-art technologies and compounds collections for applications ranging from the probing of cellular pathways to the broad area of bioactive compounds research.

We perform our automated screens in 96 and 384 well plates for the following two main categories of assays: • Screening of chemicals for a variety of biochemical target-based and cellular assays using large, chemically diverse collections • RNA interference (RNAi) cellular screens for probing gene function using collections of small interfering RNAs (siRNAs) targeting the human genome.

Services and Technologies

• Access to instrumentation dedicated to microplates and cell culture facilities • Assay development and validation for HTS • Assay automation and statistical validations • Pilot screening • Primary screening campaigns • Hits confirmation • Dose response assays • Secondary screens

• Compound storage and management of collections • Image processing for high content screening read-outs • Data management using in-house developed Laboratory Implementation Management System (LIMS).

• Cheminformatics

Selected Publications

Takahashi-Umebayashi, M., Pineau, L., Hannich, T., Zumbuehl, A., Doval, D. A., Matile, S., Heinis, C., Turcatti, G., Loewith, R., Roux, A., lien, Reymond, L., Johnsson, K., and Riezman, H. (2011) Chemical Biology Approaches to Membrane Homeostasis and Function, CHIMIA International Journal for Chemistry 65, 849-852.

Magnet, S., Hartkoorn, R. C., Székely, R., Pató, J., Triccas, J. A., Schneider, P., Szántai-Kis, C., Orfi, L., Chambon, M., Banfi, D., Bueno, M., Turcatti, G., Kéri, G., and Cole, S. T. (2010) Leads for antitubercular compounds from kinase inhibitor library screens, Tuberculosis 90, 354-360.

Kobel, S., Valero, A., Latt, J., Renaud, P., and Lutolf, M. (2010) Optimization of microfluidic single cell trapping for long-term on-chip culture, Lab on a Chip 10, 857-863.

Gormley, N.; Boutell, J., Turcatti, G.,Barnes, G. (2010). Preparation of nucleic acid templates for solid phase amplification. Patent number: US2010041561.

Ouertatani-Sakouhi, H., El-Turk, F., Fauvet, B., Cho, M.-K., Pinar Karpinar, D., Le Roy, D., Dewor, M., Roger, T., Bernhagen, J., Calandra, T., Zweckstetter, M., and Lashuel, H. A. (2010) Identification and Characterization of Novel Classes of Macrophage Migration Inhibitory Factor (MIF) Inhibitors with Distinct Mechanisms of Action, Journal of Biological Chemistry 285, 26581-26598.

Contact Information: Gerardo Turcatti, MER Station 15 EPFL CH-1015 Lausanne Switzerland Tel: +41-(0)21 693 9666 gerardo.turcatti@epfl.ch

© Copyright 2004-2012 EPFL for all material published in this report info.sv@epfl.ch 17

Core Facilities & Technology Platforms

Introduction

CORE

EPFL School of Life Sciences - 2011 Annual Report

Flow Cytometry - FCCF http://fccf.epfl.ch/

Team Members Facility Head Miguel Garcia

Collaborators Gonzalo Tapia Sintia Winkler Administrative Assistant Ursula Winter

Introduction

Flow cytometry is a technology that simultaneously measures and then analyzes multiple physical characteristics of single particles, usually cells, as they flow in a fluid stream through a beam of light. Sorting allows us to capture and collect cells of interest for further analysis.

Our mission is to provide comprehensive flow cytometric analysis and sorting including instrumentation, technical and professional assistance, training.

Services and Technologies

The Flow Cytometry Core Facility from EPFL is equipped with five self-service cytometers. For sorting, the facility has two high-speed sorters from BD (BD FACSAria II SORP & FACSVantage SE). The Facility also operates an automated immunomagnetic bead cell separator from Miltenyi Biotec MACS® Technology.

The LSRII (Becton Dickinson) is a 5 lasers benchtop analyser capable of 18 colour, forward and side scatter analysis, equipped with a PC and DIVA digital acquisition software system.

The Accuri C6 is equipped with 2 lasers and 4 active detectors to allow maximum flexibility for easy experimental design. This machine is also equipped with a plate reader (CSampler) The Cyan ADP (Beckman Coulter) is a 3-laser benchtop analyser capable of 9 colour, forward and side scatter analysis, equipped with a PC and Summit digital acquisition software system.

quick and quantitative analysis of red & green expression, apoptosis, cell viability, cell count, and much more.

The AutoMACS Pro is a fully automated bench-top sorter that can be used to perform sterile bulk sorts. Designed for ultra high-speed positive selection as well as depletion, the AutoMACS Pro can isolate virtually any cell type.

The FACSVantage DIVA (BD) is a 3-laser sorter capable of 8 colour, forward and side scatter analysis. It is equipped with DIVA digital acquisition software system.

The FACSAria (BD) is a 5 laser high-speed sorter capable of 18 colour, forward and side scatter analysis. It is equipped with DIVA digital acquisition software system and ACDU. Services : • Cell sorting • User training • Help with acquisition and data analysis • Experiment design & manuscript • Advice on cell preparation • Interpretation of results • Consulting

Contact Information: Miguel Garcia AI 0147 Sation 15 EPFL CH – 1015 Lausanne Tel: +41 21 693 0901 miguel.garcia@epfl.ch

The TaliTM Image Cytometer is a 3-channel (bright field, green & red fluorescence) benchtop assay platform giving a

© Copyright 2004-2012 EPFL for all material published in this report info.sv@epfl.ch 18

EPFL School of Life Sciences - 2011 Annual Report

Histology -

HCF & Comparative Pathology

http://hcf.epfl.ch

Team Members Facility Head Jessica Sordet-Dessimoz Collaborators Gian-Filippo Mancini Nathalie Müller Agnès Hautier Veterinary pathologist Fabio Aloisio Administrative Assistant Ursula Winter

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 who has been hired in 2011 to help researchers analyzing their slides.

Pathology service Pathology support is provided by professionals that underwent formal postgraduate training in veterinary anatomic pathology officially acknowledged by board certification of specialty. These professionals are trained to interpret morphologic changes within organs and tissues processed through the variety of histology techniques. Appropriate interpretation of tissue changes implies proper recognition of tissue abnormalities and pathologic processes of diseases that manifest as morphologic changes observable in histological preparations.

Services and Technologies

The service provides the following activities:

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 routine stains like Masson’s trichrome or cresyl violet among others. The standard stains are running on the Prisma automate from Sakura • Setup and optimization of immunohistochemistry and immunofluorescence protocols • Detection of mRNA and miRNA using cold probes on the Discovery xT automate from Roche-Ventana.

• Consulting, at the study design level for issues related to pathology investigation • Phenotyping, whole body or organ targeted for genetically engineered animals • Analysis (morphology), of histological preparations

Core Facilities & Technology Platforms

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. Furthermore a large panel of secondary antibodies are titrated and provided to the researchers by the service.

• Support, in reporting pathology data for manuscript preparation and grant application • Diagnostics. Post mortem examination of diseased animals within the colony.

Contact Information: Jessica Sordet-Dessimoz EPFL SV PTH AI 0342 Station 19 1015 Lausanne +41 (0)21 693 0962 info.hcf@epfl.ch

© Copyright 2004-2012 EPFL for all material published in this report info.sv@epfl.ch 19

CORE

EPFL School of Life Sciences - 2011 Annual Report

Proteomics - PCF http://pcf-ptp.epfl.ch/

Team Members Facility Head Marc Moniatte

Collaborators Diego Chiappe Florence Armand Adrian Schmid Research Assistants Romain Hamelin Jonathan Paz-Montoya Administrative Assistant Sophie Barret

Introduction

In the last 10 years mass spectrometry based protein analysis has become an invaluable tool in the arsenal of techniques offered to the biologist to study the proteome, the expressed and active part of the genome. The rapid evolution of the technique has been tightly bound to the continuous increase in performance of mass spectrometers. Today it is possible to get quantitative information about thousands of proteins in one experiment allowing researchers to 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 several mass spectrometers coupled to liquid chromatography: 3 Orbitraps, 2 ion traps, and 2 QQQ LC-ESI-MS/MS and 1 MALDI-TOF/TOF instruments.

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, PinPoint and Scaffold for protein identification validation and pipelining of quantitative studies.

Services The PCF-PTP has implemented several complementary workflows for protein 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 eventually quantification of PTM’s other than phosphorylation.

• Lipid mixtures profiling.

Maintains tight collaboration with other proteomics facilities (UNIL-PAF, UNIGE-PCF, UNIBE) within a network called Repp-SO and with computer science and bioinformatics research centers (Vital-IT, SIB, etc..).

Selected Publications

Dastidar EG, Dayer G, Holland ZM, Dorin-Semblat D, Claes A, Chêne A, Sharma A, Hamelin R, Moniatte M, Lopez-Rubio J-J, Scherf A, Doerig C. (2012) Involvement of Plasmodium falciparum protein kinase CK2 in the chromatin assembly pathway. BMC Biology Jan;10(1):5.

Sicard A, Semblat J, Doerig C, Hamelin R, Sicard, A., Semblat, J. P., Doerig, C., Hamelin, R., Moniatte, M., Dorin-Semblat, D., Spicer, J. A., Srivastava, A., Retzlaff, S., Heussler, V., and Waters, A. P. (2011) Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytes, Cell Microbiol.

Jun;13(6):836-845.

Schmid, A. W., Condemi, E., Tuchscherer, G., Chiappe, D., Mutter, M., Vogel, H., Moniatte, M., and Tsybin, Y. O. (2011) Tissue transglutaminase mediated glutamine deamidation of beta-amyloid peptide increases peptide solubility, whereas enzymatic cross-linking and peptide fragmentation may serve as molecular triggers for rapid peptide aggregation, J. Biol. Chem. Apr 8;286(14):12172-88.

Paleologou KE, Oueslati A, Shakked G, Rospigliosi CC, Kim H-Y, Lamberto GR, Fernandez CO, Schmid A, Chegini F, Gai WP, Chiappe D, Moniatte M, Schneider BL, Aebischer P, Eliezer D, Zweckstetter M, Masliah E, Lashuel HA. (2010) Phosphorylation at S87 Is Enhanced in Synucleinopathies, Inhibits {alpha}Synuclein Oligomerization, and Influences Synuclein-Membrane Interactions.

J. Neurosci, Mar;30(9):3184–3198.

With acknowledgements Kitagawa D, Flückiger I, Polanowska J, Keller D, Reboul J, Gönczy P. (2011) PP2A phosphatase acts upon SAS-5 to ensure centriole formation in C. elegans embryos. Dev. Cell. Apr 19; 20(4):550-62

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

• Protein separation by FPLC and HPLC.

© Copyright 2004-2012 EPFL for all material published in this report info.sv@epfl.ch 20

EPFL School of Life Sciences - 2011 Annual Report

Protein Crystallography - PCRYCF http://pcrycf.epfl.ch

Team Members Facility Head Florence Pojer

Collaborator Larry Richman

Introduction

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

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 are provided.

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. Presently,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 proteins of choice.

• Deposition of structures in the protein database.

• Preparation of images for publication using PyMol software.

Selected Publications

Mollwitz B., Brun E., Schmitt S., Pojer F., Bannwarth M.,Rothlisberger U., Schiltz M.; Johnsson K. (2012). Directed evolution of the suicide protein O6-alkylguanine-DNA alkyltransferase for increased reactivity results in an alkylated protein with exceptional stability Biochemistry. Biochemistry 51(5):986-94.

Blasco B, Stenta M, Alonso-Sarduy L, Dietler G, Peraro MD, Cole ST, Pojer F.* (2011). Atypical DNA recognition mechanism used by the EspR virulence regulator of Mycobacterium tuberculosis. Molecular Microbiology 82(1):251-64.

Contact Information: Florence Pojer SV 3533 Station 19 EPFL CH-1015 Lausanne Tel: +41 (0)21 693 1772 +41 (0)21 693 1839 florence.pojer@epfl.ch

Core Facilities & Technology Platforms

Services and Technologies

The Protein Crystallography Core Facility provides the EPFL community with: • 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 xray source and synchrotrons.

• Data processing using popular packages such as XDS and Mosflm.

• Structure determination using molecular replacement, MAD and SAD techniques.

• Structure refinement, fitting and analysis using ccp4i and Phenix software.

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CORE

EPFL School of Life Sciences - 2011 Annual Report

Protein Expression - PECF http://pecf.epfl.ch/

Team Members Facility Head David Hacker

Collaborator Sarah Thurnheer

Introduction

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 15 L using orbitally shaken bioreactors. For transient protein production in mammalian cells, we have a number of expression vectors available. With the same technical approach, we are also capable of producing virus vectors such as adeno associated virus.

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. Cultures at volumetric scales up to 15 L are possible. Expression vectors based on piggybac transposon-mediated gene delivery are available to our clients.

We produce monoclonal antibodies by scale-up of existing hybridoma cell lines. Serum-free suspension cultures based on mixing by orbital shaking can be used for a scale-up to 2 liters.

When using E. coli as a host for protein production, the scales of operation range from 100 mL – 20 L. Induced protein production at low temperatures is feasible.

We also provide services in protein recovery, mainly by affinity chromatography of antibodies and tagged proteins (Fc, 6X his, FLAG and GST) produced in either mammalian cells or E. coli.

Services and Technologies • 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

Selected Publications

Matasci M, Baldi L, Hacker DL, Wurm FM. 2011. The PiggyBac transposon enhances the frequency of CHO stable cell line generation and yields recombinant lines with superior productivity. Biotechnol Bioeng. 108(9):2141-50.

Rajendra Y, Kiseljak D, Baldi L, Hacker DL, Wurm FM. 2011. A simple highyielding process for transient gene expression in CHO cells. J Biotechnol.

153(1-2):22-6.

Tissot S, Oberbek A, Reclari M, Dreyer M, Hacker DL, Baldi L, Farhat M, Wurm FM. 2011. Efficient and reproducible mammalian cell bioprocesses without probes and controllers? N Biotechnol 28(4):382-90.

Xie Q, Michel PO, Baldi L, Hacker DL, Zhang X, Wurm FM. 2011. TubeSpin bioreactor 50 for the high-density cultivation of Sf-9 insect cells in suspension.

Biotechnol Lett. 33(5):897-902.

Wurm FM, Hacker D. 2011. First CHO genome. Nat Biotechnol 29(8):718-20.

Oberbek A, Matasci M, Hacker DL, Wurm FM. 2011. Generation of stable, high-producing CHO cell lines by lentiviral vector-mediated gene transfer in serum-free suspension culture. Biotechnol Bioeng. 108(3):600-10.

Contact Information: David Hacker Station 6 EPFL CH J2 496 CH-1015 Lausanne Tel: +41 (0)21 693 6142 david.hacker@epfl.ch

© Copyright 2004-2012 EPFL for all material published in this report info.sv@epfl.ch 22

EPFL School of Life Sciences - 2011 Annual Report

Transgenic - TCF

http://jahia-prod.epfl.ch/cms/site/tcf

Team Members Facility Head Isabelle Barde

Collaborators Blom Michelle Guichard Sabrina Offner Sandra Eloise Verp Sonia

Introduction

Services and Technologies

We offer a centralized resource and state-of-the-art technology for the generation of transgenic animals. We can perform direct pronuclear injection of DNA in the mouse oocyte, which has been the standard method of trangenesis for more than three decades.

Selected Publications

As an attractive alternative, we are one of the very few platforms that provides a fast and efficient way to generate transgenic animals through the use of lentiviral vectors. Lentivector-mediated transgenesis is relatively easy to perform and leads to high percentages of provirus-positive animals. Moreover, a wide variety of lentiviral vectors have been developed that can all be used in transgenic animals, thus allowing for a broad range of genetic manipulations including externally controllable expression and knockdown, the latter offering an economically advantageous alternative to stable knockout.

In addition to this primary service, we also offer 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 rederivation of mouse transgenic lines as a routine service.

This procedure allows cleaning and hosting of a wide range of mouse lines in the SPF area of the EPFL animal house.

• Pronuclear injection: plasmids and BACs • Lentiviral vector mediated transgenesis • Vectorology • Lentiviral vectors production/titration • Rederivation by embryo transfer • Cryopreservation by sperm freezing • In progress: ES mediated transgenesis.

Barde I, Laurenti E, Verp S, Wiznerowicz M, Offner S, Viornery A, Galy A, Trumpp A, Trono D. (2011). Lineage- and stage-restricted lentiviral vectors for the gene therapy of chronic granulomatous disease. Gene Ther. (11):1087-97.

Robyr D, Friedli M, Gehrig C, Arcangeli M, Marin M, Guipponi M, Farinelli L, Barde I, Verp S, Trono D, Antonarakis SE.(2011). Chromosome conformation capture uncovers potential genome-wide interactions between human conserved non-coding sequences. PLoS One. 6(3):e17634.

Friedli M, Barde I, Arcangeli M, Verp S, Quazzola A, Zakany J, Lin-Marq N, Robyr D, Attanasio C, Spitz F, Duboule D, Trono D, Antonarakis SE. (2010). A systematic enhancer screen using lentivector transgenesis identifies conserved and non-conserved functional elements at the Olig1 and Olig2 locus. PLoS One.;5(12):e15741.

Barde I, Salmon P, Trono D. (2010). Production and titration of lentiviral vectors. Curr Protoc Neurosci.;Chapter 4:Unit 4.21. Meyer K, Marquis J, Trüb J, Nlend Nlend R, Verp S, Ruepp MD, Imboden H, Barde I, Trono D, Schümperli D. (2009). Rescue of a severe mouse model for spinal muscular atrophy by U7 snRNA-mediated splicing modulation. Hum Mol Genet. 18(3):546-55.

Contact Information

Core Facilities & Technology Platforms

Genetic manipulation of rodents through the generation of transgenic animals is a procedure of paramount importance for biomedical research, either to address fundamental questions or to develop preclinical models of human diseases.

Isabelle Barde AI 3351 Station 19 EPFL CH-1015 Lausanne Tel: +41 (0)21 693 1702 isabelle.barde@epfl.ch

For long term preservation of a mouse line of particular interest, we now propose cryopreservation by sperm freezing via the JAX® Sperm Cryo Kit. The advantage of this technique is that it is standardized and requires only 2 competent male breeders.

© Copyright 2004-2012 EPFL for all material published in this report info.sv@epfl.ch 23

CORE

EPFL School of Life Sciences - 2011 Annual Report

Phenotyping Unit - CPG-UDP /

Team Members CPG – Head Xavier Warot

CPG – UDP Managers Philippe Cettour-Rose Raphaël Doenlen Laboratory Assistants Arnaud Bichat Cristina Cartoni Sébastien Lamy Adeline Langla Marion Varet Animal Care Takers Christine Pehm

Introduction

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 gene of interest.

The clinical phenotyping unit of the Center of PhenoGenomics is composed of highly interactive service platforms including clinical chemistry laboratory, metabolic and functional exploration platform, behavior and cognition exploration platform. The UDP provides a range of state-ofthe-art equipment to enable cardio-metabolic, biochemical and behavioural exploration of mouse models.

We offer different types of support to the users of the platform, going from general support and training in protocols establishment to full completion of tests and analysis. We benefit for doing so from the scientific expertise of Prof.

Johan Auwerx and Prof. Carmen Sandi, both authorities in their respective fields, namely cardio-metabolism and neurobiology.

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 equipment 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.

Services and Technologies

We offer tests in the different scientific fields mentioned in the 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 or diabetes.

Selected Publications

Houtkooper RH, Argmann C, Houten SM, Cantó C, Jeninga EH, Andreux PA, Thomas C, Doenlen R, Schoonjans K, Auwerx J. (2011). The metabolic footprint of aging in mice. Sci Rep. 1:134.

Marcaletti S, Thomas C, Feige JN. (2011). Exercise Performance Tests in Mice.

Current Protocols in Mouse Biology. 1:141-154.

Thomas C, Marcaletti S, Feige JN. (2011). Assessment of Spontaneous Locomotor and Running Activity in Mice. Current Protocols in Mouse Biology. 1:185198.

Contact Information:

Philippe Cettour-Rose : Cardio-metabolism Manager Tel: +41 (0)21 693 0984 philippe.cettour-rose@epfl.ch Raphael Doenlen: Neurobiology Manager Tel: +41 (0)21 693 0953 raphael.doenlen@epfl.ch Xavier Warot Tel: +41 (0)21 693 1869 xavier.warot@epfl.ch

© Copyright 2004-2012 EPFL for all material published in this report info.sv@epfl.ch 24

EPFL School of Life Sciences - 2011 Annual Report

IBI - Institute of Bioengineering The Institute of Bioengineering (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 and reporting to both deans. This dual affiliation allows great diversity in hiring faculty from different backgrounds and with different research perspectives, all focused on basic biological sciences using quantitative and systems analyses, as well as translating the biological and biochemical sciences into therapeutics and diagnostics. The dual affiliation also provides a rich educational environment, both at the BS/MS and PhD levels, especially since a joint MS program in Bioengineering has come into effect in the fall of 2010, shared between the two Schools.

In pursuit of basic biological mechanisms, IBI faculty investigate questions such as: • How the cellular micro-environment controls cellular differentiation and morphogenetic processes; • How stem cell processes, such as self-renewal and differentiation, are determined; • How cell migration and trafficking in complex environments is modulated; • How complex biological networks such as metabolism, gene expression and protein trafficking are regulated, as well as transmitted and evolved within populations; • How biophysical and biomolecular signals interact in controlling cellular behavior; • How fundamental biophysical processes are at work at the single-molecule and nano scales, and in 3-dimensional soft biological systems.

Our goal is to transform knowledge gained from our studies into clinical applications. To that end, the IBI faculty develops novel technologies in areas including: • Delivery of small molecule drugs, proteins and DNA, based on synthetic and biosynthetic biomaterials; • Materials in bio-nanotechnology; • Immunotherapy based on active biomolecules and nanomaterials; • Novel molecules for photodynamic therapy; • Tissue engineering for therapeutics; • Interventional and diagnostic biomedical micro-devices and image processing tools; • Biosensors and neuro-electrodes; • Soft bioelectronic (“electronic skin”) and brain-machine interfaces; • Sensory and motor neuroprosthetics;

IBI - Institute of Bioengineering

• Biorobotics, biomechanics and cardiovascular modelling; • Rehabilitation monitoring based on movement or gait measurement and assessment; • Biotechnology for therapeutic protein production; As well as innovative physiological modelling based on biomolecular and stem cell approaches; http://ibi.epfl.ch

© Copyright 2004-2012 EPFL for all material published in this report info.sv@epfl.ch 59

EPFL School of Life Sciences - 2011 Annual Report

Auwerx - Schoonjans Lab http://auwerx-lab.epfl.ch/

IBI

Johan Auwerx, MD, PhD and Kristina Schoonjans, PhD use a systems physiology approach to understand metabolic homeostasis and the pathogenesis of common metabolic diseases.

Johan Auwerx Full Professor NestlĂŠ Chair in Energy Metabolism

Kristina Schoonjans Adjunct Professor

Introduction

The research of the Laboratory of Integrative and Systems Physiology aims to understand how regulatory proteins, including nuclear receptors, membrane receptors and transcriptional cofactors, act as sensors for molecules of nutritional, metabolic or pharmacological origin, and translate this into altered gene expression and protein patterns affecting metabolic function.

Keywords

Aging, c.elegans, diabetes, genetics, metabolism, metabolic disease, phenogenomics, transcription.

Results Obtained in 2011

Our laboratory was among the pioneers to unravel the wide-ranging implications of the peroxisome proliferatoractivated receptors (PPARs) - PPARa, PPARb/d, and PPARg - in cardio-metabolic control. Importantly, we discovered an association between the PPARg Pro12Ala gene variant with type 2 diabetes and obesity, long before the era of genome-wide association studies, and as such identified the first gene tied with common complex metabolic disease. Furthermore, we identified many new target genes and mapped several of the pathways controlled by PPAR signaling, including those involved in glucose homeostasis, lipid and lipoprotein metabolism, inflammation, bone homeostasis, and cancer.

We also established how the enterohepatic nuclear receptors - farnesoid X receptor, liver receptor homolog-1 and short heterodimer partner - govern hepatic lipid and bile acid metabolism, regulate intestinal substrate absorption and cell proliferation, and control male and female fertility.

We furthermore identified bile acids as endocrine regulators of energy expenditure, glucose homeostasis, and immune modulation, through the activation of a novel GPCR, TGR5. This work on bile acid signaling, revealed a protective role for bile acids against the development of type 2 diabetes and atherosclerosis and sparked a paradigm shift that transformed bile acids, known to be lipid solubilizers in the gut, to versatile endocrine signals that impact almost any aspect of physiology.

More recently, our research has been on the role of transcriptional cofactors in the control of metabolic homeostasis, in general, and of mitochondrial function, in particular.

We were amongst the leading groups that established that a yin-yang between corepressors - the nuclear receptor corepressor 1 (NCoR1) and the sirtuin family of deacetylases - and coactivators - the PPARg coactivator 1a (PGC1a), the steroid receptor coactivators 2 and 3 (SRC-2 and -3) and GCN5 - fine-tunes transcriptional networks that control oxidative metabolism. We showed that increased cellular NAD+ levels during energy stress, activate SIRT1 to deacetylate and induce the activity of PGC-1a, the master controller of mitochondrial function. This process, together with reduced activity of NCoR1 favors oxidative metabolism, thereby enhancing the use of stored energy during caloric restriction. These processes are reversed by excessive energy intake, when the activity of AMP-activated kinase and SIRT1 is attenuated due to high intracellular ATP and low NAD+ levels. A high fat diet, furthermore induces the expression of the acetyltransferases, SRC-3 and GCN5, while concomitantly reducing SIRT1 levels. One result is the acetylation and inhibition of PGC1a, which in turn attenuates mitochondrial activity. Furthermore, NCoR1 is activated, accentuating the decreased transcription of genes governing mitochondrial activity, ultimately enabling the storage of excess calories in times of excessive intake. Our work has established that complex transcriptional networks convert signals associated with caloric intake and cellular energy status into changes of chromatin state and transcription. This alters mitochondrial function and whole body metabolic homeostasis.

As such, our research paved the way for novel preventive and therapeutic strategies for these common diseases. Examples of drugs for which our research contributed significantly to clinical development are the fibrates (through PPARa), thiazolidinediones (through PPARg), PPARb/d agonists, bile acid derivatives (through both TGR5 and FXR), and AMPK agonists, such as resveratrol (which activates SIRT1).

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Noriega, L., Feige, J., Canto, C., Yamamoto, H., Yu, J., Herman, M., Mataki, C., Kahn, B.B., Auwerx, J. (2011) CREB and ChREBP oppositely regulate SIRT1 expression in response to energy availability. EMBO Reports 12:1069-1076.

Du, J., Zhou, Y., Su, X., Yu, J. J., Khan, S., Jiang, H., Kim, J., Woo, J., Kim, J. H., Choi, B. H., He, B., Chen, W., Zhang, S., Cerione, R. A., Auwerx, J., Hao, Q., Lin, H. (2011) Sirt5 Is an NAD-Dependent Protein Lysine Demalonylase and Desuccinylase. Science 334: 806-809.

Pols, T.W.H., Nomura, M., Harach, T., Lo Sasso, G., Oosterveer, M.H., Thomas, C., Rizzo, G., Gioiello, A., Adorini, L., Pelliciari, R., Auwerx, J., Schoonjans, K. (2011) TGR5 activation inhibits atherosclerosis by reducing macrophage infiltration and lipid loading. Cell Metabolism 14:747-757.

Bai, P., Canto, C., Brunyánszki, A., Huber, A., Szanto, M., Cen, Y., Yamamoto, H., Houten, S., Kiss, B., Oudart, H., Gergely, P., Schreiber, V., Menissier-de Murcia, J., Sauve, A.A., Auwerx, J. (2011) PARP-2 regulates SIRT1 expression and whole body energy expenditure. Cell Metabolism 13:450-460.

Bai, P., Canto, C., Oudart, H., Brunyánszki, A., Cen, Y., Thomas, C., Yamamoto, H., Huber, A., Kiss, B., Houtkooper, R.H., Schoonjans, K., Schreiber, V., Sauve, A.A., Menissier-de Murcia, J., Auwerx, J. (2011) PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metabolism 13: 461-468.

Team Members Postdoctoral Fellows Carles Canto Pablo Fernandez-Marcos Taoufiq Harach Riekelt Houtkooper Ellen Jeninga Giuseppe Lo Sasso Adriano Maida Laurent Mouchiroud Maaike Oosterveer Eija Pirinen Thijs Pols Dongryeol Ryu Matthias Stein Hiroyasu Yamamoto Jiujiu Yu PhD Students Pénélope Andreux Elena Katsyuba Mitsonura Nomura Evan Williams Master’s Student Adrienne Mottis

Yamamoto, H., Williams, E.G., Mouchiroud, L., Canto, C., Fan, W., Downes, C. Heligon, Barish, G.D., Desvergne, B., Evans, R.M., Schoonjans, K., Auwerx, J. (2011) NCoR1 is a conserved physiological modulator of muscle mass and oxidative function. Cell 147 :827-839.

Technicians Sabrina Bichet Thibaud Clerc Amandine Moriot-Signorino-Gelo Norman Moullan

Houtkooper, R.H., Williams, R.W., Auwerx, J. (2010). Metabolic networks of longevity. Cell 142 :9-14. Canto, C., Jiang, L.Q., Desmukh, A.S., Mataki, C., Coste, A., Lagouge, M., Zierath, J., Auwerx, J. (2010). The interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and excercise in skeletal muscle. Cell Metabolism 11:213-219.

Administrative Assistant Valérie Stengel

IBI - Institute of Bioengineering

Selected Publications

Mice treated with resveratrol are protected from obesity.

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EPFL School of Life Sciences - 2011 Annual Report

Barrandon Lab http://ldcs.epfl.ch/

IBI

Yann Barrandon, MD-PhD, is joint professor in Stem Cell Dynamics at the EPFL and at the Lausanne University (Unil), and head of the Department of Experimental Surgery at the CHUV. He has made major contributions in basic epithelial stem cell biology and in stem cell therapy. Prof. Barrandon is a principal investigator in several European Commission stem cell consortia (EuroSystem, Optistem and BetacellTherapy). Professor Barrandon is a member of the EMBO and the Academia Europaea. He was elected twice best teacher in Life Sciences at EPFL. He is also a member of the EPFL research committee, EPFL Ethical committee and the Canton de Vaud Ethical committee. In 2011, he co-founded gyMETRICS SA.

Yann Barrandon

Full Professor Head of the Joint Chair of Stem Cell Dynamics EPFL – UNIL – CHUV Head of the Department of Experimental Surgery at the Lausanne University Hospital

Introduction

The laboratory of Stem Cell Dynamics at EPFL and Experimental Surgery at the CHUV pursues three main objectives aiming at improving cell and gene therapy using epithelial stem/progenitor cells: first, the laboratory would like to decipher the basic relationship between stem/progenitors cells of stratified epithelia and p63 expressing cells, second to understand the impact of the environment on stem cell behavior and third to comprehend stem cell engraftment.

The laboratory is a partner in three stem cell consortia within the EEC 7th framework program, aiming at the fundamentals of stem cells (EuroSyStem) and stem cell therapy (OptiStem and BetaCellTherapy).

Keywords

Stem cells, plasticity, reprogramming, microenvironment, hair follicle, thymus, cornea, whisker, gene and cell therapy, translational medicine.

Results Obtained in 2011

Within tissue stem cells, the skin is privileged because it’s stem cells (epithelial and mesenchymal) can be extensively cultivated and cloned, genetically manipulated and transplanted in laboratory animals, but also in human. We have demonstrated that all stratified epithelia of the rat, independent of their primary germ line origin (e.g. the endodermal esophagus or the ectodermal cornea), contain clonogenic stem cells that can respond to skin morphogenetic signals by forming epidermis, sebaceous glands and functional hair follicles in serial transplantation. Furthermore, we have demonstrated that the thymus, which has a unique 3D structure that does not resemble that of a simple or stratified epithelium, contains a population of clonogenic epithelial cells with the astonishing capability to adopt the fate of bona fide multipotent stem cells of the hair follicle when exposed to skin morphogenetic signals, a property maintained in serial transplantation. Gene profiling experiments have demonstrated that several transcription factors

important for thymic identity were either down-regulated or silenced in thymic epithelial cells recovered from skin (Bonfanti et al., Nature 2010). This clearly represents a crossing of lineage boundaries, an increase in potency and the demonstration that adult stem/progenitor cells can be robustly reprogrammed by microenvironmental cues.

Engraftment is the quintessence of stem cell behavior as it draws on all stem cell basic functions, i.e. homing, attachment, migration, proliferation, fate choice, renewal, differentiation and death. In a normal situation, these decisions are tightly controlled and influenced by the microenvironment (the niche), but in therapy, the microenvironment may be diseased, damaged by the preconditioning treatment, or even completely missing as in third degree burns or limbal deficiency. Hence, transplanted stem cells have to adapt to an environment that is far from ideal, if not hostile. Surprisingly, little is known on engraftment that remains more a lottery than a scientifically controlled process. We have demonstrated that transplanted stem cells respond to adverse conditions by favoring differentiation rather self-renewal or death (Grasset et al., submitted). We are now using state-of-the art architecture, informatics and visualization technology to construct models that will allow us to virtually manipulate stem cell behavior and predict the consequences on organ function using the skin, the thymus and the cornea as model systems. We have also completed our studies 1- on the role of small variation of temperature on stem cell behavior and demonstrated that it signals through mTOR wired to TRPVs (Brouard et al., submitted), 2- on a single stem cell strategy for ex vivo gene therapy of Recessive Dystrophic Epidermal Bullosa (Lathion Droz-Georget et al., submitted), 3- on the plasticity of stratified epithelial cells (Claudinot et al., submitted), 4- on the characterization of the clonogenic epithelial cells in human thymus (Magggioni et al., in preparation), and 5- on the organization of actin filaments which predicts the response of human clonogenic epidermal keratinocytes to epidermal growth factor (Nanba et al., submitted).

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Selected Publications

Smith E, Claudinot S, Lehl R, Pellegrinet L, Barrandon Y, Radtke F. Generation and Characterization of a Nothc1 Signaling-Specific Reporter Mouse Line. (April 2012) Genesis, epub ahead of print.

Rochat A, Grasset N, Gorostidi F. Lathion Droz-Georget S, Barrandon Y. Regeneration of epidermis from adult human keratinocyte stem cells. (2012) In Handbook of stem cells A. Atalla and R. Lanza coordinating editors Elsevier. In press.

Bonfanti P, Barrandon Y, Cossu G. “Hearts and Bones”: The Ups and Downs of “Plasticity” in Stem Cell Bioloy (2012) EMBO Molecular Medicine 4, 1-9 .

Grasset, N, Barrandon Y, Hug K, Hermeren G. Issues beyond the debate on the moral status of the embryo, in Translational Stem Cell Research, pp. 45-53, Eds Springer Verlag, New York, 2011.

Bonfanti, P., Claudinot, S., Amici, A.W., Farley, A., Blackburn, C.C, Barrandon, Y. (2010). Microenvironmental reprogramming of thymic epithelial cells to skin multipotent stem cells. Nature 466, 978-982.

Majo, F., Rochat, A., Nicolas, M., Abou Jaoudé, G., Barrandon, Y. (2008). Oligopotent stem cells are distributed throughout the ocular surface. Nature 456, 250-254. Epub 2008 Oct 1. Research Highlights in Nature Reports Stem Cells Epub Oct 9, 2008. (press release).

Majo F., Rochat A, Nicolas M, Abou Jaoude G, Barrandon Y, Location of corneal epithelial stem cells Reply, Nature, 463 (7284), 11, 2010.

Gurtner, G. C., Werner, S., Barrandon, Y., Longaker, M. T. (2008). Wound repair and regeneration. Nature 453: 314-321.

Team Members Senior scientists Brouard Michel Rochat Ariane

Postdoctoral Fellows Amici Alessandro Caillier-Veron Maïa Claudinot Stéphanie Droz-Georget Stéphanie Gonneau Christèle Grasset Nicolas Kanemitsu Michiko Volorio Christelle Wasknick Roxana PhD Students Gorostidi François Graber Julien Maggioni Melissa Manti Pierluigi Mosig Johannes Muller Georges Pluchinotta Matteo Zaffalon Andrea Master’s Students Muller Georges Pluchinotta Matteo Zaffalon Andrea Hémon Diane De Lageneste Marine Richter Solange Technicians Mercier Louis Vermot Steeve Clinical Trial Collaborator Savioz-Dayer Emmanuelle Supporting Staff Mercier Louis Vermot Steeve

IBI - Institute of Bioengineering

Administrative Assistants Guex Nathalie Savioz-Dayer Emmanuelle

Cultured neuron isolated from a trigeminal ganglion of a mouse, TUJ1 immunostaining; 10x magnification

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EPFL School of Life Sciences - 2011 Annual Report

Dal Peraro Lab http://lbm.epfl.ch/

IBI

Matteo Dal Peraro graduated in Physics at the University of Padua in 2000. He obtained his Ph.D. in Biophysics at the International School for Advanced Studies (SISSA, Trieste) in 2004. He received postdoctoral training at the University of Pennsylvania (Philadelphia) under the guidance of Prof. M. L. Klein. He was nominated Tenure Track Assistant Professor at the EPFL School of Life Sciences in late 2007, where he is heading the Laboratory for Biomolecular Modeling (LBM), within the Interfaculty Institute of Bioengineering (IBI).

Matteo Dal Peraro Tenure Track Assistant Professor

Introduction

We use molecular modeling techniques combined with high-performance computing to investigate biological systems, in particular their function emerging from structure. Our main targets are bacterial and viral systems and their mechanism of resistance towards natural and clinical drugs. We develop new multiscale schemes and models to extend the power of current molecular simulations to tackle problems such as the assembly of large macromolecular complexes and the design of remedies for pathogenic infections.

Keywords

Computational biophysics, biochemistry, and structural biology, bacteria and viruses, multiscale molecular simulations; macromolecular assembly, high-performance computing, particle swarm optimization.

Results Obtained in 2011

In the past decade, the advances of computational biophysics and biochemistry have permitted to extend our knowledge of biological function at the molecular level shedding light on features that are often experimentally inaccessible.

Proteins often assemble in large macromolecular complexes to achieve a specific biological task. Unfortunately, owing to their size and complexity, the structure of these machines is difficult to be determined at atomistic resolution. Thus, the ability to reliably predict the conformation of multimeric assemblies is desirable. To address this issue we developed a new approach called POW (Protein Optimization Workbench) that uses a Particle Swarm Optimization (PSO) search guided by experimental-based restraints to characterize protein quaternary structure. We showed how, by exploiting a limited set of known experimental restraints, our method can successfully (i) predict the arrangement of a variety of protein assemblies according to a predefined symmetry, and (ii) sample the conformation of protein-protein binary complexes (see Figure).

In addition, the inclusion of the native flexibility of each protein subunit is a key ingredient for the prediction of biologically functional assemblies. The advantage of this ap-

proach is that assembly prediction is performed using an ensemble of physically plausible structures. Upon definition of a list of geometric restraints and a specific symmetry, a PSO search tries to arrange the elements belonging to a conformational database in a multimeric assembly so that all restraints are respected, and steric clashes avoided. Geometric restraints can be typically provided by low resolution electron density maps or experiments such as cross-linking disulfide scanning, mutagenesis, FRET, etc. If necessary, POW can assemble a multimer on a given substrate. A small set of representative solutions, typically less than ten, is returned by clustering the accepted solutions.

This process is usually very fast (less than 5 minutes on an average workstation), and can produce a small ensemble of solutions being sufficiently good to generate biologically sound working hypotheses, and act as seeds for further optimization steps using more computationally expensive techniques.

This scheme has been recently used to model the heptameric soluble form of pore-forming toxin aerolysin from Aeromonas hydrophila (in collaboration with the van der Goot Lab at EPFL). The model is based on the high-resolution X-ray structure of aerolysin monomer and the lowresolution cryo-EM map of the heptamer. The same strategy has been used to determine the membrane-embedded basal body (namely the complex between YscD and YscJ) of the multi-MDa type III secretion system from Yersinia enterocolitica.

The PSO engine in our software is not sensitive to the kind of imposed symmetry, thus implementing other common symmetries (such as helical or icosaedral) is trivial, and is part of our future development plans. Moreover, improvements on (i) the fitness function with the inclusion of a broader set of geometric restraints, and/or (ii) the energy scoring with the use of more accurate molecular mechanics potentials will certainly contribute to enhance the quality of the final predicted assemblies and eventually address the prediction of protein-protein interactions in large macromolecular networks.

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Selected Publications

B. Blasco, M. Stenta, L. Alonso-Sarduy, G. Dietler, M. Dal Peraro, S. Cole, F. Pojer (2011) Atypical DNA recognition mechanism used by the EspR virulence regulator of Mycobacterium tuberculosis, Molecular Microbiology, 82:251–264.

I. Iacovache, M. Degiacomi, L. Pernot, M. Schiltz, M. Dal Peraro, F. G. van der Goot (2011) Folding of the pore-forming toxin aerolysin is catalyzed by the Cterminal propeptide, PLoS Pathogens 7(7):e1002135.

M. Stenta and M. Dal Peraro (2011) An introduction to quantum chemical methods applied to drug design, Frontiers in Bioscience, E3(1):1061-1078.

S. Wagner, M. Stenta, L. C. Metzger, M. Dal Peraro and G. R. Cornelis, (2010) Length control of the injectisome needle requires only one molecule of Yop secretion protein P (YscP), Proc. Natl. Acad. Sci. USA, 107(31):13860-13865.

Team Members Postdoctoral Fellows Davide Aleman Marco Stenta PhD Students Christophe Bovigny Matteo Degiacomi Hassan Pezeshki Thomas Lemmin Enrico Spiga Adnimistrative Assistant Marie-France Radigois

M.H. Ho, M. De Vivo, M. Dal Peraro, and M. L. Klein, (2010) Understanding the Effect of Magnesium Ion Concentration on the Catalytic Activity of Ribonuclease H through Computation: Does a Third Metal Binding Site Modulate Endonuclease Catalysis, J. Am. Chem. Soc., 132:13702-13712.

E. Khurana, R. H. Devane, M. D. Peraro and M. L. Klein (2010). Computational study of drug binding to the membrane-bound tetrameric M2 peptide bundle from influenza A virus, Biochimica et Biophysica Acta (BBA) - Biomembranes, 1808:530–537.

IBI - Institute of Bioengineering

D. Alemani, F. Collu, M. Cascella and M. Dal Peraro, (2010) A nonradial coarsegrained potential for proteins produces naturally stable secondary structure elements, Journal of Chemical Theory and Computation, 6(1):315-324.

(Left box) POW workflow.

(Right) Best symmetrical rigid assembly predictions (in yellow) superposed to known X-ray crystal structures (in blue) of a representative set of symmetric assemblies.

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EPFL School of Life Sciences - 2011 Annual Report

Deplancke Lab

http://deplanckelab.epfl.ch/

IBI

Bart Deplancke performed his undergraduate and M.Sc. studies in bio-engineering at Ghent University (Belgium), after which he pursued a Ph.D. in Immunobiology with Dr. Rex Gaskins at the University of Illinois (Urbana-Champaign, USA). He then teamed up for his post-doctoral studies with Dr. Marian Walhout, first in the laboratory of Dr. Marc Vidal at the Dana-Farber Cancer Institute of Harvard Medical School and later at the University of Massachusetts Medical School where Marian established her own laboratory, to study the structural and dynamic properties of gene regulatory networks. At the end of 2007, he started his own Laboratory of Systems Biology and Genetics at the EPFL as a tenure track assistant professor.

Bart Deplancke Tenure Track Assistant Professor

Introduction/Results 2011

Automated protein-DNA interaction screening of Drosophila regulatory elements The LSBG developed during the last two years an automated platform that enables the high-throughput protein-DNA interaction screening of Drosophila regulatory elements of interest (Hens et al., Nature Methods, 2011). Because of the availability of a high-quality genome sequence and many genetic tools, Drosophila has one of the best characterized metazoan genomes in terms of functionally annotated regulatory elements. Yet for most of these, it is still not known which the interacting TFs are. The ability to screen annotated regulatory elements for interacting TFs should therefore be of great value for the Drosophila community. To evaluate the efficacy of this platform, we screened six well-characterized regulatory elements and identified 33 TF–DNA interactions of which many were previously unidentified. To simultaneously validate these interactions and locate the binding sites of involved TFs, we implemented a powerful microfluidics-based approach, MARE (MITOMI-based Analysis of Regulatory Elements), that allows us to retrieve DNA occupancy data for each TF throughout the respective target DNA elements. Using MARE, we observed site-specific DNA binding for ~80% of the detected TFs. Importantly, we also biologically validated several interactions and identified two new regulators of sine oculis gene expression and hence eye development. This work has been well appreciated by the Drosophila community as reflected by the fact that over a dozen labs have already sent students to our lab to perform protein-DNA interaction screens.

An integrative genomics study to dissect the gene regulatory mechanisms underlying adipogenesis In the last couple of years, our Lab has invested substantial efforts to elucidate the molecular function of Nuclear Receptor Co-Repressor 2 (NCoR2, or also known as Silencing Mediator of Retinoic acid and Thyroid hormone receptor (SMRT)) during adipogenesis (Raghav et al., Molecular Cell, in press). SMRT is a member of the family of transcriptional

co-regulators, which complement the function of TFs by acting as sensors of upstream regulatory signals, as such modulating the interaction between TFs and the basal transcriptional machinery. So far, most of our time has been devoted to elucidate the role of co-activators (e.g. p300, CBP) since they provide a more convenient experimental read-out, i.e. that of gene activation. Consequently, knowledge about the role and importance of their transcriptional counterparts, i.e. co-repressors, is still in its infancy, despite the fact that several have already been implicated in a wide range of biological processes. A striking example is SMRT, which, among many other biological processes, has been shown to repress terminal white fat cell differentiation. To elucidate the regulatory role of the co-regulator SMRT during adipogenesis, we first performed genome-wide DNAbinding profiling revealing that this co-repressor, in contrast to what may have been expected, is predominantly located in active chromatin regions and that most distal SMRT binding events are lost after differentiation induction. We found that promoter-proximal tethering of SMRT in pre-adipocytes is primarily mediated by the ZBT TF KAISO through the TCTCGCGAGA site (see graphical abstract), one of the most conserved motifs in mammalian promoters. Further characterization revealed that KAISO, similar to SMRT, accelerates the cell cycle and increases fat accumulation upon knockdown, identifying KAISO as a novel adipogenic repressor that likely modulates the mitotic clonal expansion phase of this process. We found that SMRT-bound promoter-distal sites tend to overlap with C/EBPb-bound regions, which become occupied by pro-adipogenic transcription factors after SMRT clearance. This reveals a role for SMRT of masking enhancers from pro-adipogenic factors in pre-adipocytes.

Keywords

Systems biology, gene regulatory network, transcription, genomic variation, quantitative genetics, mouse, drosophila, yeast, genetic engineering.

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Selected Publications

S.K. Raghav*, S.M. Waszak*, I. Krier, A. Isakova, C. Gubelmann, T.S. Mikkelsen, and B. Deplancke. Integrative genomics identifies SMRT as a gatekeeper of early adipogenesis through the transcription factors C/EBPb and KAISO, Molecular Cell, in press.

B. Deplancke, K.J. Verstrepen. Variable outcome of mutations. Science, 335:4445, 2012.

K. Hens, J. Feuz, B. Deplancke. A high-throughput gateway-compatible yeast one-hybrid screen to detect protein-DNA interactions. Methods in Molecular Biology, 786:335-55, 2012.

S. Raghav, B. Deplancke. Genome-wide profiling of DNA binding proteins using barcode-based multiplex Solexa sequencing. Methods in Molecular Biology, 786:247-62, 2012.

K. Hens, J Feuz, A. Isakova, A. Iagovitina, A. Massouras, J. Bryois, P. Callaerts, S.E. Celniker, B. Deplancke. Automated protein-DNA interaction screening of Drosophila regulatory elements. Nature Methods, 8:1065-70, 2011.

Team Members Postdoctoral Fellows Monica Albarca Korneel Hens Sunil Raghav PhD Students Julia Cajan Carine Gubelmann Alina Isakova Irina Krier GrĂŠgoire Laporte Andreas Massouras Jovan Simicevic Sebastian Waszak Scientific assistants Jean-Daniel Feuz Wiebke Westphal Administrative assistant Marie-France Radigois

C. Gubelmann, A. Gattiker, A. Massouras, K. Hens, F. Decouttere, J. Rougemont, B. Deplancke. GETPrime: a gene- or transcript-specific primer generator for qPCR. Database, bar040, 2011.

T.M. Tabuchi*, B. Deplancke*, N. Osato, L.J. Zhu, M.I. Barrasa, M.M. Harrison, H.R. Horvitz, A.J.M. Walhout, K.A. Hagstrom. Chromosome-biased binding and gene regulation by the C. elegans DRM complex. PLoS Genetics,7: e1002074, 2011. (*, shared first authorship).

A. Massouras, K. Hens, C. Gubelmann, S. Uplekar, F. Decouttere, J. Rougemont, S.T. Cole, B. Deplancke. PrInSeS: Primer-Initiated Sequence Synthesis. Nature Methods, 7:485-6, 2010.

IBI - Institute of Bioengineering

A. Massouras, F. Decouttere, K. Hens, B. Deplancke. WebPrInSeS: automated full-length clone sequence identification and verification using high-throughput sequencing data. Nucleic Acids research, 38:W378-84, 2010.

Graphical abstract of the molecular role of the co-repressor SMRT during terminal white fat cell differentiation.

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EPFL School of Life Sciences - 2011 Annual Report

Hubbell Lab http://lmrp.epfl.ch/

IBI

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.

Jeffrey A. Hubbell

Full Professor Director of IBI Merck-Serono Chair in Drug Delivery

Introduction

We design novel materials for investigation of basic cell biological phenomena such as stem cell self-renewal and differentiation and applications in medicine such as drug delivery, regenerative medicine, and vaccination. We focus on examples where novel materials are necessary to solve the problem, thus working at the interface between materials science and biology.

Keywords

Biomaterials, tissue engineering, protein engineering, extracellular matrix, immunoengineering, vaccines, tolerance.

Results Obtained in 2011

Regenerative medicine: The laboratory made exciting advances in engineering matrix-bound morphogens for conjugation in biomaterial matrices for tissue repair and regeneration. We had previously developed a biochemical approach to incorporate morphogenetic proteins into surgical matrices such as fibrin, two of which have now entered into clinical testing in bone repair and chronic wound healing in more than 500 patients in collaboration with corporate partners. We have further developed this concept, engineering extracellular matrix proteins, based on fibronectin and other extracellular matrix proteins, to comprise a promiscuous growth factor-binding domain proximal to an integrin-binding domain. The growth factor-binding domain was observed to bind to more than 20 growth factors from very diverse families. From the reverse perspective, we have identified domains from growth factors that are capable of binding a very diverse collection of extracellular matrix proteins. Using these two approaches, we can on the one hand engineer a matrix-based material scaffold to bind to a wide variety of growth factors, or we can engineer a particular growth factor to bind to a wide variety of extracellular matrix-based scaffold materials. We are exploring these approaches in the context of angiogenesis, chronic wound repair, bone repair, nerve repair and hair cell regeneration.

Vaccines and immunotherapeutics: In collaboration with the Laboratory for Lymphatic and Cancer Bioengineering (Prof. M.A. Swartz), the laboratory demonstrated that nanoparticles can be used as a vaccine platform for targeting cells in the lymph nodes draining dermal site and the lung, in addition to secondary lymphoid tissues in the nasal cavity. This, combined with advanced design of the polymeric nanoparticle surfaces, has enabled a new generation of vaccines, highly stable and very economical, for use in both the developing and the developed world. The team has demonstrated that ultra-small particles, smaller than biological particles, can be swept into the lymphatics within a few minutes of injection, drain to the lymph nodes, and are collected there for antigen presentation. Particularly favorable antigen conjugation schemes were developed for promotion of MHC I presentation and induction of potent CD8+ T cell responses, very impressive protection of mice versus influenza and Mycobacterium tuberculosis challenge was demonstrated, much more impressive than with free antigen delivered with the same adjuvants. From a materials perspective, our focus is on self-assembling block copolymers that form polymer micelles, upon the surface of which antigens are conjugated, or polymer vesicles, in the core of which antigens are encapsulated. Given that our interest is in inducing cellular immunity for chronic disease, our materials are designed to enhance mechanisms of antigen cross-presentation. In addition to inducing cellular immunity, 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 have shown that antigens can be engineered to bind in situ to erythrocytes, and that this leads to antigen deposition in antigen presenting cells in the liver and spleen very efficiently, the antigen circulating on the erythrocyte until it is cleared in the liver and spleen as it ages. This results in clonal deletion of both CD4+ and CD8+ T cells.

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Selected Publications

Stano, A. et al. PPS nanoparticles as versatile delivery system to induce systemic and broad mucosal immunity after intranasal administration. Vaccine 29, 804812 (2011).

Nembrini, C. et al. From the Cover: Nanoparticle conjugation of antigen enhances cytotoxic T-cell responses in pulmonary vaccination. Proc. Natl. Acad.

Sci. U. S. A. 108, E989-997 (2011).

Martino, M.M. et al. Engineering the growth factor microenvironment with fibronectin domains to promote wound and bone tissue healing. Sci Transl Med 3, 100ra189 (2011). van der Vlies, A.J., O’Neil, C.P., Hasegawa, U., Hammond, N. & Hubbell, J.A. Synthesis of pyridyl disulfide-functionalized nanoparticles for conjugating thiolcontaining small molecules, peptides, and proteins. Bioconj. Chem. 21, 653662 (2010).

Martino, M.M. & Hubbell, J.A. The 12th-14th type III repeats of fibronectin function as a highly promiscuous growth factor-binding domain. FASEB J. 24, 47114721 (2010).

Kontos, S. & Hubbell, J.A. Improving protein pharmacokinetics by engineering erythrocyte affinity. Mol Pharm 7, 2141-2147 (2010).

Hubbell, J.A. Drug development: Longer-lived proteins. Nature 467, 1051-1052 (2010).

Hirosue, S., Kourtis, I.C., van der Vlies, A.J., Hubbell, J.A. & Swartz, M.A. Antigen delivery to dendritic cells by poly(propylene sulfide) nanoparticles with disulfide conjugated peptides: Cross-presentation and T cell activation. Vaccine 28, 7897-7906 (2010).

Velluto, D., Thomas, S.N., Simeoni, E., Swartz, M.A. & Hubbell, J.A. PEG-bPPS-b-PEI micelles and PEG-b-PPS/PEG-b-PPS-b-PEI mixed micelles as non-viral vectors for plasmid DNA: tumor immunotoxicity in B16F10 melanoma. Biomaterials 32, 9839-9847 (2011).

Vasdekis, A.E., O’Neil, C.P., Hubbell, J.A. & Psaltis, D. Microfluidic assays for DNA manipulation based on a block copolymer immobilization strategy. Biomacromolecules 11, 827-831 (2010).

Team Members Postdoctoral fellows Brubaker Carrie De LaPorte Laura Dane Karen Engelhardt Eva-Maria Hasegawa Urara Kontos Stephane Lorentz Kristen Martino Mikaël Mochizuki Mayumi Nembrini Chiara Patterson Jennifer Rice Jeffrey Sancho Oltra Nuria Scott Evan Alexander Tortelli Federico Van der Vlies André Velluto Diana

PhD students Ahmadloo Hamideh Damo Martina De Titta Alexandre Eby Jackson Julier Ziad Kourtis Iraklis Larsson Hans Mattias Mahou Redouan Micol Lionel Panagiotou Vasiliki Pisarek Rubin Berek Raghunathan Sandeep Schütz Catherine Stano Armando Vardar Elif

Master students Briquez Priscilla Djahanbakhsh Rafiee Sarah Liu Alexandra Bachelor students Courthion Hervé Desbaillets Nicolas Kayser Stephanie Leahu Teodor Maillat Léa Internships Boyer David, France David Allen Roberts, USA Ferreira Daniela, Portugal Hopkins Amy, USA Neubauer Stefanie, Germany Other scientific personnel Frey Peter Wandrey Christine Simeoni Eleonora Dessibourg Céline Quaglia Xavier Pasquier Miriella

IBI - Institute of Bioengineering

Administrative Assistant Bonzon Carol Anne

Antigen-specific tolerance in a mouse diabetes model.

Upper left: a normal islet, with insulin in red. Upper right, a rejecting islet, with T cell in green; islet destruction is profound. Lower left: a rejecting islet in an animal in which the tolerogenic antigen is provided as a wild-type, free protein injected iv. Lower right: islet rejection is completely blocked by tolerizing with the same antigen, however fused to an antibody fragment that binds to erythrocytes.

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EPFL School of Life Sciences - 2011 Annual Report

Lutolf Lab http://lscb.epfl.ch/

IBI

Matthias Lutolf was trained as a Materials Engineer at ETH Zurich where he also carried out his Ph.D. studies on the development of a novel class of biomolecular materials for tissue engineering (awarded with ETH medal, 2004). In 2005, Lutolf joined the Baxter Laboratory in Stem Cell Biology at Stanford University to work on hematopoietic stem cells; research sponsored by Swiss National Science Foundation and Leukemia and Lymphoma Society fellowships.

In 2007 Lutolf won a European Young Investigator (EURYI) award to start up his independent research at EPFL.

Matthias P. Lutolf Tenure Track Assistant Professor

Introduction

Results Obtained in 2011

eral adult stem cell populations including neural stem cells, mesenchymal progenitor cells and HSCs. Single mouse long-term HSCs (LT-HSC) were analyzed by time-lapse microscopy and showed distinct in vitro clonal proliferation kinetics in response to putative niche signaling cues. These experiments showed that specific single cell growth kinetics could be correlated with their long-term repopulation potential, the only definitive test of HSC function. Interestingly, we also found that very early (i.e. after one hour in culture) changes in lipid raft distribution on single HSCs could serve as an indicator of the quiescent and activated state of HSCs. Extrinsic factors that decreased the lipid raft clustering slowed down cell cycle kinetics, while factors that increased clustering led to faster and more synchronous cell cycling.

For example, a micro-engineered platform consisting of soft hydrogel microwell arrays with modular stiffness was developed where individual microwells can be functionalized with combinations of candidate biomolecules spotted by robotic technology. Using this novel platform, it is possible to probe the effect of key micro-environmental perturbations on the fate of virtually any stem cell type at single cell level and in high-throughput. We have successfully validated this system by studying niche-regulation of sev-

To understand whether daughter cells generated by cell division of a mother LT-HSC keep their long-term multipotency or have committed, we utilized single cell multi-gene expression analysis to identify gene expression profiles associated with the most primitive stem and progenitor cell states in the mouse bone marrow. Apart from the CDK inhibitor p57 we found several genes involved in regulating cell-cell interactions (e.g. Junctional adhesion molecule C, JAM3, a component of tight junctions) whose expression was significantly upregulated in LT-HSC versus ST-HSC and multipotent progenitors. We showed that these proteins are expressed at the cell surface and can be used as additional phenotypic markers of live LT-HSCs. We then used multigene expression analysis in combination with micromanipulation to analyze paired daughter cells of dividing single HSCs. In vitro divisions under serum-free conditions supplemented with well-known hematopoietic cytokines, that is, in the absence of a functional niche, resulted in significant downregulation of the key niche interaction genes.

Interestingly, several of the analyzed genes appear to be differentially expressed in the two paired daughter cells suggesting asymmetric divisions. Preliminary LT-HSC culture experiments on artificial niches displaying the identified cell-cell interaction proteins such as JAM3 show delayed cell cycle entry and maintenance of an LT-HSC-like gene expression profile.

Adult stem cells can hardly be grown in a culture dish (‘ex vivo’), posing a substantial hurdle for their clinical use. By merging biomaterials science with microfabrication technologies, the Lutolf laboratory develops and applies innovative bioengineering tools to probe and manipulate single stem cell behavior in vitro in an unprecedented fashion.

These technologies are expected to have the potential to be translated into clinical settings.

Keywords

Stem cells, self-renewal, single cell analysis, niche, hydrogel engineering, microfluidics.

One question the lab has been pursuing using this paradigm is the regulation of mouse hematopoietic stem cell (HSC) fate decision-making. That is to say, despite a remarkable extent of knowledge regarding the biology of hematopoietic stem cells (HSCs), the mechanisms governing the long-term maintenance of their function have not been elucidated. Compelling evidence shows that the microenvironment, or niche, plays the key role in regulating HSC function in vivo, but just how the stem cells remain quiescent and, upon activation, integrate the multiple niche signaling cues to either undergo self-renewal or commitment remains unknown. We have been tackling this crucial question by first identifying a minimal functional artificial HSC niche, i.e. by discovering candidate extrinsic factors that can influence in vitro HSC maintenance without loss of in vivo function, and then exploring their mechanisms of action.

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EPFL School of Life Sciences - 2011 Annual Report

Selected Publications

Gobaa S, Hoehnel S, Roccio M, Negro A, Kobel S, Lutolf MP*, Artificial niche microarrays for probing stem cell fate in high-throughput, Nature Methods, 2011 Oct 9;8(11):949-55. (highlighted by a News & Views from F. Watt and J. Burdick).

Kobel S, Lutolf MP*, Biomaterials meet Microfluidics: Building the next generation of artificial niches, Current Opinion in Biotechnology, 2, pp. 690-697 (2011).

Ehrbar M*, Sala A, Lienemann P, Rizzi SC, Weber FE and Lutolf MP*, Elucidating the role of matrix stiffness in 3D cell migration and remodeling, Biophysical Journal, 100, 284-293 (2011).

Allazetta S, Cosson S, Lutolf MP*, Programmable microfluidic patterning of protein gradients on hydrogels, Chemical Communications, 47 (1): 191-193 (2011).

Gilbert PM, Havenstrite KL, Sacco A, Leonardi N, Peggy Kraft, Nguyen NK, Lutolf MP, and Blau HM (2010). Matrix rigidity regulates skeletal muscle stem cell self-renewal in culture, Science, 329 (5995): 1078 – 1081.

Mosiewicz, K., Johnsson, K. and Lutolf, M.P. (2010). Phosphopantetheinyl Transferase-Catalyzed Formation of Bioactive Hydrogels for Tissue Engineering, JACS, 132 (17): 5972–5974.

Kobel, S. and Lutolf, M.P.*, High-throughput methods to define complex stem cell niches, Biotechniques, Vol. 48, No. 4, pp. ix–xxii (2010)

Team Members Postdoctoral Fellows Samy Gobaa Marta Roccio Nicola Vannini Olaia Naveiras PhD Students Simone Allazetta Steffen Cosson Mukul Girotra Sylke Hoehnel Andrea Negro Yuya Okawa Adrian Ranga Aline Roch Master Students Ryan Erickson Sonia Hallen Luc Gervais Mbida Teodor Leahu Technician Vasco Campos Administrative Assistant Maria Fernandes Coelho

IBI - Institute of Bioengineering

Kobel, S., Valero, A., Latt, J. Renaud, P., and Lutolf, M.P. (2010). Optimization of microfluidic single cell trapping for long-term on-chip culture, Lab on a Chip, 10: 857 - 863.

Automated high-throughput screening of cell fate in nearphysiological 3D artificial microenvironments (‘niches’).

(A) A materials library is synthesized which is amenable to robotic liquid dispensing. (B) Cell-containing gel precursors are microarrayed as 3D ‘spots’ into 1536-well plates. (C) Upon cell culture, colony formation and phenotypes in 3D can be readily visualized, quantified to reveal novel regulatory mechanisms.

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Naef Lab

http://naef-lab.epfl.ch/

IBI

Felix Naef studied theoretical physics at the ETHZ and obtained his PhD from the EPFL in 2000. He received postdoctoral training at the Center for Studies in Physics and Biology at the Rockefeller University (NYC). His research focuses on the study of biomolecular oscillators, modeling, and transcription regulation. He was nominated Tenure Track Assistant Professor at the EPFL School of Life Sciences in 2005.

He is currently a member of the Institute of Bioengineering (IBI).

Felix Naef

Tenure Track Assistant Professor

Introduction

Our lab is interested in quantitative and systems biology.

We work on various problems including circadian biology, developmental patterning, transcription regulatory networks, and stochastic transcription in single cells. To study these systems we apply theoretical, computational and experimental methods.

Keywords

Gene regulation, chronobiology, circadian rhythms, stochastic gene expression.

Results Obtained in 2011

Circadian gene regulation in mouse liver.

The circadian clock is a timing system that allows organisms to keep behavioral, physiological, and cellular rhythms in resonance with daily environmental cycles. In mammals, such clocks use transcriptional regulatory loops in which the heterodimeric transcription factor BMAL1/CLOCK plays a central role. Recently, we performed the first comprehensive time series analysis of the binding profiles of the core circadian transcription factor BMAL1 in a complex tissue, namely the mouse liver (Rey et al, 2011). The mouse liver has been a prime model in circadian biology showing high amplitude rhythms; moreover, it has high relevance to study the timely issue of how the clock interacts with metabolism. The approach used ultra-high throughput sequencing (UHTS) combined with chromatin immuno-precipitation (ChIP) assays and bioinformatics modeling to characterize the rhythmic DNA-binding and its role in controlling circadian gene transcription and accumulation. Our temporal analysis revealed widespread daily rhythms in DNA-binding with maximum levels at midday. BMAL1 targets clearly indicated a circadian function in carbohydrate and lipid metabolism, mediated via nuclear receptors. Moreover, detailed in vitro and in cellulo assays elucidated the role of cooperative interactions at E1-E2 enhancer sites. Our results strengthened BMAL1’s primary function as master regulator of the core circadian oscillator, while it is implicated more weakly in a variety of hepatic output functions.

Stochastic transcription in single mammalian cells.

This work lies at the interface of circadian transcription regulation and basic transcription biology. Our previous discovery of cell-autonomous transcriptional circadian oscillations in 2004 (Nagoshi et al., 2004) used a single gene promoter (RevErba) with a relatively long-lived (half-live of ~3 hours) fluorescent reporter (venus-YPF). The question then arose as to what temporal patterns in transcription can be found in a mammalian cell when measured (i) in unbiased fashion (genome-wide); and (ii) using a shorter lived reporter such that rhythms of shorter period (ultradian frequencies) or transcriptional discontinuities (transcriptional bursting) could be characterized. In Suter et al., 2011, we provided a systematic and quantitative time-lapse study of transcriptional bursting in mammalian cells using high temporal resolution measurements of transcription in individual cells. Specifically, we discovered how discontinuous transcription of mammalian genes leads to broad spectra of temporal bursting in mRNA synthesis. To obtain these results, we monitored transcription at high temporal resolution by designing chromosomally integrated vectors encoding a destabilized luciferase in combination with ultrasensitive bioluminescence microscopy. We then developed a novel mathematical framework that combines a stochastic model of transcription with Bayesian inference to (i) calibrate model parameters, and (ii) compute the statistical properties of switching times in gene activity. This revealed gene-specific transcription burst sizes, switching rates, and we discovered refractory periods of variable duration in the inactive state. Relevant to chronobiology, we found that the circadian transcription of the Bmal1 gene is accompanied by an ultradian frequency band in the range of two hours, which persisted after treatment with TSA (resulting in a state of hyper-acetylated histones and transcriptionally permissive chromatin).

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EPFL School of Life Sciences - 2011 Annual Report

Selected Publications

D. M. Suter, N. Molina, D. Gatfield, K. Schneider, U. Schibler*, F. Naef*, “Mammalian Genes Are Transcribed with Widely Different Bursting Kinetics”, Science 332, 472 (2011).

G. Rey, F. Cesbron, J. Rougemont, H. Reinke, M. Brunner, F. Naef*, “GenomeWide and Phase-Specific DNA-Binding Rhythms of BMAL1 Control Circadian Output Functions in Mouse Liver”, Plos Biology 9, (2011).

J. Bieler, C. Pozzorini, F. Naef*, “Whole-embryo modeling of early segmentation in Drosophila identifies robust and fragile expression domains”, Biophys J 101, 287 (2011).

I. Gyurjan, B. Sonderegger, F. Naef, D. Duboule, “Analysis of the dynamics of limb transcriptomes during mouse development.” BMC Dev Biol. 11(1):47 (2011).

G. Stoll, M. Bischofberger, J. Rougemont, F. Naef*, “Stabilizing patterning in the Drosophila segment polarity network by selecting models in silico”, Biosystems 102, 3 (2010).

Team Members Postdoctoral Fellows Teresa Ferraro Nacho Molina Bhaswar Ghos PhD Students Mirko Bischofberger Guillaume Rey Thomas d’Eysmond Simon Blanchoud Jonathan Bieler Laura Symul Julia Cajan Johannes Becker Benjamin Zoller Rosamaria Cannavo Jerome Mermet Administrative Assistant Sophie Barret

M. Preti, C. Ribeyre, C. Pascali, M. C. Bosio, B. Cortelazzi, J. Rougemont, E. Guarnera, F. Naef, D. Shore, G. Dieci, “The Telomere-Binding Protein Tbf1 Demarcates snoRNA Gene Promoters in Saccharomyces cerevisiae”, Molecular Cell 38, 614 (2010).

IBI - Institute of Bioengineering

S. Blanchoud, Y. Budirahardja, F. Naef*, P. Gonczy*, “ASSET: A Robust Algorithm for the Automated Segmentation and Standardization of Early Caenorhabditis elegans Embryos”, Developmental Dynamics 239, 3285 (2010).

Transcription of individual mammalian genes shows refractory period in gene re-activation. A) two single-cell bioluminescence traces form the same clone. B) Signal deconvolution. C) Duration of ‘off’ state shows peaked distribution. D) Minimal model of gene transcription needs three-states.

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EPFL School of Life Sciences - 2011 Annual Report

Swartz Lab

http://swartz-lab.epfl.ch/

IBI

Melody Swartz is a Professor in the Institutes of Bioengineering (IBI) and Experimental Cancer Research (ISREC). She received her BS from Johns Hopkins and PhD from M.I.T., both in Chemical Engineering. After a postdoc at Harvard, she moved to Northwestern University as an Assistant Professor of Biomedical Engineering, and moved to the EPFL in 2003. Throughout her career, she has focused on the lymphatic system, integrating physiology, bioengineering, tissue mechanics, and cell biology to elucidate their functional-biological regulation and more recently how immune cells and cancer cells gain access to the lymphatics. Her lab has helped to define new paradigms in the field of lymphangiogenesis and cancer metastasis.

Melody A. Swartz Full Professor

Introduction

The lymphatic system is an important regulator of fluid balance, innate immunity and peripheral tolerance. We are fascinated by this network of vessels that drain fluid, antigens, and cells from the periphery, through the lymph nodes, and back into the blood. By uncovering its complex roles in immunity and tolerance, we hope to understand – and ultimately manipulate – its participation in cancer progression and metastasis.

Keywords

Lymphatic system, immunoengineering, tumor microenvironment, lymph node metastasis, interstitial flow, mechanobiology, biotransport phenomena.

Results Obtained in 2011

In 2011, we contributed new fundamental understanding of how the lymphatic microenvironment affects immunity and cancer, and how dendritic cells (DCs) interpret different types of cues in this biomechanically complex environment. We also contributed to the mechanobiology of lymphatic endothelium, demonstrating the importance of flow on lymphatic function – namely, its active transport mechanisms for water, solutes, proteins, and nanoparticles.

way, lymphatic endothelium can directly protect the tumor against host immune responses, and may limit the efficacy of immunotherapy aimed to activate host immunity against the tumor.

This has implications for cancer immunotherapy strategies. In collaboration with Jeff Hubbell’s lab (EPFL), we are finding improved cancer vaccine efficacy when targeted specifically to tumor-draining lymph nodes, presumably by replacing the tumor-primed, tolerogenic milieu of the tumor-draining lymph node with immune activation signals. In other areas of lymphatic-targeting nanoparticle vaccines, we have demonstrated that nanoparticle coupling of adjuvant gives more efficacy with lower doses, presumably because it concentrates the signal in the lymph node.

We have also demonstrated similar effects of nanoparticlecoupled vaccines particularly when delivered to the lung, where mucosal immunity is enhanced with lower vaccine doses.

We showed that tumor-associated lymphatic hyperplasia, both in the tumor and its draining lymph node, plays important immune regulatory roles that can protect the tumor from even pre-existing host immunity. In collaboration with Stephanie Hugues’s lab at the University of Geneva, we demonstrated that lymphatic endothelial cells in the tumor microenvironment can scavenge tumor antigens and crosspresent them for subsequent CD8 T cell deletion. In this

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EPFL School of Life Sciences - 2011 Annual Report

Selected Publications

JD Shields, I.C. Kourtis, AA Tomei, J. Roberts, and MA Swartz (2010). Induction of lymphoid-like stroma and immune escape by tumors that express the chemokine CCL21. Science. 328(5979):749-52. (comment: “Perspectives,” Science 328:697-7, 2010; “Research Highlights,” Nature Rev. Cancer, 10(5):292, 2010).

DO Miteva, JB Dixon, W Kilarski, JM Rutkowski, JD Shields, and MA Swartz (2010). Transmural flow modulates cell and fluid transport functions of lymphatic endothelium: A potential early cue for inflammation. Circ. Res. 106(5):920-31.

JM Rutkowski, CE Markhus, C.C. Gyenge, K. Alitalo, H. Wiig, and MA Swartz (2010). Dermal collagen and fat accumulation correlate with tissue swelling and hydraulic conductivity in murine lymphedema. Am J Pathol. 176(3):1122-9.

S Hirosue, IC Kourtis, AJ van der Vlies, JA Hubbell*, and MA Swartz* (2010).

Antigen delivery to dendritic cells by poly (propylene sulfide) nanoparticles with disulfide conjugated peptides: Cross-presentation and T cell activation. Vaccine 28:7897-7906.

JA Pedersen, S. Lichter, and MA Swartz (2010). Cells in 3D matrices under interstitial flow: Effects of pericellular matrix alignment on cell shear stress and drag forces. J Biomech 43:900-905.

U Haessler, M Pisano, M Wu, and MA Swartz (2011). Dendritic cell chemotaxis in 3D under defined chemokine gradients reveals differential response to CCL21 and CCL19. Proc. Natl. Acad. Sci. U.S.A. 108:5614-18.

AC Shieh, HA Rozansky, B Hinz and MA Swartz (2011). Tumor cell invasion is promoted by interstitial flow-induced matrix priming by stromal fibroblasts.

Cancer Res. 71(3):790-800.

SN Thomas, AJ van der Vlies, CP O’Neil, SS Yu, TD Giorgio, MA Swartz*, and JA Hubbell* (2011). Engineering complement activation on polypropylene sulfide vaccine nanoparticles. Biomaterials 32(8):2194-203.

AC Shieh and MA Swartz (2011). Regulation of tumor invasion by interstitial fluid flow. Physical Biol. 8: 015012.

M Ballester, C Nembrini, N Dhar, A de Titta, C de Piano, M Pasquier, E Simeoni, AJ van der Vlies, JD McKinney, JA Hubbell, and MA Swartz (2011). Nanoparticle conjugation and pulmonary delivery enhance the protective efficacy of Ag85B and CpG against tuberculosis. Vaccine 29:6959– 6966.

Team Members Postdoctoral Fellows Francesca Capotosti Witold Kilarski Amanda Lund Alexandra Magold Munson Jennifer Scott Ryan Oliver Jeremy Teo Susan Thomas

PhD Students Marie Ballester Marie Alexandre de Titta Manuel Fankhauser Esra Güç Laura Jeanbart Iraklis Kourtis Marco Pisano Sandeep Raghunathan Marcela Rincon-Restrepo Valentina Triacca Vokali Efthymia Master’s Students Iro Oikonomidi Sabrina Riedl Efthymia Vokali Research Associate Sachiko Hirosue Technicians Borel Véronique Corthésy Henrioud Patricia Foretay Didier Pasquier Miriella Visiting Fellows/Trainee Vidya Raghavan Vanessa Kennedy Renata Mezyk-Kopec Tú Nguyen Le Thanh (Trainee) Administrative Assistant Ingrid Margot

IBI - Institute of Bioengineering

C Nembrini, A Stano, KY Dane, M Ballester, A van der Vlies, BJ Marsland, MA Swartz*, and JA Hubbell* (2011). Nanoparticle conjugation of antigen enhances cytotoxic T cell responses in pulmonary vaccination. Proc. Natl. Acad. Sci. U.S.A. 108(44):E989-97 (*=equal contribution).

Human primary lymphatic endothelial cells exposed to physiological flow show extensive microtubular networks (green). Blue: cell nuclei, purple: podoplanin, red: F-actin red. Photo credit: Dr. Isabelle Magold.

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EPFL School of Life Sciences - 2011 Annual Report

Wurm Lab

http://lbtc.epfl.ch/

IBI

Florian M. Wurm obtained his PhD in Genetics at the University of Giessen, Germany. After having worked for 5 years at Hoechst AG in Marburg, Florian joined Harvard Medical School and then in 1986 he joined Genentech Inc., San Francisco, holding leading positions in Process Sciences. Since 1995 he is professor of Biotechnology at the EPFL, and in 2008 he was appointed Visiting Professor at Jinan University in Guangzhou, China. He has published more than 200 scientific papers and holds more than 10 patents. He is the founder and CSO of ExcellGene SA, a Swiss biotechnology company in Monthey, Valais.

Florian M. Wurm Full Professor

Introduction

Research at the LBTC is situated on the crossroads between biology and engineering, and it addresses the expression of recombinant proteins from suspension cultures of mammalian cells, which is the major approach to therapeutic protein production. Mammalian cells are the most versatile and productive system for the manufacture of recombinant proteins. The major goal of the Laboratory of Cellular Biotechnology is the development of novel and/or improved tools for gene transfer to cultured mammalian cells and subsequent high-level expression of recombinant proteins from such cells in innovative and scalable production systems (bioreactors). We are investigating two major thematic areas: (1) gene delivery, integration and expression in animal cells and their respective impacts on the host cells physiology and genetics (2) orbital shaking technology and novel bioreactor systems.

Keywords

Recombinant protein expression, mammalian cell culture, bioreactor, bioprocess control, gene transfer, DNA integration, microinjection, stable cell line development, orbital shaking.

Results Obtained in 2011

Transient gene expression and stable transgene integration.

The transient transfection approach allows to express a fully glycosylated recombinant protein at high titers (up to 1 g/L for IgGs in HEK-293 cells) only 2-3 weeks after gene cloning. We have studied the cellular uptake and disassembly of PEI-DNA complexes in mammalian cells, and by combining our knowledge of cellular metabolism in suspension cultures with our most recent results, we were able to increase recombinant protein productivity from transiently transfected cells. To study the stable integration of recombinant genes into the genome of a host cell we have focused on the Chinese hamster ovary cell line (CHO), which is the most widely used cell line in the industry. We have inves-

tigated the cytogenetics of CHO-derived stable cell lines generated using different DNA delivery techniques, including transposon-mediated and lentivirus-mediated gene integration. Understanding transgene integration at the molecular level will allow us to develop strategies to prevent the widely observed phenomenon of gene silencing, which lowers productivity in cell clones over time. We demonstrated that transposon (integrase) mediated DNA delivery is a very efficient method to generate high producing, stable CHO cell lines, and we proved the superiority of this technology compared to other gene transfer approaches. More recently, we extended our research to insect cells-based expression systems, and we are developing non-viral, scalable gene delivery methods for these hosts.

The orbitally shaken (OrbShake) bioreactor technology for mammalian cell cultivation, designed in our lab, has been scaled-up to 1’000 L. Orbitally shaken cylindrical vessels (with nominal volumes from 50 mL to 250 L) are being extensively studied in order to characterize the hydrodynamics of this type of agitated systems. A scale-up factor for the OrbShake bioreactors could be determined by mixing time analysis in small-scale experiments. In collaborations with Prof. Alfio Quarteroni (Chair of Modelling and Scientific Computing) and Dr. Mohamed Farhat of the Laboratory of Hydraulic Machines, a fluid dynamics model of the OrbShake bioreactor could be determined and tested. Overall, our research provided useful insights for understanding cell cultivation in suspension, gene integration and protein expression. These studies are of general interest in cellular biology and biotechnology.

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EPFL School of Life Sciences - 2011 Annual Report

Rajendra Y., Kiseljak D., Baldi L., Hacker D. L. and Wurm F. M. (2011) Reduced glutamine concentration improves protein production in growth-arrested CHODG44 and HEK-293E cells. Biotechnology Letters, vol 34 (4): 619-626.

Wurm F. M. and Hacker D.L. (2011) First CHO genome. Nature Biotechnology, vol 29 (8): 718-720.

Tissot S., Oberbek A., Reclari M., Dreyer M., Hacker D. L. et al. (2011) Efficient and reproducible mammalian cell bioprocesses without probes and controllers?

New Biotechnology, vol 28 (4): 382-390.

Matasci M., Baldi L., Hacker D. L. and Wurm F. M. (2011) The PiggyBac transposon enhances the frequency of CHO stable cell line generation and yields recombinant lines with superior productivity and stability. Biotechnology and Bioengineering, vol 108 (9): 2141-2150.

Rajendra Y., Kiseljak D., Baldi L., Hacker D. L. and Wurm F. M. (2011) A simple high-yielding process for transient gene expression in CHO cells. Journal of Biotechnology, vol 153 (1-2): 22-26.

Xie Q., Michel P. O., Baldi L., Hacker D. L., Zhang X. and and Wurm F. M. (2011) TubeSpin bioreactor 50 for the high-density cultivation of Sf-9 insect cells in suspension. Biotechnology Letters, vol 33 (5): 897-902.

Oberbek A, Matasci M, Hacker DL, Wurm FM. (2011) Generation of stable, high-producing CHO cell lines by lentiviral vector-mediated gene transfer in serum-free suspension culture. Biotechnol Bioeng vol 108 (3): 600-10.

Wulhfard S, Baldi L, Hacker DL, Wurm F. (2010) Valproic acid enhances recombinant mRNA and protein levels in transiently transfected Chinese hamster ovary cells. J Biotechnol vol 148 (2-3): 128-32.

Zhang XW, Garcia IF, Baldi L, Hacker DL, Wurm FM. (2010) Hyperosmolarity enhances transient recombinant protein yield in Chinese hamster ovary cells.

Biotechnol Lett vol 32 (11): 1587-1592.

Tissot S, Farhat M, Hacker DL, Anderlei T, Kühner M, Comninellis C, Wurm F. (2010). Determination of a scale-up factor from mixing time studies in orbitally shaken bioreactors. Biochem Eng J vol 52 (2-3): 181-186.

Team Members Senior Scientists Lucia Baldi David Hacker

Postdoctoral Fellow Patrik Olavi Michel PhD Students Sowmya Balasubramanian Divor Kiseljak Dominique Monteil Yashas Rajendra Xiao Shen Stéphanie Tissot Francesca Zagari Master Students Archita Chaudhary Riad Gacem Guillaume Lüthi Joao Pereira Ghimire Saroj Giulia Tontodonati Exchange Student Jake Yeung Laboratory Support Ione Gutscher Veronika Knapkova Trainees Clara Douet Sarah Grezet Mélanie Hubert Samjhana Thapa Technical Assistants Virginie Bachmann Gilles Broccard Administrative Assistant Fabienne Rudin

IBI - Institute of Bioengineering

Selected Publications

Chromosome spread of CHO K1 cell analyzed by confocal microscopy after staining with YOYO-1 (491/509). 3-D image reconstructed from 23 images (0.04 μm per section) (Picture from PO Michel)

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Co-affiliated Research Groups EPFL School of Life Sciences - 2011 Annual Report

Aminian Lab -

coaffiliated

http://lmam.epfl.ch/

IBI

Kamiar Aminian received the M.S. degree in electrical engineering in 1982, the Ph.D degree in biomedical engineering in 1989 and the Postgraduate degree on technical computing in 1993 from EPFL. He is currently Professor of Medical Instrumentation and the Director of the Laboratory of Movement Analysis and Measurement in the Institute of Bioengineering of EPFL. He is a member of the International Society of Posture and Gait Research, the Institute of Electrical and Electronics Engineers, the European Society of Movement Analysis in Adults and Children, the Prevention of Falls Network Europe, the Intentional Society of Biomechanics and the future president of the 3D analysis of the human movement group.

Kamiar Aminian

Adjunct Professor School of Engineering (STI)

Research Interests

The Laboratory of Movement Analysis and Measurement investigates fundamental functions in human movement, sport science and locomotion that relate to health and disease. Performance or failure affecting the motor function is characterized in real world condition through a multidisciplinary approach involving wearable and implanted instrumentation, signal processing, biomechanics and clinical evaluation. This involves the design of advanced algorithms for the long-term monitoring and analysis of physical behaviour, measurement of 3D joint kinematics and kinetics of the movement and estimation of spatio-temporal parameters of locomotion. In sport science, performance evaluation is particularly studied in snow sports and aquatic locomotion. In clinics, the outcomes consist particularly to characterize failure affecting motor functions by identifying relevant disease/health related features hidden in human biomechanical signals. Based on these features new metrics are defined and validated to provide early diagnosis and objective clinimetry for outcome evaluation in orthopaedics and aging, to assess the change of motor function with pain, to detect motor failure in movement disorder such as stroke and Parkinson disease, and to analyse the frailty behaviour in elderly population in order to investigate appropriate intervention for disease prevention and rehabilitation.

Selected Publications

Rouhani, H., Favre, J., Crevoisier, X., and Aminian, K. (2011) Ambulatory measurement of ankle kinetics for clinical applications, Journal of Biomechanics, 44, 2712-2718.

Aissaoui, R., Ganea, R., & Aminian, K. (2011). Conjugate momentum estimate using non-linear dynamic model of the sit-to-stand correlates well with accelerometric surface data. Journal of Biomechanics, 44(6), 1073-1077.

Ganea, R., Paraschiv-Ionescu, A., Büla, C., Rochat, S., Aminian, K. (2011) Multiparametric Evaluation of Sit-to-Stand and Stand-to-Sit Transitions in Elderly People, Medical Engineering & Physics (33), 1086-1093.

Rouhani, H., Favre, J., Crevoisier, X., & Aminian, K. (2011). Outcome evaluation of ankle osteoarthritis treatments: Plantar pressure analysis during long-distance walking, Clinical Biomechanics, 26(4), 397-404.

Mariani, B., Hoskovec, C., Rochat, S., Büla, C., Penders, J., & Aminian, K. (2010). 3D gait assessment in young and elderly subjects using foot-worn inertial sensors. Journal of Biomechanics, 43(15), 2999-3006.

Favre, J., Crevoisier, X., Jolles, B. M., & Aminian, K. (2010). Evaluation of a mixed approach combining stationary and wearable systems to monitor gait over long distance. Journal of Biomechanics, 43(11), 2196-2202.

Salarian, A., Horak, F. B., Zampieri, C., Carlson-Kuhta, P., Nutt, J. G., & Aminian, K. (2010). ITUG, a sensitive and reliable measure of mobility. IEEE Transactions on Neural Systems and Rehabilitation Engineering, 18(3), 303-310.

Rouhani, H., Favre, J., Crevoisier, X., & Aminian, K. (2010). Ambulatory assessment of 3D ground reaction force using plantar pressure distribution. Gait and Posture, 32(3), 311-316.

Team Members Scientist Anisoara Ionescu

Postdoctoral Fellows Hooman Dejnabadi Arash Salarian PhD Students Arash Arami Arnaud Barré Farzin Dadashi Julien Chardonnens Cyntia Duc Raluca Ganea Benoit Mariani Fabien Massé Hossein Rouhani Master’s Students Matthieu Hayoz Francois Curdy Technicians Jean Gramige Pascal Morel Administration assistant Danielle Alvarez

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EPFL School of Life Sciences - 2011 Annual Report

Fantner Lab -

coaffiliated

http://lbni.epfl.ch/ Georg Fantner is a Tenure Track Assistant Professor for bio-and nanoinstrumentation in the Interfaculty Institute of Bioengineering, with an affiliation in the department of science and engineering (STI). His research focuses on answering fundamental biological questions using novel nanoscale characterization methods. These research questions include understanding the mechanical properties of bacterial membranes and protein-membrane interactions, as well as the molecular scale mechanisms that determine the mechanical properties of biomaterials such as bone. Prof. Fantner has a strong background in atomic force microscopy, biomaterials and microfabriaction. He received his MS from the Technical University of Graz, his PhD from UC Santa Barbara and did his post-doc in the biomolecular materials lab at MIT.

Georg Fantner

Tenure Track Assistant Professor School of Engineering (STI)

Our research aims to advance nanoscale measurement technology for life-science applications, with a special focus on high-speed atomic force microscopy (HS-AFM). Towards this end, we work on the integration of high-speed 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 modelmembranes with nanometer resolution, and can observe changes two orders of magnitude faster than previously possible with AFM. This high spatial and temporal resolution allows us to study how membrane-disrupting toxins, such as antimicrobial peptides, pore-forming toxins and antimicrobial polymers interact with the membrane. This technique can also be applied to study the action of enzymes such as Topoisomerase II on DNA. Other research interests include molecular interactions in organic/inorganic composites such as bone, and their contribution to bone fracture toughness. In bone, we have found a molecular level energy dissipation mechanism called the “sacrificialbond, hidden-length mechanism”, which protects bone against the formation of micro-fractures. Currently we are studying which factors (such as age and disease) can influence the sacrificial bonds, and if this mechanism is a potential target for therapeutic approaches against osteoporosis.

Selected Publications

Bozchalooi, I. S., Youcef-Toumi, K., Burns, D. J., & Fantner, G. E. (2011).

Compensator design for improved counterbalancing in high speed atomic force microscopy. The Review of scientific instruments, 82(11), 113712. doi:10.1063/1.3663070.

Fantner, Georg E, Barbero, R. J., Gray, D. S., & Belcher, A. M. (2010). Kinetics of antimicrobial peptide activity measured on individual bacterial cells using highspeed atomic force microscopy. Nature nanotechnology, 5(4), 280-5. Nature Publishing Group. doi:10.1038/nnano.2010.29.

Nam, Y. S., Shin, T., Park, H., Magyar, A. P., Choi, K., Fantner, G., Nelson, K. a, et al. (2010). Virus-templated assembly of porphyrins into light-harvesting nanoantennae. Journal of the American Chemical Society, 132(5), 1462-3. doi:10.1021/ja908812b.

Team Members Postdoctoral Fellows Jonathan Adams Blake Erickson PhD Students Maja Dukic Maksim Kazanskii Pascal Odermatt Master’s Students Cyrus Rashti Oliver Peric

IBI - Co-affiliated Research Groups

Research Interests

Administrative Assistant Ruth Fiaux

Burns, D. J., Youcef-Toumi, K., & Fantner, G. E. (2011). Indirect identification and compensation of lateral scanner resonances in atomic force microscopes.

Nanotechnology, 22(31), 315701. doi:10.1088/0957-4484/22/31/315701.

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EPFL School of Life Sciences - 2011 Annual Report

Guiducci Lab

- coaffiliated

http://clse.epfl.ch/

Carlotta Guiducci

Tenure Track Assistant Professor Swiss Up Engineering Chair School of Engineering (STI)

Carlotta Guiducci holds a PhD in Electrical Engineering from the University of Bologna (I). She was a postdoc at the Nanobiophysics Lab at ESPCI ParisTech (F) sine 2007. In 2006 she presented with Infineon Technologies the first CMOS chip for DNA label- free electrical detection. In 2009, she joined the Institute of Bioengineering at EPFL, as Tenure-Track Assistant Professor with a double appointment at the Institute of Electrical Engineering. Since 2009, she coordinate the ISyPeM Nano-tera.ch project on therapeutic drug monitoring for personalized medicine. Recently, she served as invited lecturer at the IEEE Solid-State Circuits Conference and she was interviewed by the Journal Electronics Letters on the present and future role of semiconductor technologies in the health care area. She is Associate Editor of the ACM JETC.

Research Interests

The development of biochips based on the present and future electronic technologies of CMOS entails enormous potential and challenges. The Laboratory of Life Sciences Electronics (CLSE) is committed to providing new process technologies and measurements techniques to fully exploit the possibilities offered by electronics and microtechnologies in the life science domain.

The team consists of an enthusiastic group of engineers in microtechnologies and electronics, bioengineers and pure biologists committed to address some of the key issues in the field of electronic biochips, such as wet environment compatibility, the integration of nanosensors and the development of devices for personalized medicine. In particular, we focus on micromachining and 3D integration solutions to enhance the robustness of the biochip surface, to develop hybrid electronic biochips with disposable parts and to develop microchannels with conductive pillars. Our technologies for electrode-based systems are applied to membrane-amyloids interaction studies and to cell-adhesion assays.

Nanosensors such as silicon nanowires and plasmonic nanoislands are characterized and compared to standard sensing techniques for real-time label-free molecular detection.

In the framework of the ISyPeM nano-tera.ch project, the laboratory addresses the development of aptamer-based sensor systems for the detection of small drugs in blood and for the personalized drug dose adjustment based on therapeutic drug monitoring approaches.

Selected Publications

Temiz, Y.; Kilchenmann, S.; Leblebici, Y.; Guiducci, C., “3D integration technology for lab-on-a-chip applications,” Electronics Letters, vol.47, no.26, pp.S22S24, December 22 2011.

Temiz, Y.; Zervas, M.; Guiducci, C.; Leblebici, Y., “Die-level TSV fabrication platform for CMOS-MEMS integration,” Solid-State Sensors, Actuators and Microsystems Conference (TRANSDUCERS), 2011 16th International, vol., no., pp.1799-1802, 5-9 June 2011.

Guiducci, C.; Temiz, Y.; Leblebici, Y.; Accastelli, E.; Ferretti, A.; Cappi, G.; Bianchi, E., “Integrating bio-sensing functions on CMOS chips,” Circuits and Systems (APCCAS), 2010 IEEE Asia Pacific Conference on, vol., no., pp.548-551, 6-9 Dec. 2010.

Bianchi, E., Boschetti, F., Dubini, G., and Guiducci, C. (2010). Model of an Interdigitated Microsensor to Detect and Quantify Cells Flowing in a Test Chamber. Proc. of the 6th annual COMSOL Conference, Paris, France, November 17-19 2010.

Temiz, Y., Ferretti, A., Accastelli, E., Leblebici, Y., and Guiducci, C. (2010).

Robust Microelectrodes Developed for Improved Stability in Electrochemical Characterization of Biomolecular Layers . Proc. of the 9th Annual IEEE Sensors Conference (Sensors’10), pages 1051-1055, Hawaii, USA, November 1-4, 2010.

Guiducci, C., Temiz, Y., Leblebici, Y., Accastelli, E., Ferretti, A., Cappi, G., and Bianchi, E. (2010). Integrating Bio-sensing Functions on CMOS Chips, Proc. of Asia Pacific Conference on Circuits and Systems, Kuala Lumpur, Malaysia, December 6 – 9, 2010.

Team Members Postdoctoral Fellows Fabio Mario Spiga Elena Bianchi

PhD Students Enrico Accastelli Giulia Cappi Anna Ferretti Samuel Kilchenmann Yuksel Temiz Interships Enrica Rollo Valeiria Davì Marco Spinsanti Master’s Students Nadia Sarait Vertti Sophie Crettaz Administrative Assistant Homeira Salimi

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IBI

EPFL School of Life Sciences - 2011 Annual Report

Hatzimanikatis Lab -

coaffiliated

http://lcsb.epfl.ch/

Associate Professor School of Basic Sciences (BS)

Research Interests

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.

Selected Publications

Integrating computational methods to retrofit enzymes to synthetic pathways.

Brunk E, Neri M, Tavernelli I, Hatzimanikatis V and Rothlisberger U. Biotechnol Bioeng, EPUB 28 Sep 2011.

Modeling of uncertainties in biochemical reactions. Miskovic L and Hatzimanikatis V. Biotechnol Bioeng, 108(2), 413-423 (2011).

Manipulating redox and ATP balancing for improved production of succinate in E. coli. Singh A, Soh KC, Hatzimanikatis V and Gill RT. Metabol Eng, 13(1), 76-81 (2011).

Thermodynamic Calculations for Biochemical Transport and Reaction Processes in Metabolic Networks. Stefan JJ, Kuemmel A, Hatzimanikatis V, Beard DA, and Heinemann M. Biophys J, 99 (10), 3139-3144 (2010).

DREAMS of metabolism, Soh KC and Hatzimanikatis V, Trends Biotech, 28 (10), 501-508 (2010).

Production of biofuels and biochemical: in need of an ORACLE. Miskovic L and Hatzimanikatis V. Trends Biotech, 28 (8), 391-397 (2010).

Network thermodynamics in the post-genomic era. Soh KC and Hatzimanikatis V. Curr Opin Microbiol., 13 (3), 350-357 (2010).

In silico feasibility of novel biodegradaion pathways for 1,2,4-trichlorobenzene. Finley SD, Broadbelt LJ, and Hatzimanikatis V. BMC Sys Biol, 4:7, doi:10.1186/1752-0509-4-7 (2010).

The Origins of Time-Delay in Template Biopolymerization Processes. Mier-y-Teran L, Silber M and Hatzimanikatis V, PLoS Comp Biol, Apr 1;6(4):e1000726 (2010).

Discovery and analysis of novel metabolic pathways for the biosynthesis of industrial chemicals: 3-hydroxypropanoate. Henry CS, Broadbelt LJ and Hatzimanikatis V. Biotechnol Bioeng, 106(3), 462-473 (2010).

Team members Postdoctoral fellows Ho Ki Fung Georgios Savoglidis Marianne Seijo Katerina Zisaki

PhD students Mahdi Alemohammad Stefano Andreozzi Elizabeth Brunk James Clulow Noushin Hadadi Julien Racle Andrijana Radivojevic Maryam Sadat Zoee Keng Cher Soh Stepan Tymoshenko

IBI - Co-affiliated Research Groups

Vassily Hatzimanikatis

Vassily Hatzimanikatis received his Diploma (1991) in Chemical Engineering from the Uni Patras, his PhD (1996) and MS (1994) in Chemical Engineering from the California Institute of Technology.

He has held the positions of Group leader (ETH Zurich), Senior research Scientist (DuPont and Cargill) and Assistant Professor (Northwestern University). Professor Hatzimanikatis has over 70 technical publications, three patents and patent applications and has given over 100 invited lectures. He is an Associate editor of the journals Biotechnology & Bioengineering , Metabolic Engineering, and Biotechnology Journal and is on the editorial advisory board of four biotechnology journals.

Honors and Awards: DuPont Young Professor (2001-2003); the Jay Bailey Young Investigator Award in Metabolic Engineering (2002); AIMBE Fellow (2010); the ACS Gaden Award (2011).

Research Associate Ljubisa Miskovic Bachelor/Master Students Flavien Morel Pascal Sutter Administrative Assistant Christine Kupper

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EPFL School of Life Sciences - 2011 Annual Report

Ijspeert Lab -

coaffiliated

http://biorob.epfl.ch/

IBI

Auke Ijspeert is an associate professor at the EPFL in the Institute of Bioengineering, and head of the Biorobotics Laboratory. He is also Adjunct faculty at the Department of Computer Science at the University of Southern California. He has a “diplôme d’ingénieur” in physics from the EPFL, and a PhD in artificial intelligence from the University of Edinburgh. With his colleagues, he has received the Best Paper Award at ICRA2002, the Industrial Robot Highly Commended Award at CLAWAR2005, and the Best Paper Award at the IEEE-RAS Humanoids 2007 conference. He is an associate editor for the IEEE Transactions on Robotics. For more information see: http:// biorob.epfl.ch

Auke Ijspeert

Associate Professor School of Engineering (STI)

Research Interests

Our research is at the intersection of robotics and computational neuroscience. It addresses the topics of movement control, sensorimotor coordination, and learning in autonomous robots with multiple degrees of freedom (from snake robots to quadruped robots to humanoid robots). Our ambition is two-fold: (1) to program and design robots that exhibit motor skills with the same efficiency, adaptivity, and robustness as animals, and (2) to get a better understanding of the functioning of animals using numerical simulation and robots as scientific tools.

Together with neurobiologists (Jean-Marie Cabelguen and Sten Grillner), we have developed mathematical models of the neural circuits controlling locomotion in lower vertebrates. We have demonstrated how a primitive neural circuit for swimming like the one found in the lamprey can be extended by phylogenetically more recent limb oscillatory centers to explain the ability of salamanders to switch between swimming and walking. These models have been tested in an innovative salamander-like robot capable of swimming and walking.

We also develop a dynamical systems approach for controlling movements in robots. For instance, we designed the concept of dynamical movement primitives: nonlinear dynamical systems with well-defined attractor properties that can learn demonstrated discrete or rhythmic movements.

Our methods are applied to various robots (quadruped, humanoid and reconfigurable modular robots) and more recently to lower limb exoskeletons for patients with locomotor deficiencies.

Selected Publications

R. Ronsse, N. Vitiello, T. Lenzi, J. van den Kieboom and M. C. Carrozza et al.

Human-Robot Synchrony: Flexible Assistance Using Adaptive Oscillators, IEEE Transactions On Biomedical Engineering, vol. 58, p. 1001-1012, 2011.

S. Dégallier Rochat, L. Righetti, S. Gay and A. Ijspeert. Towards simple control for complex, autonomous robotic applications: Combining discrete and rhythmic motor primitives, Autonomous Robots, vol. 31, num. 2, p. 155-181, 2011.

D. Ryczko, V. Charrier, A. Ijspeert and J.-M. Cabelguen. Segmental Oscillators in Axial Motor Circuits of the Salamander: Distribution and Bursting Mechanisms, Journal of Neurophysiology, vol. 104, p. 2677-2692, 2010.

S. Dégallier and A. Ijspeert. Modeling Discrete and Rhythmic Movements through Motor Primitives: A Review, Biological Cybernetics, vol. 103, num. 4, p. 319-338, 2010.

A. Spröwitz, S. Pouya, S. Bonardi, J. van den Kieboom, R. Möckel, A. Billard, P. Dillenbourg, A.J. Ijspeert. Roombots: Reconfigurable Robots for Adaptive Furniture, IEEE Computational Intelligence Magazine, 5(3): 20-32, 2010.

Ijspeert A.J., Central pattern generators for locomotion control in animals and robots: a review. Neural Networks, 21(4):642-653, 2008.

Buchli J., Righetti L., and Ijspeert A.J.. Frequency Analysis with a Nonlinear Dynamical System, Physica D, 237: 1705–1718, 2008.

Sproewitz A., Moeckel R., Maye J., Ijspeert A.J., Learning to move in modular robots using central pattern generators and online optimization. International Journal of Robotics Research. 27(3-4):423-443, 2008.

Ijspeert A.J., Crespi A., Ryczko D., and Cabelguen J.M.. From swimming to walking with a salamander robot driven by a spinal cord model. Science, 315(5817):1416-1420, 2007.

Righetti L., Buchli, J. and Ijspeert A.J.: Dynamic Hebbian learning in adaptive frequency oscillators, Physica D, 216(2), 2006 pp 269-281.

Team Members

Postdoctoral Fellows Crespi Alessandro Guyot Luc Möckel Rico Morel Yannick Spröwitz Alexander PhD Studnets Ajallooeian Mostafa Bicanski Andrej Bonardi Stéphane Dégallier arah Gay Sébastien Karakasiliotis Konstantinos Knüsel Jérémie Pouya Soha Tuleu Alexandre

van den Kieboom Jesse Vespignani Massimo Administrative Assistant Fiaux Sylvie

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EPFL School of Life Sciences - 2011 Annual Report

Johnsson Lab

- coaffiliated

http://lip.epfl.ch/

Kai Johnnson

Kai Johnsson is Professor at the Institute of Chemical Sciences and Engineering. His current research interests are the development and application of chemical approaches to study and manipulate protein function. Professor Johnsson has been Associate Editor of ACS Chemical Biology since 2005. He is member of the Editorial Advisory Board of Science, of the Research Council of the Swiss National Science Foundation and of a number of scientific journals. He is co-founder of Covalys Biosciences which was based on protein labeling technologies developed in his laboratory; these technologies are now available through New England BioLabs. He received the Prix APLE for the invention of the year 2003 of EPFL and the Novartis Lectureship Award 2012/13.

Full Professor School of Basic Sciences (SB)

Research Interests

The visualization and characterization of biologically relevant molecules and activities inside living cells continues to transform cell biology into a truly quantitative science.

However, despite the spectacular achievements in some areas of cell biology, the majority of cellular processes still operate invisibly. Further progress will therefore depend increasingly on the development of new (fluorescent) sensors and chemical probes to target and characterize these activities. Our research addresses this need by developing and applying chemical approaches to observe and manipulate protein function in living cells. For example, we have introduced general methods for the covalent and specific labeling of fusion proteins with chemically diverse compounds that open up new ways of studying proteins (i.e.

SNAP-tag, CLIP-tag and ACP-tag). We are pursuing the further development of such approaches and their application to biological problems that cannot be resolved by traditional approaches.

Selected Publications

“A yeast-based screen reveals that sulfasalazine inhibits tetrahydrobiopterin biosynthesis” Christopher Chidley, Hirohito Haruki, Miriam Gronlund Pedersen, Evelyne Muller, Kai Johnsson, Nature Chemical Biology, 7, 375-83 (2011).

“Semisynthesis of fluorescent metabolite sensors on cell surfaces” Matthias A. Brun, Rudolf Griss, Luc Reymond, Kui-Thong Tan, Joachim Piguet , Ruud Peters, Horst Vogel, Kai Johnsson, J. Am. Chem. Soc., 133, 16235-42 (2011).

“Benzothiazinones are prodrugs that covalently modify the decaprenylphosphoryl-ß-D-ribose 2’-epimerase DprE1 of Mycobacterium tuberculosis” Claudia Trefzer, Monica Rengifo-Gonzalez, Marlon J. Hinner, Patricia Schneider, Vadim Makarov, Stewart T. Cole, Kai Johnsson, J. Am. Chem. Soc., 132,13663-5 (2010).

“A Targetable and Highly Sensitive Calcium Indicator based on BODIPY-fluorophore” Mako Kamiya, Kai Johnsson, Analytical Chemistry, 82, 6472-9 (2010).

“Photoactivatable and photoconvertible fluorescent probes for protein labeling” Damien Maurel, Sambashiva Banala, Thierry Laroche, Kai Johnsson, ACS Chemical Biology 5, 507-16 (2010).

Currently, we are interested in the following topics:

• Identifying the protein targets of bioactive molecules.

• Engineering of new protein functions for applications in functional proteomics.

• Synthesis of new spectroscopic probes for applications in cell biology.

Team Members Postdoctoral Fellows Hirohito Haruki Katarina Gorska Grazvydas Lukinavicius Luc Reymond Keitaro Umezawa

IBI - Co-affiliated Research Groups

• Development of semisynthetic fluorescent sensor proteins to measure key metabolites in living cells.

PhD Students Cindy Fellay Rudolf Griss Miriam Grolund Petersen Birgit Mollwitz Alberto Schena Administrative Assistant Claudia Gasparini

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EPFL School of Life Sciences - 2011 Annual Report

Jolles-Haeberli Lab

- coaffiliated

http://cbt.epfl.ch/

IBI

Brigitte Jolles-Haeberli graduated from EPFL with a MSc Diploma of Professional Engineer in Microtechnology in 1990 with honors.

In 1995 she obtained her MD and Doctoral thesis in Medicine with honors (UNIL). In 2002 she received the Diploma in Clinical Epidemiology and successfully completed a Clinical Fellowship in Arthritis Surgery at the University of Toronto and obtained also the FMH-Swiss Federal Diploma of Specialist in Orthopaedic Surgery.

She was nominated Assistant Professor (PD) at UNIL in 2005, Adjunct Professor (EPFL) in 2008 where she heads the Interinstitutional Center of Translational Biomechanics (CBT). She was nominated Associate Professor (UNIL) in 2010 where she is the Team leader for Knee Arthroplasty Surgery (CHUV).

Brigitte Jolles-Haeberli

Adjunct Professor School of Engineering (STI) Director of Center of Translational Biomechanics

Research Interests

We promote and support the transfer of findings from the basic science laboratory to clinical application with a strong relationship between clinicians and engineers for each specific project. We develop medical devices and wearable systems to characterize human mobility and locomotion in daily conditions. Based on these instruments, we provide objective clinical metrics for diagnosis and outcome evaluation of treatments as well as useful parameters to increase sport performances.

We also carry out work in tissue engineering of musculoskeletal tissues, implant and joints biomechanics, drug delivery systems and mechanobiology. A combination of biomechanical and biological approaches is used to describe and understand different clinical problems of interest such as bone loss following total joint arthroplasty, arthritis or intervertebral disc degeneration. Based on these analyses, original solutions are developed such as fetal cell therapy, scaffolds with high mechanical properties or orthopaedic implants used as drug delivery systems.

Hirt-Burri N, Ramelet AA, Raffoul W, de Buys Roessingh A, Scaletta C, Pioletti D, Applegate LA. Biologicals and fetal cell therapy for wound and scar management. Dermatol. 2011;2011:549870.

Roshan-Ghias A, Lambers FM, Gholam-Rezaee M, MĂźller R, Pioletti DP. In vivo loading increases mechanical properties of scaffold by affecting bone formation and bone resorption rates. Bone. 2011 Dec;49(6):1357-64.

Center Groups Aminia Lab Pioletti Lab

Administrative Assistant Sabrina Martone

Selected Publications

Favre J, Crevoisier X, Jolles BM, Aminian K. Evaluation of a mixed approach combining stationary and wearable systems to monitor gait over long distance.

J Biomech. 2010; 43(11): 2196-202.

Rouhani H, Favre J, Crevoisier X, Jolles BM, Aminian K. Segmentation of foot and ankle complex based on kinematic criteria.Comput Methods Biomech Biomed Engin. 2011; 14(9):773-81.

Jolles BM, Aminian K, Coley B, Pichonnaz C, Bassin JP, Leyvraz PF, Farron A. Objective evaluation of shoulder function using body-fixed sensors: a new way to detect early treatment failures? J Shoulder Elbow Surg. 2011; 20(7):1074-81.

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EPFL School of Life Sciences - 2011 Annual Report

Lacour Lab

- coaffiliated

http://lsbi.epfl.ch/ Stéphanie P. Lacour is an Assistant Professor at the EPFL, affiliated with the Institutes of Microengineering and Bioengineering. She 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 has pioneered the development of stretchable electronics, demonstrating elastic metallization and the first stretchable electronic circuit, and was named to the “Top 35 Innovators under the age of 35” by MIT Technology Review in 2006. She was awarded a University Research Fellowship from the Royal Society in 2007 and the Zonta Award in 2011 for her research achievement as a young female academic.

Stéphanie P. Lacour

Tenure Track Assistant Professor Bertarelli Foundation Chair in Neuroprosthetic Technology School of Engineering (STI)

The Laboratory for Soft Bioelectronics Interfaces (LSBI) explores how to shape traditionally rigid electronic circuits into conformable, skin-like formats. Our mission is to engineer and implement novel materials and technologies overcoming the “hard to soft” mechanical mismatch between man-made devices and biological tissues.

We currently have two main activities: tactile electronic skins and soft neural electrodes. Both systems are fabricated using standard microfabrication processes but adapted to mechanically compliant silicone substrate. Tactile e-skins are designed to conform a robotic or prosthetic hand and provide distributed sensory feedback (pressure, shear and strain). Ultra-compliant neural electrodes are designed for in vitro platforms combining mechanical stimulation and electrophysiology, surface microelectrode arrays to conform the surface of the spinal cord or the brainstem, and regenerative peripheral nerve implants.

Selected Publications

Delivopoulos D., Chew D., Minev I.R., Fawcett J.W. and Lacour S.P. (2012) Concurrent recordings of bladder afferents from multiple nerves using a microfabricated PDMS microchannel electrode array. Lab on Chip, 2012, DOI: 10.1039/C2LC21277C. FitzGerald J.J., Lago N., Benmerah S., Serra J., Watling C.P., Cameron R.E., Tarte E., Lacour S.P., McMahon S.B. and Fawcett J.W. (2012) A regenerative microchannel neural interface for recording from and stimulating peripheral axons in vivo. Journal of Neural Engineering 9:016010.

Minev I.R., Chew D.J., Delivopoulos E., Fawcett J.W. and Lacour S.P. (2012) High sensitivity recording of afferent nerve activity using ultra-compliant microchannel electrodes: an acute in vivo validation. Journal of Neural Engineering 9:026005.

Lacour S.P., Graz I.M., Bauer S., Wagner S. (2011) Elastic components for prosthetic skin. Conf Proc IEEE Eng Med Biol Soc. 2011 8373-6.

Graz I.M., Cotton D.P.J., Robinson A., Lacour S.P. (2011) Silicone substrate with in situ relief for stretchable thin-film transistors. Applied Physics Letters, 98:124101.

Lacour S.P., Benmerah S., Tarte E., FitzGerald J., Serra J., McMahon S., Fawcett J., Graudejus O.,Yu Z. and Morrison III B. (2011) Flexible and stretchable micro-electrodes for in vitro and in vivo neural interfaces, Medical & Biological Engineering & Computing 48, 945-954.

Team Members

Postdoctoral Fellows Katherine Musick Tom Oppenheim Hugues Vandeparre Evangelos Delivopoulos Atif Aziz Adam Robinson

IBI - Co-affiliated Research Groups

Research Interests

PhD students Ivan Minev Cédric Paulou Alessia Romeo Masters Student Amélie Guex Administrative Assistant Carole Weissenberger

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EPFL School of Life Sciences - 2011 Annual Report

Maerkl Lab

- coaffiliated

http://lbnc.epfl.ch/

IBI

Sebastian Maerkl obtained a PhD degree from the California Institute of Technology in 2008. His thesis on “Microfluidic Large Scale Integration and its Application to Systems Biology” received the Demetriades-Tsafka-Kokkalis Prize for the best Caltech PhD thesis in Biotechnology. In the same year, Prof. Maerkl accepted a tenure track assistant professorship at the EPFL, where he is currently running a lab consisting of 3 Post-Docs and 6 PhD students. Prof. Maerkl coaches the EPFL iGEM team and teaches a masters level course on Genome & Network Architecture.

Sebastian Maerkl

Tenure Track Assistant Professor School of Engineering (STI)

Research Interests

The Maerkl lab is principally interested in developing highly integrated microfluidic devices and applying these to pertinent problems in biology. Of particular interest to the lab are systems biology, synthetic biology, and diagnostics, which will benefit tremendously from the development of novel, high-throughput technologies. We are actively developing methods for single cell analysis in S.cerevisiae and S.pombe, as well as M.smegmatis in collaboration with the McKinney Lab (SV/GHI). Using these methods, we are interested in characterizing global protein expression dynamics on the single cell level (S.cerevisiae), understand how genotypic variants affect fitness (S.pombe), and discover leads towards understanding and possibly counteracting bacterial persistence (M.smegmatis). The lab is also interested in understanding transcriptional regulatory networks by developing and characterizing promoter variants in vivo, as well as through the biophysical characterization of transcription factors in vitro.

Team Members Postdoctoral Fellows Luis Miguel Fidalgo Jose Garcia-Cordero

PhD Students Matthew Blackburn Nicolas Denervaud Henrike Niederholtmeyer Jean-Bernard Nobs Arun Rajkumar Sylvie Rockel Administrative Assistant Helen Chong

Selected Publications

Schultzaberger R.K., Maerkl S.J., Kirsch J.F. and M.B. Eisen (2012). ”Probing the Informational and Regulatory Plas- ticity of a Transcription Factor DNA-Binding Domain.” accepted to PLoS Genetics..

He B., Holloway A., Maerkl S.J., and Kreitman M. (2011). “Does positive selection drive transcription factor binding site turnover? A test with Drosophila cisregulatory modules.” PLOS Genetics 7(4): e1002053.

Fidalgo L.M., and Maerkl S.J. (2011). “A software-programmable microfluidic device for automated biology.” Lab on a Chip 11: 1612-19.

Geertz M., and Maerkl S.J. (2010). “Experimental strategies for studying transcription factor-DNA binding specificities.” Briefings in Functional Genomics doi:10.1093/bfgp/elq023.

Maerkl S.J. (2010). “Next generation microfluidic platforms for high-throughput protein biochemistry.” Current Opinion in Biotechnology 22(1): 59-65.

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EPFL School of Life Sciences - 2011 Annual Report

Mermod Lab -

coaffiliated

http://www.unil.ch/biotech/

Full Professor IBI-UNIL

Research Interests

Our translational research activities are focused on the elucidation of the mechanisms that control gene expression in mammals including humans, and to obtain reliable gene expression for medical use, for instance to express therapeutic proteins in the bioreactor in gene and cell-based therapies .

Four research lines are currently being followed by the laboratory: • Gene regulation by cell growth factors upon tissue regeneration • Expression of genes of biotechnological interest in mammalian cells

Team Members Postdoctoral Fellows Niko Niederländer Stéphanie Renaud Stefania Puttini Niamh Harraghy Elena Aritonovska Christophe Debonneville Maxime Albesa PhD students Ruthger van Zwieten Stefano Majocchi Deborah Ley Simone Edelmann Kaja Kostyrko Yaroslav Shcherba Matthias Contie

• Characterization and modeling of regulatory genomic regions in cancer

Master’s student Arnaud Rivier

• Development of more efficient and safer vectors for gene and stem cell-based therapies

Engineers Etienne Lançon

Plasari G, Edelmann S, Hogger F, Dusserre Y, Mermod N and Calabrese A. (2010) Nuclear Factor I-C regulates TGF-beta-dependent hair follicle cycling. J Biol. Chem. 285:34115–34125.

Technicians and informaticians Yves Dusserre Jacqueline Masternak Ionie Gutscher Armindo Texeira Daniel Peter

Buceta M, Galbete JL, Kostic C, Arsenijevic Y, and Mermod N. (2011). Use of human MAR elements to improve retroviral vector production. Gene Ther. 18:7-13.

Apprentice Alessia Cochard

Kerschgens J, Renaud S, Grasso L, Egener-Kuhn T, Delaloye JF, Lehr HA, Vogel H and Mermod N. (2011). Detection and analysis of tumor suppressor AP-2α DNA binding activity by protein-binding microarrays. PLOS One, 6:e22895.

Administrative Assistant Nassim Berberat

Selected Publications

IBI - Co-affiliated Research Groups

Nicolas Mermod

Nic Mermod did his PhD on bacterial gene regulation and environmental biotechnology with Ken Timmis at the University of Geneva.

As a postdoc with Bob Tjian at the University of California at Berkeley, he identified and characterized some of the first mammalian transcription factors. He then 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. Nic heads a laboratory of 25 scientists at the Center for Biotechnology of the University of Lausanne and of the Swiss Institute of Technology Lausanne (EPFL). He is also co-founder of Selexis SA, a biotechnology company developing therapeutic-producing cell lines. His research bridges fundamental work on genomics and epigenetics to molecular biotechnology and gene and cell therapies.

Nic has authored a number of scientific publications and patents.

Pjanic M, Pjanic P, Schmid C, Ambrosini G, Gaussin A, Plasari G, Mazza C, Bucher P, and Mermod N. (2011). Nuclear factor I revealed as family of promoter binding transcription activators. BMC Genomics, 12:181.

Grandjean M, Girod P-A, Calabrese D, Wicht M, Beckman JS, Martinet D and Mermod N. (2011). High-level transgene expression by homologous recombination-mediated gene transfer. Nucl. Acids Res., 39:e104.

Harraghy N, Regamey A, Girod PA, and Mermod N. (2011). Identification of a potent MAR element from the mouse genome and assessment of its activity in stable and transient transfections. J. Biotechnol. 154:11-20.

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EPFL School of Life Sciences - 2011 Annual Report

Millán Lab

- coaffiliated

http://cnbi.epfl.ch/

IBI

José del R. Millán explores the use of brain signals for multimodal interaction and, in particular, the development of brain-controlled robots and neuroprostheses. In this multidisciplinary research effort, Dr. Millán is bringing together his pioneering work on the two fields of brain-machine interfaces (BMI) and adaptive intelligent robotics.

He received his Ph.D. in computer science from the Univ. Politècnica de Catalunya (Barcelona, Spain) in 1992. Among other honors, his research on BMI was nominated finalist of the European Descartes Prize 2001 and he has been named Research Leader 2004 by the journal Scientific American for his work on brain-controlled robots.

José del Rocio Millán

Associate Professor Defitech Foundation Chair in Non-Invasive Brain-Machine Interface Center for Neuroprosthetics School of Engineering (STI)

Research Interests

The Defitech Foundation Chair in Non-Invasive BrainMachine Interface (CNBI) carries out research on the direct use of human brain signals for controlling devices and interacting with the environment. In this multidisciplinary research, CNBI is bringing together its pioneering work in the two fields of brain-machine interfaces and adaptive intelligent robotics. A brain-machine interface (BMI) monitors a subject’s brain activity, extracts specific features from the brain signals that reflect his/her intent, and translates these features into actions —such as moving a wheelchair or selecting a letter from a virtual keyboard, without use of muscles or peripheral nerves. CNBI focuses on non-invasive methods for recording brain activity, in particular using electroencephalographic (EEG) signals recorded from electrodes placed on the scalp. The goal of CNBI is to develop principled methods to design intelligent brain-actuated devices that people can efficiently operate them in a natural and intuitive manner over long periods of time. Such neuroprosthetic devices allow interaction by exploiting brain signals associated to different aspects of voluntary behavior.

Selected Publications

A. Tzovara, M. Murray, N. Bourdaud, R. Chavarriaga, J. d. R. Millán and M. De Lucia. The timing of exploratory decision-making revealed by single-trial topographic EEG analyses. Neuroimage, vol. 4, num. 1, 2012.

R. Leeb, H. Sagha, R. Chavarriaga and J. d. R. Millán. A hybrid BCI based on the fusion of EEG and EMG activities.in Journal of Neural Engineering, vol. 8, num. 2, 2011.

G. R. Müller-Putz, C. Breitwieser, F. Cincotti, R. Leeb, M. Schreuder, F. Leotta, M. Tavella, L. Bianchi, A. Kreilinger, A. Ramsay, M. Rohm, M. Sagebaum, L. Tonin, C. Neuper and J. d. R. Millán. Tools for brain-computer interaction: a general concept for a hybrid BCI. in Frontiers in Neuroinformatics, vol. 5, num. 30, 2011.

A. Biasiucci, R. Chavarriaga Lozano, B.Hamner, R. Leeb, F. Pichiorri, F. De Vico Fallani, D. Mattia and J. d.. R. Millán. Combining Discriminant and Topographic Information in BCI: Preliminary, Results on Stroke Patients. IEEE EMBS Conference on Neural Engineering, Cancún, Mexico, April 27 - May 1, 2011.

G. Garipelli, R. Chavarriaga and J. d. R. Millán. Single Trial Recognition of Anticipatory Slow Cortical Potentials: The Role of Spatio-Spectral Filtering. IEEE EMBS Conference on Neural Engineering, Cancun, Mexico, April 27-May 1, 2011.

Team Members Senior Post doctoral Fellow Ricardo Chavarriaga Postdoctoral Fellows Tom Carlson Sarah Degallier Robert Leeb Aleksander Sobolewski PhD Students Andrea Biasiucci Nicolas Bourdaud Zahra Khaliliardali Mohit K. Goel Eileen Y.L. Lew Serafeim Perdikis Sareh Saeidi Hesam Sagha Michele Tavella Luca Tonin Marija Uscumlic Huaijian Zhang Visiting Researcher Lucian Gheorghe Administrative Assistant Najate Guechoul

L. Tonin, T. E. Carlson, R. Leeb and J. d. R. Millán. Brain-Controlled Telepresence Robot by Motor-Disabled People. IEEE Engineering in Medicine and Biology Society (EMBC’11), Boston, USA, 2011.

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EPFL School of Life Sciences - 2011 Annual Report

Pioletti Lab

- coaffiliated

http://lbo.epfl.ch/ Dominique Pioletti received his Master in Physics and obtained his PhD in biomechanics in 1997 from the EPFL. He developed original constitutive laws taking into account viscoelasticity in large deformations. Then he did a post-doc at UCSD focusing on osteoblast reaction to different implant surface types. Since April 2006, Dominique Pioletti is appointed Assistant Professor tenure-track at the EPFL and is director of the Laboratory of Biomechanical Orthopedics. His research topics include biomechanics and tissue engineering of musculo-skeletal tissues; mechano-transduction in bone; development of orthopedic implant as drug delivery system.

Dominique P. Pioletti

Tenure Track Assistant Professor Center of Translational Biomechanics School of Engineering (STI)

The research interests of the LBO are in the fields of tissue engineering, joint and implant biomechanics, mechano-transduction, and drug delivery system. By combining these different fields, we use biomechanics to functionalize tissue engineering scaffolds and drug delivery systems for musculo-skeletal applications. The final goal of our research is to translate the obtained results into clinical applications. We have been pioneer in the development of orthopedic implant as drug delivery system. In particular, we have developed a technique allowing to decrease the peri-implant bone loss following the implantation of a prosthesis. This result is now translated into a clinical product with the collaboration of a large orthopedic company. In parallel, we have developed different strategies for bone or cartilage tissue engineering. The originality of our approach is to combine the intrinsic in vivo mechanical loading to the development of scaffold with the goal of rendering the scaffold more osteoinductive for the bone application.

Selected Publications

Roshan Ghias A., Vogel A., Rakotomanana L., Pioletti D.P. Prediction of spatiotemporal bone formation in scaffold by diffusion equation. Biomaterials, 32, 7006-7012, 2011.

Stadelmann V. A., Bonnet N., Pioletti D.P. Combined effects of zoledronate and mechanical stimulation on bone adaptation in an axially loaded mouse tibia, Clinical Biomechanics, 26, 101-105, 2011.

Roshan Ghias A., Lambers F., Gholam-Rezaee M., Müller R., Pioletti D.P. In vivo loading increases mechanical properties of scaffold by affecting bone formation and bone resorption rates. Bone, 49, 1357-1364, 2011.

Gortchacow M, Wettstein M., Pioletti D.P. Terrier A. A new technique to measure micromotion distribution around a cementless femoral stem, J Biomechanics, 44, 557-560, 2011.

Blecha L.D., Rakotomanana L., Razafimaheri F., Terrier A., Pioletti D.P. Mechanical interaction between cells and fluid for bone tissue engineering scaffold: modulation of the interfacial shear stress. J Biomechanics, 43, 933-937, 2010.

Team Members Group leaders Alexandre Terrier

Postdoctoral Fellows Xabier Larrea Hicham Majd Lab assistants Sandra Jaccoud Corinne Scaletta (UNIL/CHUV) Engineers Tanja Hausherr Damien Joss Patricia Scheuber Julien Ston PhD students Philippe Abdel-sayed Salim Darwich Christoph Anselm Engelhardt Sohrab Emami Naeini Michael Gortchacow Anthony Grognuz (UNIL/CHUV) Jérôme Hollenstein (UCSD) Ulrike Kettenberger Adeliya Latypova Mohamdreza Nassajian Moghadam Alireza Roshan Ghias Marion Röthlisberger Arne Vogel Medical Advisors Martin Broome, P.D. Xavier Crevoisier, P.D. Alain Farron Brigitte Jolles-Haeberli Wassim Raffoul Hannes Rudiger, P.D. Constantin Schizas. P.D. Pierre-Yves Zambelli

IBI - Co-affiliated Research Groups

Research Interests

Administrative Assistant Virginie Kokocinski

Krattinger N., Applegate L.A., Biver E., Pioletti D.P., Caverzasio J. Regulation of proliferation and differentiation of human fetal bone cells. e Cells Materials, 21, 46-58, 2011.

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EPFL School of Life Sciences - 2011 Annual Report

Psaltis Lab

- coaffiliated

http://lo.epfl.ch/

IBI

Demetri Psaltis was educated at Carnegie-Mellon University where he received the Bachelor of Science degree in Electrical Engineering and Economics in 1974, the Master’s in 1975, and the PhD in Electrical Engineering in 1977. In 1980, he joined the faculty at the Caltech, California and 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. He was director of the Center for Optofluidic Integration at Caltech. In 2007, he moved to the EPFL where he is professor and director of the optics laboratory and also the Dean of School of Engineering.

Demetri Psaltis

Full Professor Dean of the School of Engineering (STI)

Research Interests

Holography is the most persistent thread in Demetri Psaltis’ research. It goes back to his PhD thesis work on invariant pattern recognition using the Mellin transform which he demonstrated holographically. His work on optical neural networks (which originated as collaboration with Nabil Farhat) established a link between adaptive volume holography and Hebbian learning in the nervous system. His work on holographic memories in the late 80’s and early 90’s spearheaded the rebirth of the field. His recent work on holographic filters for telecommunications and other applications was featured on the cover of Science in November 2002 and it has led to commercialization of this technology. In recent years, Demetri Psaltis’ research has moved towards nonlinear optics.

Team Members Post-doctoral Fellows Andreas Vasdekis Jae-Woo Choi Marcin Zielinski Salma Farahi Ye PU PhD students Alexandre Goy Grégoire Laporte Ioannis Papasopoulos Julien Cuennet Thomas Lanvin Wuzhou Song Xin Yang Administrative Assistant Carole Berthet

Selected Publications

“Optofluidics for energy applications”, Erickson D, Sinton D, Psaltis D - Nature Photonics, Vol. 5, pp. 583-590, October 2011.

“Imaging withsecond-harmonic radiation probes in living tissue” Grange R, Lanvin T, Hsieh CL, Pu Y, Psaltis D - Biomedical Optics Express, Vol. 2, pp.

2532-2539, August 2011.

“Imaging with second-harmonic radiation probes in living tissue” Grange R, Lanvin T, Hsieh CL, Pu Y, Psaltis D - Biomedical Optics Express, Vol. 2, pp.

2532-2539, August 2011.

“Optofluidic modulator based on peristaltic nematogen microflows” J.G.Cuennet**, A.E. Vasdekis*, L. De Sio, Psaltis D. (*Equivalent first authors) – Nature Photonics, Vol5, pp 234-238, February 2011.

“Nonlinear optical properties of core-shell nanocavities for enhanced secondharmonic generation” - Pu Y, Grange R, Hsieh CL, Psaltis D - Physical Review Letters, Vol. 104, Art. 207402, May 2010.

“Coherent anti-Stokes Raman holography for chemically selective single-shot nonscanning 3D imaging” Shi K, Li H, Xu Q, Psaltis D, Liu Z - Physical Review Letters, Vol. 104, Art. 093902, March 2010.

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EPFL School of Life Sciences - 2011 Annual Report

Radenovic Lab -

coaffiliated

http://lben.epfl.ch/

Aleksandra Radenovic earned a degree in physics from the University of Zagreb before joining Professor Giovanni Dietler’s Laboratory of Physics of Living Matter at the University of Lausanne. There she earned her Doctor of Sciences degree in 2003. She then undertook postdoctoral study at the University of California, Berkeley in the group of Prof. Liphardt. From July 2008 she is an assistant tenure track professor at the Institute of Bioengineering.

Aleksandra Radenovic Tenure Track Assistant Professor School of Engineering (STI)

Research Interests

The research of the Laboratory of Nanoscale Biology focuses on developing tools and probes for single-molecule biophysics. The group uses optical tweezers, AFM, singlemolecule fluorescence, PhotoActivated Light microscopy PALM and nanofabricated structures to study biomolecular systems and advance new nanotechnology techniques.

Current experimental work in our lab focuses on two interconnecting areas: Nanofabricated probes and platforms for single-molecule biophysics experiments: Including nanofabricated SHG nanocylinders, solid-state nanopores, local nanolectrodes for molecular sensing and sequencing.

Local probe studies of single biomolecules: For example RNA polymerase, DNA binding proteins, membrane proteins such G protein–coupled receptors (GPCRs).

Team Members Postdoctoral Fellows Husale Sudhir Scarselli Marco Steinbock Lorentz Traversi Floriano PhD Students Annibale Paolo Brando Serena Dutto Fabrizia Kayci Metin Raillon Camille Arun Shivanandan Master’s students Garcia Cordero Eric Mattia Greco Administrative Assistant Chong Helen

Selected Publications

Nanopore Detection of Single Molecule RNAP–DNA Transcription ComplexC. Raillon, P. Cousin, F. Traversi, N. Hernandez and A.Radenovic Nano Letters DOI 10.1021/nl3002827 (2012).

IBI - Co-affiliated Research Groups

Identification of clustering artifacts in photoactivated localization microscopy P. .Annibale, S. Vanni, M. Scarselli, U. Rothlisberger and A. Radenovic Nature Methods (2011).

Single-layer MoS2 transistors B. Radisavljevic, A. Radenovic, J. Brivio, V. Giacometti, A. Kis1* Nature Nanotechnology Volume:6,147–150 (2011) cover article Nonlinear Optical Response in Single Alkaline Niobate Nanowires F. Dutto, C. Raillon, K.Schenk and A. Radenovic Nano Letters., 2011, 11 (6), pp 2517–252.

Quantitative Photo Activated Localization Microscopy: unraveling the effects of photoblinking P. Annibale, S. Vanni, M. Scarselli, U. Rothlisberger and A. Radenovic PloS One July 2011, Volume 6, Issue 7, e2267.

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EPFL School of Life Sciences - 2011 Annual Report

Roke Lab -

coaffiliated

http://lbp.epfl.ch/

Sylvie Roke

IBI

Sylvie Roke received her bachelor’s degree in chemistry and physics at Utrecht University (NL, highest honors) and her PhD degree from Leiden University (highest honors) in the field of nonlinear optics. In 2005 she obtained a Max-Planck Group Leader position and Research Group. Professor Roke was awarded an ERC startup grant (2009), and in 2010 she became a fellow of the Young Academy of the German Academy of Sciences. In April 2011 she started the Laboratory for Fundamental BioPhotonics (LBP) as a tenure track Assistant Professor at the EPFL, School of Engineering. She has been awarded the LJ Oosterhoff prize (2003), an Alexander von Humboldt Fellowship (2005), the Minerva Prize (FOM, NL, 2006) and the Hertha Sponer prize (DPG, DE,2008).

Tenure Track Assistant Professor Julia Jacobi Chair in Photomedicine School of Engineering (STI)

Research Interests

Life occurs in three dimensions. Living cells and organelles, such as the nucleus, mitochondria and ribosomes require membranes for protection and as vital part of their production units. Viruses consist of capsides that can self assemble into nanoscopic projectiles, ready to deliver DNA or RNA to the next willing host. This illustrates the complexity of small biological systems. The ability to respond, adapt and reform according to the needs of the specific molecular environment is enormous. If we could harness those abilities a huge leap in technological performance from the nanosciences to the life sciences is possible.

Currently our understanding of soft biological systems is limited to macro- or microscopic theories. Molecular understanding is often absent. To change this and to arrive at tomorrows’ diagnostics we work on four main themes: • The investigation of structure and properties of biologically and medically relevant interfaces (supported lipid bilayers, biopolymer interfaces, water, protein-surface interactions).

• Development of theory for nonlinear light scattering techniques to understand fundamental light matter interaction processes.

• Development of experimental methods for nonlinear light scattering and microscopy.

These techniques are ‘tomorrows’ diagnostics’ for biomedical research. IV. In-situ probing of nanodroplets, liposomes, and biological or living systems with particular interest in interfaces, ultrafast processes, and 3D self-assembly.

Selected Publications

Vacha, R., Rick S., Jungwirth P., de Beer A. G. F., de Aguiar H. B., Samson J-S and Roke S. The structure and charge of water around a surfactant free oil in water emulsion. J. Am. Chem. Soc 2011, 133 (26),10204–10210. de Beer A. G. F., Samson J-S, Hua W., Huang Z., Chen X., Allen H. C. and Roke S. A direct comparison of Phase-Sensitive Vibrational Sum Frequency generation with the Maximum Entropy Method: a case study of water. J. Chem. Phys 135, 224701 (2011).

de Beer A. G. F., Roke S. and Dadap J. I. Second-order nonlinear light scattering: of arbitrarily shaped particles. J. Opt. Soc. Am. B 2011, 28, 1374-1384 .

Strader M. L., de Aguiar H. B., de Beer A. G. F. and Roke S. Direct detection of vesicle bilayer asymmetry in catanionic vesicles using vibrational sum frequency scattering. Soft Matter 2011, 7 (10), 4959 – 4963 . de Aguiar H. B., Strader M. L., de Beer A. G. F. and Roke S. Surface structure of SDS Surfactant and oil at the oil-in-water droplet liquid/liquid interface: A manifestation of a non-equilibrium surface state. J. Phys. Chem. B 2011, 115, 2970-2978 . de Beer A. G. F., Campen R. K. and Roke S. Separating surface structure and surface charge with second-harmonic and sum-frequency scattering. Phys. Rev. B, 2010, 82, 235431. de Aguiar H. B., de Beer A. G. F., Strader M. L. and Roke S. The Interfacial Tension of Nanoscopic Oil Droplets in Water Is Hardly Affected by SDS Surfactant.

J. Am. Chem. Soc 2010, 132, 2122-2123. de Beer A. G. F. and Roke S. Obtaining molecular orientation from second harmonic and sum frequency scattering experiments: angular distribution and polarization dependence. J. Chem. Phys 2010, 132, 234702-1-8.

Team Members Postdoctoral Fellows Nikolaos Gomopoulos Kailash C. Jena Carlos Macias-Romero PhD Students Yixing Chen Cornelis Luetgebaucks Ekaterina Rostova Rüdiger Scheu Qinchao Sun Research Assistants Benjamin Hamner Guillaume Monnard Administrative Assistant Dominique Widmer

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EPFL School of Life Sciences - 2011 Annual Report

Stergiopulos Lab -

coaffiliated

http://lhtc.epfl.ch/ 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 120 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.

Nikos Stergiopulos

Full Professor School of Engineering (STI)

Research Interests

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.

Selected Publications

Tsamis A, Rachev A, and Stergiopulos N. A constituent-based model of age-related changes in conduit arteries. Am J Physiol Heart Circ Physiol 301: H12861301, 2011.

Reymond P, Bohraus Y, Perren F, Lazeyras F, and Stergiopulos N. Validation of a patient-specific one-dimensional model of the systemic arterial tree. Am J Physiol Heart Circ Physiol 301: H1173-1182, 2011.

Team Members Engineer Stéphane Bigle

Scientific collaborators & Postdoctoral Fellows Luciano Capettini Rafaela Fernandes da Silva Dimitrios Kontaxakis Bryn Martin Sylvain Roy PhD students Aristotelis Agianniotis Thiresia Gialourou Orestis Vardoulis Adan Villamarin Masters students Olivier Frémont Vu Thanh-Hieu Nguyen Eline Coppens Administrative Assistant Tamina Sissoko

Rezakhaniha R, Fonck E, Genoud C, and Stergiopulos N. Role of elastin anisotropy in structural strain energy functions of arterial tissue. Biomech Model Mechanobiol 10: 599-611, 2011.

IBI - Co-affiliated Research Groups

Augsburger L, Reymond P, Rufenacht DA, and Stergiopulos N. Intracranial stents being modeled as a porous medium: flow simulation in stented cerebral aneurysms. Ann Biomed Eng 39: 850-863, 2011.

Rezakhaniha R, Agianniotis A, Schrauwen JT, Griffa A, Sage D, Bouten CV, van de Vosse FN, Unser M, and Stergiopulos N. Experimental investigation of collagen waviness and orientation in the arterial adventitia using confocal laser scanning microscopy. Biomech Model Mechanobiol 11: 461-473, 2011.

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EPFL School of Life Sciences - 2011 Annual Report

Van de Ville Lab

- coaffiliated

http://miplab.epfl.ch/

Dimitri Van De Ville

SNSF Professor School of Engineering (STI)

Dimitri Van De Ville received his MS and PhD in Computer Sciences from Ghent University, Belgium (1998, 2002) and did his postdoc at EPFL (2002-2005). He was a research associate and coordinator of the CIBM Signal Processing Unit at University of Geneva (2005-2009), awarded SNSF professorship (2009) and currently is a tenure-track assistant professor affiliated with EPFL and University of Geneva. Prof.

Van De Ville chairs the Biomedical Image & Signal Processing Technical Committee of the IEEE Signal Processing Society and was an Associate Editor of IEEE Transactions on Image Processing (2006-2009) and Guest Editor of the Special Issue on Brain Decoding in Elsevier Pattern Recognition. Dr. Van De Ville was a recipient of the Pfizer Research Award 2012 in the category “Neurosciences and Diseases of the Nervous System”.

Research Interests

To advance our understanding of the human body, in particular of brain function in health and disorder using noninvasive imaging techniques. To that aim, we pursue the development and integration of innovative methodological tools from signal and image processing at various stages of the acquisition, processing, and analysis pipeline. The first highlight of our research is on temporal dynamics of spontaneous brain activity; e.g., we showed fractal organization of the rapid switching between scalp topographies in spontaneous EEG and how it interlinks with fMRI that is governed by slow hemodynamics. We also develop advanced regularization techniques that exploit prior knowledge of the neurovascular system that dominates hemodynamic-related imaging techniques. The second highlight is on the analysis of functional brain networks using multi-scale graph models and techniques from pattern recognition to interpret and predict cognitive and clinical conditions based on signatures of functional connectivity. Finally, we are looking into new approaches to MR spectroscopic imaging and source imaging from boundary measurements such as in ultrasound tomography and photo-acoustic imaging.

Selected Publications

Van De Ville, D., Britz, J., and Michel, C. M. (2010). EEG Microstate Sequences in Healthy Humans at Rest Reveal Scale-Free Dynamics. Proc. Natl. Acad. Sci. U S A. 107(42), 18179-18184.

Binzoni, T., Seelamantula, C. S., and Van De Ville, D. (2010). A Fast Time-Domain Algorithm for the Assessment of Tissue Blood Flow in Laser-Doppler Flowmetry. Physics in Medicine and Biology, 55, N383-N394.

Britz, J., Van De Ville, D. and Michel, C. M. (2010) BOLD Correlates of EEG Topography Reveal Rapid Resting-State Network Dynamics. NeuroImage, 52, 1162-1170.

Richiardi, J., Eryilmaz, H., Schwartz, S., Vuilleumier, P. and Van De Ville, D. (2011) Decoding Brain States from fMRI Connectivity Graphs. NeuroImage, 56, 616-626.

Van De Ville, D. , Kocher, M. (2011) Non-Local Means with Dimensionality Reduction and SURE-Based Parameter Selection. IEEE Transactions on Image Processing, 20, 2683-2690.

Karahanoglu, I., Bayram, I. and Van De Ville, D. (2011) A Signal Processing Approach to Generalized 1D Total Variation. IEEE Transactions on Signal Processing, 59, 5265-5274.

Khalidov, I., Fadili, J., Lazeyras, F., Van De Ville, D. and Unser, M. (2011) Activelets: Wavelets for Sparse Representation of Hemodynamic Responses. Signal Processing, 91, 2810-2821.

Team Members Postdoctoral Fellows Ivana Balic Yury Koush Jonas Richiardi Frank Scharnowski Yves Wiaux PhD students Zafer Dogan Soheil Faridi Isik Karahanoglu Jeffrey Kasten Rotem Kopel Nora Leonardi Master’s students Romain Pirson Ahmed Abdulkadir Hamid Behjat Administrative Assistant Ruth Fiaux

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IBI

EPFL School of Life Sciences - 2011 Annual Report

Van den Bergh Lab -

coaffiliated

http://lpas.epfl.ch/PDT Hubert van den Bergh obtained a BA in chemistry at Williams College Massachusetts USA, a PhD in physical chemistry at Cambridge University UK, and did postdoctoral work in physics at the Max Planck Institut für Strömungsforschung in Göttingen, Germany. He is professor at EPFL and a member of the Council of the Swiss National Science Foundation. He was awarded the prize of the Swiss Chemical Society, the Ruzicka Prize and the prize of the Swiss Biomedical Technology Society.

Hubert van den Bergh Full Professor School of Engineering (STI)

Hubert van den Bergh has contributed in the fields of basic chemical kinetics (including the development of the T-jump method in the gas-phase and molecular beam investigations of the cage effect), laser- and beam-induced chemical vapor deposition, and air pollution studies (modeling and measurements). The atmospheric measurements by LIDAR include a Raman system for measuring H2O vapor and temperature that was delivered to the Swiss Meteorological Institute for routine daily round the clock measurements.

Other contributions include a novel method for the separation of isotopes by laser-induced inhibition of condensation, which has led to the large scale separation of Uranium isotopes now in use at Wilmington NC by GE, Hitachi and Cameco.

Contributions to photomedicine include part of the development of Visudyne® technology for the treatment of wet age-related macular degeneration (FDA approval in 2000) with Novartis and QLT, the development of Hexvix® for the detection and removal of early stage bladder cancer (FDA approval in 2010) with Photocure and GE Healthcare, and the development of a fluorescence endoscope with Wolf GmbH in Germany.

Selected Publications

Gabriel D., Zuluaga M.F., van den Bergh H., Gurny R., and Lange N. (Accepted). It is all about proteases: from drug delivery to in vivo imaging and photomedicine, Current Medical Chemistry.

Nowak-Sliwinska P., Ballini J.-P., Wagnières G., van den Bergh H.. (2010). Processing of fluorescence angiograms for the quantification of vascular effects induced by anti-angiogenic agents in the CAM model, Microvascular Research, 79, 21-28.

Debefve E., Cheng C., Schaefer S.C., Yan H., Ballini J.-P., van den Bergh H., Lehr H.-A., Ris H.-B., and Krueger T. (2010). Photodynamic therapy induces selective extravasation of macromolecules : Insights using intravital microcospy, Journal of Photochem. and Photobiol. B ; Biology 98, 69-76.

Lovisa B., Jichlinski P., Weber B.C., Aymon D., van den Bergh H., and Wagnières G. (2010). High-magnification vascular imaging to reject false-positive sites in situ during Hexvix ® fluorescence cystoscopy, Journal of Biomedical Optics, 15(5), 051606, 1-8.

Gabrecht T., Lovisa B., van den Bergh H., and Wagnières G. (2009). Autofluorescence bronchoscopy: quantification of inter-patient variations of fluorescence intensity intensity, Lasers in Medical Sciences, 24(1), 45-51.

Gabriel D., Busso N., So A., van den Bergh H., Gurny R. and Lange N. (2009).

Thrombin-sensitive photodynamic agents : A novel strategy for selective synovectomy in rheumatoid arthritis, Journal of Controlled Release, vol.138, (3), 225-234.

Team Members Postdoctoral Fellows Thomas Braschler Elodie Debefve Sandrine Gay Blaise Lovisa Karine Mondon Senthil Kumar Rajendran Patrycja Nowak-Sliwinska Magdalena Swiderska Georges Wagnières Yaboo Wang

IBI - Co-affiliated Research Groups

Research Interests

PhD Students Gilles Kratzer Cédric Paulou

Nowak-Sliwinska P., van Beijnum J.R., van Berkel M., van den Bergh H. and Griffioen A.W. (2010). Vascular regrowth following photodynamic therapy in the chicken embryo chorioallantoic membrane, Angiogenesis, 13, 281-292.

Master’s Students Deborah Forte Stephanie Kappel Carla Martoccia Vincent Mazoyer Andrea Weiss

Cheng C., Debefve E., Haouala A., Andrejevic Blant S., Krueger T., Ballini J.-P., Peters S., Decosterd L.-A., van den Bergh H., Wagnières G., Perentes Y., and Ris H.-B. (2010). Photodynamic therapy selectively enhances liposomal Doxorubicin uptake in sarcoma tumors to rodent lungs, Lasers in Surgery and Medicine, 42, 391-399.

Administration Véronique Bauler Roxane Mischler

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2011 Annual Report

Other SV Professors and Newcomer Professors

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EPFL School of Life Sciences - 2011 Annual Report

Knowles

-Translational Research

Jonathan Knowles Full Professor

Research Interests

Jonathan Knowles was named as Professor of Translational Research at EPFL, Sciences de la Vie at the beginning of 2010. He is working to help better establish translational research, the critical bridge between bench and bedside at EPFL and other partners in Switzerland and abroad. His interests span all aspects of technology and fundamental biological science particularly in the context of how they could be applied to help patients now, or in the future, and he interacts with a number of groups at EPFL to help bring this about. He believes that better public-private partnerships are essential to bring the advances of technology to society.

Dr. Knowles was Head of Group Research and Member of the Executive Committee at Roche for 15 years until the end of 2009. He was a member of the Genentech Board for 12 years and a member of the Chugai Board for seven years. Dr. Knowles was also the chairman of the Corporate Governance Committee of Genentech.

From 1987 to 1997, he was director of the Glaxo Institute for Molecular Biology in Geneva, a privately funded Research Institute with an excellent academic publication record. From 1992 until 1997 until he moved to Roche, Jonathan Knowles was the head of the European Research Division and head of the Glaxo Genetics Initiative.

Board of the Innovative Medicines Initiative, a unique public-private partnership between 28 Pharmaceutical companies, the European Commission and over one hundred of European academic centres with a budget of more than 2 billion Euros over five years.

Jonathan Knowles is a Member of the European Molecular Biology Organization and also holds a Distinguished Professorship in Personalized Medicine at FIMM (Institute for Molecular Medicine Finland) at the University of Helsinki.

He has been appointed to a Visiting Chair at the University of Oxford and is a Visiting Fellow of Pembroke College Cambridge. In 2011, Jonathan Knowles was appointed as a Trustee of Cancer Research UK, one of the worlds leading Cancer Research organisations.

He remains very excited by the short term prospects for more personalised medicine through molecular diagnostics, especially for the treatment of cancer, as he believes this is the best and perhaps only way in which effective new therapies can be created and used.

Contact: jonathan.knowles@epfl.ch

He was for 5 years the Chairman of the Research Directors’ Group of EFPIA (European Federation of Pharmaceutical Industry Associations) and was the founding chairman of the

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Molinari Group http://www.irb.ch/

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Maurizio Molinari earned a PhD in Biochemistry at the ETH-Zurich in 1995. He worked as a postdoctoral fellow in the laboratories of Cesare Montecucco (Padua, 1996-1997) and of Ari Helenius (Zurich, 1998-2000). Since October 2000, he is group leader at the IRB in Bellinzona. Dr. Molinari has received the Science Award 2002 from the Foundation for Study of Neurodegenerative Diseases, the Kiwanis Club Award 2002 for Medical Science, the Friedrich-Miescher Award 2006 and the Research Award Aetas 2007. Since 2008, Dr. Molinari is Adjunct Professor at the EPFL.

Maurizio Molinari

External Adjunct Professor Institute for Research in Biomedicine Bellinzona

Introduction

The endoplasmic reticulum (ER) contains high concentrations of molecular chaperones and enzymes that assist maturation of newly synthesized polypeptides destined to the extracellular space, the plasma membrane and the organelles of the endocytic and secretory pathways. It also contains quality control factors that select folding-defective proteins for ER retention and/or ER-associated degradation (ERAD). Mutations, deletions and truncations in the polypeptide sequences may cause protein-misfolding diseases characterized by a “loss-of-function” upon degradation of the mutant protein or by a “gain-of-toxic-function” upon its aggregation/deposition. Pathogens hijack the machineries regulating protein biogenesis, quality control and transport for host invasion, genome replication and progeny production. The aim of our work is to understand the molecular mechanisms regulating chaperone-assisted protein folding and the quality control processes determining whether a polypeptide can be secreted, should be retained in the ER, or should be transported across the ER membrane for degradation. A thorough knowledge of these processes will be instrumental to design therapies or to identify drug targets for interventions aiming at delaying the progression or even at curing diseases caused by inefficient functioning of the cellular protein factory, resulting from expression of defective gene products, or elicited by pathogens.

Keywords

Cell biology, protein folding, quality control and degradation, endoplasmic reticulum; molecular chaperones, folding enzymes, conformational diseases.

Results Obtained in 2011

ERAD Tuning: The Selective Clearance of ERAD Regulators from the ER Lumen-Several regulators of ERAD have shorter half-life compared to conventional ER chaperones.

At steady state, they are selectively removed from the ER in a series of poorly defined events that we named ERAD tuning (Bernasconi and Molinari 2011). In an environment, the ER, where folding and disposal of newly synthesized cargo polypeptides are in kinetic competition, ERAD tuning sets ERAD activity at levels that do not interfere with

completion of ongoing folding programs and is therefore crucial to maintain cellular proteostasis. We have identified the complex comprising a type-I ER protein and the cytosolic protein LC3-I as an ERAD tuning receptor that regulates the COPII-independent vesicle-mediated removal of the luminal ERAD regulators EDEM1 and OS-9 from the ER (Submitted).

Hijacking of ERAD Tuning by Viral Pathogens: the unconventional role of non-lipidated LC3-The COPII-independent vesicle-mediated removal of EDEM1 and OS-9 from the ER is hijacked by Coronaviruses (CoV) during their infection cycle and crucially depends on LC3-I, a cytosolic, ubiquitin-like protein. Before our reports (Calì et al 2008 and Reggiori et al 2010), LC3-I was simply considered as a cytosolic precursor of the autophagosomal protein LC3II. By revealing the role of LC3-I in ERAD tuning and in cell infection by CoV, our studies show for the first time an autophagy-independent function of this protein (deHaan et al. 2010, Reggiori et al. 2011).

Malectin-We have functionally characterized Malectin, a novel ER-resident, stress-induced lectin binding di-glucosylated oligosaccharides displayed on newly synthesized polypeptides. Malectin shows prolonged association with misfolded protein conformers, consistent with a crucial role in ER quality control (Galli et al. 2011).

Alzheimer’s Disease (AD)-In collaboration with the group of Patrick Aebischer, we have developed a novel technique for chronic in situ delivery of antibodies as an alternative to passive vaccination strategies. A polymer device loaded with genetically engineered C2C12 cells was implanted in the brain parenchyma of APP23 transgenic mice. Implanted cells supported secretion of single chain antibodies to the amyloid precursor protein, thereby preventing deposition of toxic Abeta aggregates. This substantially contrasted the worsening of behavioral, anxiety and memory defects, which are hallmarks of progressive AD (Marroquin et al.

2011).

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Selected Publications

Bernasconi, R., Soldà, T., Galli, C., Pertel, T., Luban, J. and Molinari, M. (2010) Cyclosporine A-Sensitive, Cyclophilin B-Dependent Endoplasmic ReticulumAssociated Degradation. PLoS ONE 5, e13008.

Aebi, M., Bernasconi, R., Clerc, S. and Molinari, M. (2010) N-Glycan Structures: Recognition and Processing in the ER. TIBS 35, 74-82.

Bernasconi, R., Galli, C., Calanca, V., Nakajima, T. and Molinari, M. (2010) Stringent Requirement for HRD1, SEL1L and OS-9/XTP3-B for Disposal of ERAD-LS Substrates. J. Cell Biol. 188, 223-235.

Team Members Post doctoral Riccardo Bernasconi PhD Students Jessica Merulla Julia Noack Senior Scientists Elisa Fasana Carmela Galli Tatiana Soldà

-Highlights in J. Cell Biol 188, 176.

Reggiori, F., Monastyrska, I., Verheije, M.H., Calì, T., Ulasli, M., Bianchi, S., Bernasconi, R., deHaan, C.H.M. and Molinari, M. (2010) Coronaviruses Hijack the LC3-I-Positive EDEMosome, ER-Derived vesicles Exporting Short-Lived ERAD Regulators, for Replication. Cell Host & Microbe 7, 500-508.

-Highlights in Cell Host & Microbe 7, 424-426.

-Editors’ Choice in Science 329, 14.

-Leading Edge, Microbiology Select in Cell 142, 5.

-Recommended by the Faculty of 1000.

de Haan, C.A.M., Molinari, M. and Reggiori, F. (2010) Autophagy-Independent LC3 Function in Vesicular Traffic. Autophagy 6, 994-996.

Hebert, D.N. Bernasconi, R. and Molinari, M. (2010) ERAD Substrates: Which Way Out? Semin. Cell Dev. Biol. 21, 526-532.

Galli, C., Bernasconi, R., Soldà, T., Calanca, V. and Molinari, M. (2011) Malectin Participates in a Backup Glycoprotein Quality Control Pathway in the Mammalian ER. PLoS ONE 6, e16304.

Bernasconi, R. and Molinari, M. (2011) ERAD and ERAD Tuning: Disposal of Cargo and of ERAD Regulators from the Mammalian ER. Curr. Opin. in Cell Biol. 23, 176-183.

Marroquin, O.B., Cordero, M.I., Setola, V., Bianchi, S., Galli, C., Bouche, N. Mlynarik, V. Gruetter, R., Sandi, C., Bensadoun, J.-C., Molinari, M. and Aebischer, P. (2011) Chronic Delivery of Antibody Fragments Using Immunoisolated Cell Implants as a Passive Vaccination Tool. PLoS ONE 6, e18268.

Reggiori, F., deHaan, C.A.M. and Molinari, M. (2011) The Unconventional Use of LC3 by Coronaviruses through the Alleged Subversion of the ERAD Tuning Pathway. Viruses 3, 1610-1623.

External Adjunct Professors

A, Receptor-mediated exported from the ER of ERAD regulators, which is hijacked by CoV for replication.

B, Misfolded polypeptides inhibit the receptor-mediated clearance of ERAD factors from the ER. This results in UPR-independent enhancement of the intraluminal concentration of ERAD regulators.

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Rainer Group www.unifr.ch/inph/vclab

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Gregor Rainer obtained a Diploma in experimental physics from the University of Vienna, and then completed a Ph.D. at the Massachusetts Institute of Technology in systems neuroscience. Following nine years of experience as postdoc and research group leader at the Max Planch Institute for biological cybernetics in TĂźbingen, he joined the faculty of medicine at the University of Fribourg in 2008 and was subsequently appointed adjunct professor at EPFL.

Gregor Rainer

External Adjunct Professor University of Fribourg

Introduction

Research in the Visual Cognition Laboratory encompasses the study of higher cognitive functions in the mammalian visual system, with a focus on cholinergic neuromodulation. We use analysis of behavior during various visually based tasks, multi-channel recording of neurons and field potentials and quantitative neuropeptide analyses using mass spectrometry.

Keywords

Visual system, cortex, neural plasticity, learning, acetylcholine.

Results Obtained in 2011

One line of investigation has focused on plasticity of representations in higher level visual cortex in primates. We have recently published findings related to how inferior temporal cortex neurons mediate categorization of faces belonging to the own species compared to other species faces. We found that the inter-species boundary in the neural representation was shifted towards the own species, showing that visual experience with members of the own species profoundly affects memory representation. In a related pharmacological study, we have shown that cholinergic activation is crucial for the performance of categorization tasks. We have also examined the relation between the local field potential and spiking activity in different parts of the visual processing hierarchy. We found close correspondence between these signals in prefrontal but not visual cortex, a finding that is of importance for the interpretation of neural mass signals in humans. We have performed detailed laminar recordings in primary visual cortex in tree

shrews, examining layer-specific aspects of temporal and feature selective neural activity. Of particular interest is the high temporal fidelity of tree shrew visual cortical neurons to transient visual stimulation, which is clearly visible as response bursts following each visual transient. Detailed laminar specific information about temporal aspects of visual responses is crucial for obtaining a mechanistic understanding of information flow in cortex. Finally, we have established a database based on nano-flow liquid chromatography and mass spectrometry analysis of brain tissue data. We have described a large number of neuropeptides in the tree shrew brain, which provides a tool for investigating functional changes in neuropeptide regulation during cholinergic activation.

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Selected Publications

Team Members

Rainer G. Allocating attention in rank-ordered groups. Neuron 70(1):5-7 (2011).

PhD Students Anwesha Bhattacharyya Julia Veit Abbas Khani Filomena Petruzziello Sara Falasca Vaclav Ranc

Hoerzer GM, Liebe S, Schloegl A, Logothetis NK and Rainer G Directed coupling in local field potentials of macaque V4 during visual short-term memory revealed by multivariate autoregressive models. Front.Comput. Neurosci. 4:14 (2010).

Chablais F, Veit J, Rainer G, Jazwinska A. The zebrafish heart regenerates after cryoinjury-induced myocardial infarction. BMC Dev Biol. 7;11(1):21 (2011).

Post doctoral Xiaozhe Zhang

Sigala R, Logothetis NK, Rainer G. Own-species bias in the representations of monkey and human face categories in the primate temporal lobe. J Neurophysiol 105: 2740-2752 (2011).

Liebe S, Logothetis NK, Rainer G. Dissociable effects of natural image structure and color on LFP and spiking activity in the lateral prefrontal cortex and extrastriate visual area V4. J Neurosci 31(28):10215-10227 (2011).

Veit J, Bhattacharyya A, Kretz R, Rainer G. Neural response dynamics of spiking and local field potential activity depend on CRT monitor refresh-rate in the tree shrew primary visual cortex J Neurophysiol 106: 2303-2313 (2011).

Aggelopoulos NC, Liebe S, Logothetis NK, Rainer G. Cholinergic control of visual ategorization in macaques. Front Behav Neurosci 5 (73): 1-10 (2011).

External Adjunct Professors

Petruzziello F, Fouillen L, Wadenstein H, Kretz R, Andren P, Rainer G, Zhang XJ. Extensive characterization of Tupaia belangeri Neuropeptidome using an integrated Mass Spectrometry Approach. J Proteome Res dx.doi.org/10.1021/ pr200709 (2011).

Each refresh monitor causes a distinct visual transient in primary visual cortex (V1) of the tree shrew. The stimulus is shown between 0 to 80ms (vertical dashed bars) at a refresh rate of 120Hz in this example. The neural response latency is around 25ms.

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Schorderet Group www.irovision.ch

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After attending medical school at the Universities of Fribourg and Geneva, Dr Schorderet obtained an FMH in Pediatrics. He then trained in medical genetics at the University of Washington, Center for Inherited Diseases in Seattle, USA, where he was appointed research assistant professor. On his return to Switzerland, he developed the Unit of Molecular Genetics of the CHUV and later was appointed head of the Division of Medical Genetics. He obtained a FMH in Medical Genetics and a FAMH in analyses in Medical Genetics. In 2003, Dr. Schorderet was appointed director of the Institute of Research in Ophthalmology (IRO) in Sion. He is a member of the SV faculty since 2005.

Daniel Schorderet

External Adjunct Professor Institute for Reserch in Ophthalmology (IRO), Sion Director

Introduction

The Institute for Research in Ophthalmology (IRO) develops research in various aspects of vision, from understanding the development of the eye in animal models like the zebrafish and the mouse to identifying new genes and characterizing their molecular and cellular pathways for better diagnosis and treatment. Through various Swiss and international collaborations, IRO is shaping a new way in providing molecular diagnosis and understanding the inherited conditions behind some of the diseases leading to blindness.

particularly during the formation of the digits. Recently, we identified mutations in a transporter that was exchanging magnesium for calcium in the retina and the teeth. Taken together, these results pinpoint the importance of calcium/ magnesium homeostasis in the development of the eye.

We also associated mutations in PRSS56, a proteinase with trypsin-like serine protease activity, with posterior microphthalmia, a particular form of microphthalmia. This leads us to hypothesize that proteins of the sclera need to be digested to allow for correct expansion of the eye globe.

Keywords

Blindness, genetics of eye diseases, retinitis pigmentosa, glaucoma, age-related macular degeneration, diabetic retinopathy.

Results Obtained in 2011

At IRO, research centers around 4 axes: identification of new genes, understanding their function, developing animal models of eye diseases and new therapeutic tools.

Anophthalmia /microphthalmia, a disease in which children are born with no or very small, non functional eyes, has recently emerged as one of the main research areas in gene identification in my laboratory. In 2011, we identified two new genes, SMOC1 in Waardenburg-anophthalmia syndrome and PRSS56 in posterior microphthalmia. These two genes illustrate two different pathways leading to small eyes. SMOC1, a calcium-binding protein, is assumed to interact with calcium signaling both in the retinal progenitors during eye development, and in bone formation, more

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Selected Publications

Team Members

Gal A et al. Autosomal recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease. Am J Hum Genet, 88(3):382-390,2011.

Postdoctoral Fellows Gaëlle Boisset Arnaud Boulling Lysianne Follonier Castella Anne Oberson Nathalie Produit Leila Tiab

Abouzeid H, Boisset G, Favez T, Youssef M, Marzouk I, Shakankiry N, Bayoumi N, Descombes P, Agosti C, Munier FL, Schorderet DF. Mutations in the SPARCrelated modular calcium-binding protein 1 gene, SMOC1, cause Waardenburg anophthalmia syndrome. Am J Hum Genet 88(1):92-98,2011.

Emery M, Schorderet DF, Roduit R. Acute hypoglycemia induces retinal cell death in mouse. Plos ONE, 6(6):e21586,2011.

Escher P, Schorderet DF, Cottet S. Altered expression of t he transcription factor Mef2c during retinal degeneration in Rpe65-/- mice. Invest. Ophthalmol Vis Sci, 52(8):5933-40,2011.

Kotoulas A, Kokotas H, Kopsidas K, Droutsas K, Grigoriadou M, Bajrami H, Schorderet DF, Petersen M. A novel PIKFYVE mutation in fleck corneal dystrophy. Molec Vision 17:2776-2781,2011.

Le Carré J, Schorderet DF, Cottet S. Altered expression of β-galactosidase-1-like protein 3 (Glb1l3) in the retinal pigment epithelium (RPE)-specific 65-kDa protein knock-out mouse model of Leber’s congenital amaurosis. Mol Vis 17:128797,2011.

Ouechtati F et al. Clinical and genetic investigation of a large Tunisian family with complete achromatopsia: identification of a new nonsense mutation in GNAT2 gene. J Hum Genet. 56(1):22-8, 2011.

Research Associates Nathalie Allaman-Pillet Raphaël Roduit

PhD Students Séverine Hamann Fabienne Marcelli Lionel Page Gaëtan Pinton Désirée von Alpen Linda Wicht Laboratory technicians Céline Agosti Martine Emery Tatiana Favez Carole Herkenne Sylviane Métrailler Loriane Moret Administrative Assistants Pascale Evéquoz Sandra Théodoloz

Normal retina

Retina, 5 days post injury.

Necrotic cells are observed at the site of the injury indicated by the arrow.

No retinal layers are identifiable.

External Adjunct Professors

Neuroregeneration in the retina of an adult zebrafish after local external injury.

Retina, 100 days post injury.

Retina is almost completely regenerated (arrow). The various retinal layers can be observed.

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Tanner

EPFL School of Life Sciences - 2011 Annual Report

http://www.swisstph.ch

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Marcel Tanner

External Adjunct Professor Swiss TPH Insitute, Basel Director

Keywords

Epidemiology, public health, vaccines, drugs and diagnostics.

Research Interests

Swiss TPH (Tropical and Public Health Institute) and the EPFL School of Life Sciences are collaborating with the goal to bring together complementary expertise of the two institutions in research on host-pathogen interaction in infectious and chronic diseases and the development of new diagnostics, drugs and vaccines. Besides the collaboration in research, exchanges of teaching faculty and students within the MSc courses continued.

Joint research activities with pathogenic mycobacteria and nematodes as target pathogens have been initiated. These disease-specific joint activities are complemented by collaborations in the fields of lipidomics and bioinformatics.

The nematodes comprise a plethora of pathogens of medical, veterinary, and agricultural importance. Most of the pathogenic nematodes are difficult to maintain in the lab and their life-cycles cannot be completed in vitro. The freeliving nematode Caenorhabditis elegans, widely used as a model in developmental biology, provides an attractive tool for identification of novel anthelmintics and for functional characterization of the existing ones. Medium-throughput in vitro screening of chemical libraries against C. elegans

have been initiated in order to identify novel anthelmintic scaffolds and synthetic lethal compounds against drugresistant nematodes.

Other collaborations between EPFL and Swiss TPH are focused on the mycobacterial pathogens Mycobacterium tuberculosis and M. ulcerans, the etiologic agents of tuberculosis and Buruli ulcer. Facilitated by access to the BSL3 laboratories at the GHI, a mouse model for Buruli ulcer has been established and will be used for the assessment of vaccine and drug candidates. In tuberculosis, it is planned to jointly investigate the human and bacterial genetic factors contributing to the immune reconstitution inflammatory syndrome (IRIS) in HIV-coinfected tuberculosis (TB) patients.

The biannual report of Swiss TPH: http://www.swisstph.ch/fileadmin/user_upload/Pdfs/Biennial_Reports/Br_2009-10_full.pdf

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Welcome To Our New Collaborators!

Former Home Institution University of Zurich, Department of Neurology EPFL School of Life Sciences (BMI) since December 2011 Keywords Neurorehabilitation, neuroregeneration, neuroprosthetics, locomotion, spinal cord injury

GrĂŠgoire Courtine Associate Professor IRP Chair on Spinal Cord Repair

Former Home Institution University of Massachusetts EPFL School of Life Sciences (IBI) since October 2011 Keywords: Population genetics, evolutionary biology, statistical inference.

Jeffrey D. Jensen

New Collaborators

Tenure Track Assistant Professor

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