EPFL Institute of Bioengineering Annual Report 2012 by EPFL School of Life Sciences

EPFL School of Life Sciences - 2012 Annual Report

Preamble The School of Life Sciences is organized to teach students at the interface of biology and engineering - indeed quantitative, analytical and design-oriented life scientists, whether pursuing a Bachelor of Science in Life Sciences and Technology, a Master of Science in Life Sciences and Technology or Bioengineering, or a Doctor of Philosophy in Molecular Life Sciences, Neurosciences, or Biotechnology and Bioengineering. The School’s professors come from diverse backgrounds in biology, chemistry, physics, engineering and medicine to bring their passion for developing new fundamental understanding of critical questions in the life sciences and translating that understanding toward impacting human health through engineering solutions. The School’s span from the fundamental to the translational incorporating both basic scientists and engineers positions it in a unique position for profound impact.

Jeffrey A. Hubbell - Dean of Life Sciences

Introduction

The situation within the School in 2012 is exciting. Our professors have been awarded a total of 18 ERC grants, reflecting the broad enthusiasm of the scientific community for our scientific performance. The Center for Neuroprosthetics, a collaboration with the School of Engineering, has been launched and is fully up to speed, including ongoing human clinical investigations. The Human Brain Project, led by professors in the Brain Mind Institute, is having broad impact in neuroscience in Europe and worldwide. The Swiss Institute for Experimental Cancer Research has launched a collaboration with the University of Lausanne and the Centre Hospitalier Universitaire Vaudoise to create the Swiss Cancer Center Lausanne, bringing together basic and translational scientists and engineers to solve fundamental problems in cancer biology and therapy. These and other strategic activities are exciting expressions of the enthusiasm and leadership roles of the professors of the School of Life Sciences.

EPFL School of Life Sciences - 2012 Annual Report

Table Of Contents

Preamble.....................................................................................................................................3 Highlights of 2012.......................................................................................................................6 Honors-Awards-Announcements.................................................................................................7 Undergraduate Studies.................................................................................................................8 Doctoral Programs.......................................................................................................................9 SV Doctoral Graduates..............................................................................................................10 SV Masters Graduates................................................................................................................12 School of Life Sciences at a Glance...........................................................................................13

Centers.............................................................................................................................14

Blue Brain Project......................................................................................................................14 Center for Biomedical Imaging Research....................................................................................16 Center for Neuroprosthetics ......................................................................................................18

BMI..................................................................................................................................21

Aebischer Lab............................................................................................................................22 Blanke Lab.................................................................................................................................24 Courtine Lab..............................................................................................................................26 Fraering Lab...............................................................................................................................28 Gerstner Lab..............................................................................................................................30 Herzog Lab................................................................................................................................32 Lashuel Lab...............................................................................................................................34 Magistretti Lab...........................................................................................................................36 Markram Lab.............................................................................................................................38 Moore Lab.................................................................................................................................40 Petersen Lab..............................................................................................................................42 Sandi Lab...................................................................................................................................44 Schneggenburger Lab................................................................................................................46

IBI....................................................................................................................................49

Auwerx - Schoonjans Lab..........................................................................................................50 Baekkeskov Lab.........................................................................................................................52 Barrandon Lab...........................................................................................................................54 Dal Peraro Lab...........................................................................................................................56 Deplancke Lab..........................................................................................................................58 Hubbell Lab...............................................................................................................................60 Jensen Lab.................................................................................................................................62 Lutolf Lab..................................................................................................................................64 Naef Lab....................................................................................................................................66 Swartz Lab.................................................................................................................................68 Wurm Lab.................................................................................................................................70

Co-affiliated Research Groups.........................................................................................72

Aminian Lab..............................................................................................................................72 Fantner Lab ...............................................................................................................................73 Guiducci Lab.............................................................................................................................74 Hatzimanikatis Lab....................................................................................................................75 Ijspeert Lab................................................................................................................................76 Johnsson Lab.............................................................................................................................77 Jolles-Haeberli Lab ...................................................................................................................78 Lacour Lab ................................................................................................................................79 Maerkl Lab ...............................................................................................................................80 Mermod Lab..............................................................................................................................81 Micera Lab ...............................................................................................................................82 Millán Lab ................................................................................................................................83 Pioletti Lab ...............................................................................................................................84

EPFL School of Life Sciences - 2012 Annual Report

Psaltis Lab .................................................................................................................................85 Radenovic Lab ..........................................................................................................................86 Renaud Lab ..............................................................................................................................87 Roke Lab ..................................................................................................................................88 Stergiopulos Lab .......................................................................................................................89 Van de Ville Lab ........................................................................................................................90 Van den Bergh Lab ...................................................................................................................91

GHI..................................................................................................................................93

Blokesch Lab.............................................................................................................................94 Cole Lab....................................................................................................................................96 Fellay Lab..................................................................................................................................98 Harris Lab................................................................................................................................100 Lemaitre Lab............................................................................................................................102 McKinney Lab.........................................................................................................................104 Trono Lab................................................................................................................................106 Van der Goot Lab....................................................................................................................108

ISREC.............................................................................................................................111

Aguet Lab................................................................................................................................112 Brisken Lab..............................................................................................................................114 Constam Lab............................................................................................................................116 De Palma Lab..........................................................................................................................118 Duboule Lab............................................................................................................................120 Gönczy Lab.............................................................................................................................122 Hanahan Lab...........................................................................................................................124 Hantschel Lab..........................................................................................................................126 Huelsken Lab ..........................................................................................................................128 Kühn Lab.................................................................................................................................130 Lingner Lab..............................................................................................................................132 Meylan Lab..............................................................................................................................134 Radtke Lab...............................................................................................................................136 Simanis Lab.............................................................................................................................138 Bucher Group..........................................................................................................................140

Other Professors............................................................................................................142

Knowles...................................................................................................................................142 Tanner - Swiss TPH..................................................................................................................143 Molinari Group........................................................................................................................144 Rainer Group...........................................................................................................................146 Schorderet Group....................................................................................................................148 Core Facilities & Technology Platforms.....................................................................................151 Bioelectron Microscopy...........................................................................................................152 BioImaging & Optics...............................................................................................................153 Bioinformatics & Biostatistics...................................................................................................154 Biomolecular Screening...........................................................................................................155 Flow Cytometry ......................................................................................................................156 Histology ................................................................................................................................157 Proteomics...............................................................................................................................158 Protein Crystallography............................................................................................................159 Protein Expression...................................................................................................................160 Transgenic ..............................................................................................................................161 Phenotyping Unit.....................................................................................................................162

Introduction

Core Facilities & Technology Platforms..........................................................................151

EPFL School of Life Sciences - 2012 Annual Report

Highlights of 2012 February: Marc Moniatte, EPFL Proteomics Core Facility and INSERM-EPFL joint laboratory led by Christian Doerig joined forces with a team at Institut Pasteur (Paris) on an Antivalarial joint research project. http://actu.epfl.ch/news/ antimalarial-successful-joint-research/

March: The SV labs welcomed 17 enthusiastic high school students from all corners of Switzerland under the framework of La Science Appelle les Jeunes! (Schweizer Jugend forscht!) These students experienced lab work first-hand while completing and presenting a mini-project. http:// fr.sjf.ch/index.cfm

March : As a part of “Science, qui tourne.” , Denis Duboule (ISREC) and Jacques Neirynck, a national councilor, held a joint interview at the Rolex Learning Center on the subject of the future effect on society caused by low cost human DNA sequencing. http://actu.epfl.ch/news/low-cost-genome-decoding-for-better-or-for-worse-2/

EPFL Announces the Next Phase for its Center for Neuroprosthetics, (CNP) defining and establishing a truly interdisciplinary field of study merging neuroscience with engineering and medicine, and efficiently translating major breakthroughs from bioengineering and neuroscience into clinical settings. http://cnp.epfl.ch/

March: EPFL Prospective Students Days: The Life Sciences Teaching Section welcomed more than 200 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 December. More information : http://sv.epfl.ch/ prospective-students/march2012

Summer: The 2012 International Summer Research Program for undergraduate students hosted 25 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. http://sv.epfl.ch/summer-research

August: The annual Life Sciences Symposium was hosted by GHI, on the theme “Global Health meets Infection Biology” with a topnotch roster of speakers. The symposium as usual was a resounding success. During the symposium, the 2012 Debiopharm Life Sciences Award was given to Professor Daniel D. Pinschewer (University of Geneva) and Doctors Daan Noordermeer (EPFL) and Kelly Tan (University of Geneva) each received a Junior Debiopharm Group™ Life Sciences Award. http://actu.epfl.ch/news/three-scientiﬁc-prizes-awarded-by-debiopharm/

For more information and up-to-date SV news:

http://actu.epfl.ch/search/sv/

EPFL School of Life Sciences - 2012 Annual Report

Honors-Awards-Announcements Dimitri Van De Ville (IBI - STI) - Pfizer Award

Olaia Naveiras (IBI) - Jose Carreras Junior Investigator

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Career Fellowship

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Denis Duboule (ISREC) - New member of the British Royal Society.

Nicola Harris (GHI) and Felix Naef (IBI) - 2012 Leenaards

Swiss Final, Zurich.

Hilal Lashuel (BMI) - World Economic Forum Honoree

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Switzerland participants, CERN, Geneva. Muralidhar -

Shruti Muralidhar (BMI) & Adrian Ranga (IBI) - FameLab

Foundation Scientific Prize

QGel (start-up) - IBI co-founders: Matthias Lutolf and Jeff

Kai Johnsson (IBI-SB) – new member of the EMBO-

Hubbell - PERL Prizes

European Molecular Biology Organization.

Denis Duboule (ISREC) - US National Academy election.

QGel (start-up) - IBI co-founders: Matthias Lutolf and Jeff

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Hubbell - Vigier Prizes

Daan

Noordermeer

(ISREC)

Junior

Douglas Hanahan (ISREC) - 2012 Award for Cancer

Debiopharm

Research from the Fondazione San Salvatore, Lugano, CH

Group™ Prize

Melanie Blokesch (GHI), Nicola Harris (GHI), Jeffrey Melody Swartz (GHI)

Jensen (IBI), and Matthias Lutolf (IBI) European Research

- 2012 MacArthur Foundation

Council (ERC) Starting Grants

A ug

Fellow

Bart Deplancke (IBI) Prix SSV- Ambition Wulfram Gerstner (BMI) Prix SSV – Education

Jacques Fellay (GHI) - National Latsis Prize

Gisou van der Goot (GHI) - Prix Polysphère d-Or

Melanie Blokesch (GHI) - Best Teaching Evaluation prize

Olaf Blanke (BMI) - Cloëtta Foundation Prize

Introduction

Friedemann Zenken (BMI) - Teaching Assistant IC Award

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Swiss League Against Cancer

Joerg Huelsken (ISREC) - Robert Wenner Prize by the

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Ambition prize

Bart Deplancke (IBI) and Sebastian Maerkl (IBI - STI) -

EPFL School of Life Sciences - 2012 Annual Report

Undergraduate Studies 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 specializations. Among these are Neurosciences and Neuroengineering, Molecular Medicine and System Biology. Each specialization is made up of 19 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 Biocomputing and Computational Neurosciences. 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), Biocomputing (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. Bertrand Rey - photographer

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/

EPFL School of Life Sciences - 2012 Annual Report

Doctoral Programs 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 during our Hiring Days which occurs twice a year, the end of January and the end of June. Hiring Days last two and a half days: one-half day of general information followed by two days of lab immersion and evaluation.

Neuroscience (EDNE) provides its stu-

dents 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

Biotechnology and Bioengineering (EDBB) prepares doctoral students

to become leaders in the fast-growing academic and industrial biotechnology and bioengineering sectors by providing a depth of knowledge and competence in their specific research areas as well as a breadth of knowledge in biology, bioengineering, and biotechnology. Focus areas include: biomolecular engineering and biomaterials; cell, tissue, and process engineering; stem cell biotechnology; orthopaedic engineering; microtechnology and nanotechnology; biomechanics and mechanobiology; molecular and cellular biophysics; computational biology; genomics and proteomics; advanced biomedical imaging and image processing. http:// phd.epfl.ch/edbb

Molecular Life Sciences (EDMS) aims at providing doctoral students with the education necessary to become leaders in biological research, implementing the latest state of the art. The combination of laboratory based research with access to modern technological platforms, coursework, in-house seminars, national and international conferences, etc., forms the basis of this education. The programâ&#x20AC;&#x2122;s themes include cell biology, developmental biology, biochemistry & biophysics, molecular genetics, cancer research, microbiology, host-pathogen interactions, immunology, systems biology, computational biology, human genetics, stem cells and metabolism. The EDMS PhD program offers exciting PhD positions to talented and ambitious young researchers.

Introduction

http://phd.epfl.ch/edmshttp://phd.epfl.ch/edms

EPFL School of Life Sciences - 2012 Annual Report

SV Doctoral Graduates

Introduction

EPFL School of Life Sciences - 2012 Annual Report

SV Masters Graduates Master Bioengineering Graduates 2012

Master Life Sciences & Technology Graduates 2012

EPFL School of Life Sciences - 2012 Annual Report

Introduction

School of Life Sciences at a Glance

Centers

EPFL School of Life Sciences - 2012 Annual Report

Blue Brain Project http://bluebrain.epfl.ch/

Director: Prof. Henry Markram Introduction

The ultimate goal of the Blue Brain Project is to reverse engineer the mammalian brain by iteratively reconstructing models using biological data and principles and building on predictions generated. To achieve this goal the project has set itself four key objectives: • Create a generic Brain Simulation Facility with the ability to reconstruct brain models of the healthy and diseased brain, at different scales, with different levels of detail for different species. • Demonstrate the feasibility and value of this strategy by creating and validating a biologically detailed model of the neocortical column in the somatosensory cortex of young rats. • Use this model to refine the basic strategy to reconstruct brain models using biological data and principles and determine the extent to which new design insights can be predicted. • Exploit these validated and predicted principles to create larger more detailed brain models, and to develop strategies to eventually reconstruct the complete human brain using.

Keywords

Neocortex, simulation-based research, reverse engineering, high performance computing, unifying models, cortical column, mesocircuits, human brain project.

Description of BBP activities & results 2012

The combination of experiment and theory has long formed the basis of the scientific method. As computers become faster, computer simulations – combining experimental measurements and theoretical models – are beginning to capture the biological complexity of the brain. This is the goal of the Blue Brain Project, now in its eighth year. Over this time the project has constructed a prototype brain simulation facility with the software tools, the knowhow and the supercomputing infrastructure to build unifying models of the detailed structure of neuronal circuits and to simulate the way they function. The first version of the unifying model of the neocortical column was completed in 2008 and presented at the FENS meeting by the Blue Brain Project. The BBP integrated (and continually integrates) vast amounts of biological data on the rat neocortex and uses this reservoir of reconciled data to generate a continuously updated model, which is then simulated on Blue Brain Simulation Platform. The results were showcased during a presidential lecture at the Forum for European Neuroscience (FENS, Barcelona) and discussed with the scientific community at the largest annual convention of neuroscientists (Neuroscience, New Orleans), where 20 coordinated scientific posters were presented to detail the development and refinement of the cortical column unifying model.

Several insights from this first unifying model have been published in high impact journal publications and the full publication and release of the model are foreseen for 2013. Technical advances to the platform have been published at competitive conferences and a keynote lecture at the major supercomputing conference (Supercomputing, Salt Lake City) have been given. A notable insight from the model (published in PNAS 2012) is that the locations of synapses (the local connectome) between neurons can be accurately predicted using the reconstruction algorithms developed. Through the reconstruction the column, the BBP was able to identify key principles that determine synapse-scale connectivity by comparing the reconstructed circuit to a mammalian sample. Using these principles, it has become possible to accurately predict synapse location with 75-95% accuracy . Additionally, a systemic simplification strategy for the detailed model of the neocortical column was developed, which allows BBP to develop progressively abstract (simpler) models such that it is possible to focus on a particular aspect or function. Another scientific focus of the BBP in 2012 was to drive and coordinate the preparation of the Human Brain Project (HBP) proposal, selected as a FET Flagship initiative of the European Commission in 2013. This enormous effort involved numerous BBP scientists and managers as well as 150 scientific groups in various parts of the world. The preparatory phase project HBP-PS was successfully completed in April 2012 and a publically available report was created and disseminated. The HBP, involving initially 87 partner institutions, will be coordinated by EPFL and have a budget of one billion euros to deliver 10 years of world-beating science at the crossroads of science and technology. This success, essentially the largest research grant in EU funding history, represents a huge success for the EPFL and the ETH Board, who have backed the project during its preparation, and Swiss science in general. Following the mandate of the ETH Board, substantial efforts also went into the preparation of Blue Brain in the form of a national research infrastructure from 2013 onwards. Most notably, this includes the technical and infrastructural preparation for a future opening of certain Blue Brain assets to a larger group of scientists. This work will intensify in 2013 and lead to the release of a first web-based portal allowing scientists to use the Blue Brain Simulation Platform. Lastly, the Blue Brain Project succeeded in securing important international collaborations such as a strategic alliance between the King Abdullah University of Science and Technology (KAUST) and EPFL/BBP on neuro-inspired high performance computing and a participation in the Helmholtz Portfolio Grant allowing future collaboration with important computing centers in Germany.

EPFL School of Life Sciences - 2012 Annual Report

Team Members

Selected Publications

S.L.Hill, Y.Wang, I.Riachi, F.Schürmann, H.Markram: Statistical connectivity provides a sufficient foundation for specific functional connectivity in neocortical neural microcircuits, PNAS, 2012 Oct 16;109(42):E2885-94. doi: 10.1073/ pnas.1202128109. Epub 2012 Sep 18. S.Druckmann, S.Hill, F.Schürmann, H.Markram, I.Segev: A Hierarchical Structure of Cortical Interneuron Electrical Diversity Revealed by Automated Statistical Analysis, Cerebral Cortex, Cereb. Cortex (2012), doi: 10.1093/cercor/bhs290. A.Gidon and I.Segev: Principles governing the operation of synaptic inhibition in dendrites, Neuron, 2012 Jul 26;75(2):330-41. G.Khazen, S.L.Hill, F.Schürmann, and H.Markram: Combinatorial Expression Rules of Ion Channel Genes in Juvenile Rat (Rattus norvegicus) Neocortical Neurons, PLoS One, 7(4): e34786. doi:10.1371/journal.pone.0034786. S.Lasserre, J.Hernando, S.Hill, F.Schürmann, P. de Miguel Anasagasti, G.Abou Jaoudé, H.Markram: A Neuron Mesh Representation for Visualization of Electrophysiological Simulations, IEEE Transactions on Visualization and Computer Graphics, 18 (2): p. 214-217. S.Ramaswamy, S.L.Hill, J.G.King, F.Schürmann, Y.Wang, and H.Markram: Intrinsic Morphological Diversity of Thick-tufted Layer 5 Pyramidal Neurons Ensures Robust and Invariant Properties of in silico Synaptic Connections. J Physiol. 2012 Feb 15;590(Pt 4):737-52. Epub 2011 Nov 14. F.Tauheed, T.Heinis, F.Schürmann, H.Markram, A.Ailamaki: SCOUT: Prefetching of Latent Structure Following Queries, VLDB 2012 S.Eilemann, A.Bilgili, M.Abdellah, J.Hernando, M.Makhinya, R.Pajarola, and F.Schürmann: Parallel Rendering on Hybrid Multi-GPU Clusters, EGPGV 2012 J. Hernando, F.Schürmann, L.Pastor (2012), Towards real-time visualization of detailed neural tissue models: view frustum culling for parallel rendering, BioVis 2012 1Tauheed F, Biveinis L, Heinis T, Schürmann F, Markram H, Ailamaki A. Accelerating range queries for brain simulations, Proceedings of the 28th International Conference on Data Engineering (2012), pp. 941-952

General Project Manager Felix Schürmann Project Managers Buncic Nenad Fabien Delalondre Marc-Oliver Gewaltig Sean Hill Eilif Muller Julian Shillcock Stefan Eilemann Senior Science Writer Richard Walker Operations Alejandro Schiliuk Postdoctoral Fellows Guy Antoine Atenekeng Ahmet Bilgili Joe Graham Juan Hernando Daniel Keller Srikanth Ramaswamy Rajnish Ranjan Martin Telefont Benjamin Torben-Nielsen Werner Van Geit Thomas Heinis Research Assistant Melissa Cochrane

Engineers Carlos Aguado Sanchez Athanassia Chalimoudra Jean-Denis Courcol Valentin Haenel James Gonzalo King Bruno Ricardo Magalhaes Daniel Nachbaur Jeff Muller Stefano Zaninetta Sandro Wenzel PhD Students Marwan Abd Ellah Guiseppe Chindemi Lida Kanari Michael Reimann Renaud Richardet Farhan Tauheed Anirudh Vij Rahul Valiya Veettil Willem Wybo Interns Jafet Villafranca Diaz Ronny Hatteland Dan Ibanez Amine Achkar Kay G Hartmann Drew P Minnear Sarah Strauss Berat Denizdurduran Bidur Bohara Visiting Researcher Yun Wang Visiting Professors Karlheinz Wilhelm Meier Michael Hines Administration Christian Fauteux Catherine Hanriot Amanda Pingree Daphne Rondelli

of selected touch between neurons.

locations

Centers

Illustration

EPFL School of Life Sciences - 2012 Annual Report

Center for Biomedical Imaging Research http://www.cibm.ch/

Director: Prof. Rolf Gruetter

From Mouse to Patient History of the Center

The CIBM is the result of a major research and teaching initiative of the partners in the Science-Vie-Societe (SVS) project, i.e. Ecole Polytechnique Federale de Lausanne (EPFL), Universite de Lausanne (UNIL), Universite de Geneve (UNIGE), Hopitaux Universitaire Geneve (HUG), Centre Hospitalier Universitaire Vaudois Lausanne (CHUV), founded with generous support from the Fondations Jeantet and Leenaards. The CIBM was designed an imaging research center, committed to conducting biomedical imaging research in the context of biomedical research questions of importance, with the overall aim to bring together as equals imaging scientists and biomedical researchers. The Center is comprised of seven Research Cores focused on specialized research support and technology development and is active on three main sites at the EPFL, CHUV and HUG.

2012 Highlights • 115 publications • 1 starting ERC grant

Mission and Aim

The CIBMseeks to advance our understanding of biomedical processes in health and disease, focusing on mechanisms of normal functioning, pathogenic mechanisms, characterization of disease onset prior to structural damage, metabolic and functional consequences of gene expression, and non-invasive insights into disease processes under treatment. The research uses model systems ranging from transgenic animals to human subjects (“from mouse to man”) and fosters multi-disciplinary collaboration between basic science, biomedical science and clinical applications. The goal is to advance biomedical imaging, i.e. functional and metabolic imaging, while addressing biomedical questions of importance at the same time. This is accomplished by establishing a research network in imaging science to enhance biomedical research capabilities of the founding institutions and beyond, as well as within the CIBM.

Contact

To establish research projects, feel free to contact the Core director concerned (see below or www.cibm.ch) or info@ cibm.ch and we will be delighted to assist you.

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EPFL School of Life Sciences - 2012 Annual Report

Structure and Scope CIBM: 1 Center, 3 Sites, 5 Institutions, 7 Research Cores

Signal Processing and Image analysis core (M. Unser): The infrastructure includes multiple servers for data storage and processing. The aim is to perform high-level research in medical image analysis and develop theoretical foundations for new algorithms and mathematical tools for imaging addressing the need for advanced signal processing with large datasets being acquired, and complex questions to be answered. Phase Contrast Radiology core (G. Margaritondo): Ultra-high spatial and temporal resolution using using the TOMCAT beamline of the high quality swiss light source at the PSI in Villigen. The aim is to reach isotropic resolutions at the submicron scale within milliseconds and to develop novel approaches for phase-contrast radiology using conventional, laboratory-based sources. PET core (O. Ratib): A micro PET scanner linked to advanced radiochemistry research at the HUG, as well as a scanner at EPFL. The aim is to provide “conventional” imaging capabilities for the immediate evaluation of novel radiotracers, another is to focus on the synergies provided with combined studies on MR, including innovative mechanism for image registration.

Clinical Research Satellite at the HUG (F. Lazeyras): Clinical 3 Tesla TIM Trio scanner, 50% dedicated to clinical research and 50% to clinical service, with a complete accessary of functional-MRI equipment up to simultaneous EEG and MRI acquisition. A minimally invasive abdominal tumor ablation HiFU platform is operational. The aim is to develop and maintain state of the art MRI capabilities relevant for clinical research focusing on cognitive (dys)function and recovery in humans, as well as brain development. Clinical Research Satellite at the CHUV (M. Stuber): Clinical 3 Tesla TIM Trio scanner, 50% dedicated to clinical research and 50% to clinical service. A 32-channel cardiac coil and a 4-element carotid coil are available for cardiovascular research together with numerous high-end coils for neuro applications. The aim is to advance research and discovery through a better fundamental understanding of biological processes through advanced methods development enabling a direct translation from the bench to the bedside. Animal Imaging and Technology core (R. Gruetter): Ultra-high field MR equipment (100% research) • human 7 Tesla (1st actively shielded) • rodent 14 Tesla (world’s first) • rodent 9.4 Tesla The short bore of the 7 Tesla magnet makes it particularly suited for clinical studies and novel interventions, supported by a room for accommodating patients/volunteers. To minimize stress due to transport from the collaborating labs, a small on-site animal holding facility is present. Complemented with an RF laboratory and physiology support laboratories. The aim is to develop magnetic resonance imaging and spectroscopy capabilities in the context of specific biomedical research questions for animal imaging in rodents (primarily rats and mice) and for human brain imaging at very high magnetic fields. For more information see http://www.cibm.ch/page-60484-en.html.

A selection of images from all seven research cores.

Centers

EEG Brain Mapping core (C. Michel): State-of-the-art high density (MRI-compatible) EEG in- stallations at the university hospital in Geneva (HUG), the university medical school in Geneva (CMU), and at the university hospital in Lausanne (CHUV). The aim is to provide recording and analysis tools that allow studying the spatiotemporal dynamics of large-scale networks.

EPFL School of Life Sciences - 2012 Annual Report

Center for Neuroprosthetics http://cnp.epfl.ch/

Director: Prof. Olaf Blanke

Introduction

The Center for Neuroprosthetics (CNP) capitalizes on its unique access to advanced technologies and state of the art brain research present on the EPFL campus. Its aim is to develop new technologies that could support, repair and replace functions of the nervous system. The development of such technologies or devices, called neuroprostheses, requires a fundamental understanding of the neurobiological mechanisms of the functions that should be replaced or repaired, for example sensory perception, cognitive operations or the generation of motor commands. It also requires technological capabilities to design novel devices, to record and process signals and to translate them into control signals that can commend artificial limbs, bodies and robots, for motor function, or produce signals to activate the brain, in the case of sensory prostheses. The impact of neuroprosthetics for the treatment of sensory loss and impaired mobility has already been demonstrated. Over 200,000 people with impaired hearing have received cochlear implants and over 80,000 patients suffering from Parkinson’s disease and other neurological movement disorders have been treated with deep brain stimulation. With approximately a third of the population in Europe and the US afflicted by brain disorders, breakthroughs in cognitive neuroprosthetics will be necessary for treating patients suffering from cognitive deficits such as those caused by Alzheimer’s disease and vascular stroke.

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The Center for Neuroprosthetics is part of both the School of Engineering and the School of Life Sciences. It draws upon the EPFL’s expertise in biology, neuroscience, brain imaging, and genetics as well as biomedical, electrical, mechanical engineering, and nanotechnology. The Center will also draw upon EPFL’s cutting edge research in signal analysis, theoretical and computational neuroscience, the recently launched European Flagship “Human Brain Project” and the Swiss National Center of Competence in Research in “Robotics”. In addition, through support from the Bertarelli foundation, a new research collaboration - dedicated to translational neuroscience and neuroengineering - has been created between Harvard Medical School, EPFL’s Institute of Bio-engineering, and the Center for Neuroprosthetics. The Center for Neuroprosthetics is currently developing strategic partnerships with Geneva University Hospital (Hôpitaux Universitaires de Genève, HUG), Lausanne University Hospital (Centre Hospitalier Universitaire Vaudois, CHUV), and a major Swiss Rehabilitation Clinic (Clinique Romande de Réadaptation, CRR in Sion), as well as with the regional biomedical industry.

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EPFL School of Life Sciences - 2012 Annual Report

Four key projects define the core activities of the center: Walk again Restoring sensorimotor functions after spinal cord injury Intentions of a paralyzed rodent with spinal cord injury are decoded from real-time recording of brain activity. Decoded information is directly fed into a brain-spinal interface that computes optimal spinal cord stimulation patterns to execute the desired movement. As a result the animal is capable of locomotion and obstacle avoidance, even though the spinal cord motoneurons are physically separated from the brain. Bionic hand Restoring sensory and motor functions after arm or hand amputation Biocompatible flexible electrodes are implanted into different peripheral arm nerves of amputee patients. Movement commands of the amputee patient are decoded from signals in the implanted electrodes and transmitted to the prosthetic hand, where they are translated into movements of the prosthetic hand and fingers. Signals from different sensors in the prosthetic hand can also be transmitted via the implanted electrodes to the peripheral nerve to enable sensory functions such as the sense of touch and of finger position.

Rehabilitation of upper limb sensorimotor loss Providing neuro-technological tools for vascular stroke rehabilitation Merging insights from robotics and neuroengineering, our devices enable novel neurorehabilitation training for patients suffering from sensorimotor loss of the upper extremity. These tools are complemented by techniques from brain computer interfaces and virtual reality to further enhance rehabilitation outcomes for patients with sensorimotor loss, but also for patients suffering from chronic pain or cognitive deficits. Human-Computer confluence Decoding brain activity for feeling and moving artificial bodies and robots With robust real-time movement control of wearable devices and robots and with pioneering work in brain-machine interface and cognitive neuroscience, novel interaction paradigms are provided for mobility restoration, communication, neuroscience research, and entertainment.

Selected Publications:

Courtine G, Micera S, DiGiovanna J and MillĂĄn JdR (2013). Brain-machine interface: closer to therapeutic reality? The Lancet 381:515-7. Van den Brand R, Heutschi J, Barraud Q, DiGiovanna J, Bartholdi K, Huerlimann M, Friedli L, Vollenweider I, Moraud EM, Duis S, Dominici N, Micera S, Musienko P, Courtine G (2012). Restoring voluntary control of locomotion after paralyzing spinal cord injury. Science 336(6085):1182-5. Blanke O Multisensory brain mechanisms of bodily self-consciousness (2012). Nat Rev Neurosci 13(8):556-571. Dominici N, Keller U, Vallery H, Friedli L, van den Brand R, Starkey ML, Musienko P, Riener R, Courtine G (2012). Novel robotic interface to evaluate, enable, and train locomotion and balance after neuromotor disorders. Nature Medicine 18:1142-7. Panarese A, Colombo R, Sterpi I, Pisano F, Micera S (2012). Tracking motor improvement at the subtask level during robot-aided neurorehabilitation of stroke patients. Neurorehabil Neural Repair 26(7):822-33. Tombini M, Rigosa J, Zappasodi F, Porcaro C, Citi L, Carpaneto J, Rossini PM, Micera S (2012). Combined analysis of cortical (EEG) and nerve stump signals improves robotic hand control. Neurorehabil Neural Repair 26(3):275-81. Delivopoulos E, Chew D, Minev IR, Fawcett JW, Lacour SP (2012). Concurrent recordings of bladder afferents from multiple nerves using a microfabricated PDMS microchannel electrode array. Lab on Chip 12:2540-2551. Huang YY, Terentjev E, Oppenheim T, Lacour SP, Welland ME (2012). Fabrication and electromechanical characterization of near-field electrospun composite fibers. Nanotechnology 23:105305. Tzovara A, Murray M, Bourdaud N, Chavarriaga R, MillĂĄn JdR and De Lucia M (2012). The timing of exploratory decision-making revealed by single-trial topographic EEG analyses. Neuroimage 4:1959-69.

Centers

Ionta S, Heydrich L, Lenggenhager B, Mouthon M, Fornari E, Chapuis D, Gassert R, Blanke O (2011). Multisensory mechanisms in temporo-parietal cortex support self-location and first-person perspective. Neuron 70(2):363-74.

EPFL School of Life Sciences - 2012 Annual Report

IBI

Institute of Bioengineering

Melody Swartz - Director The Institute of Bioengineering (IBI) brings together discovery in fundamental biology with engineering design principles. Its labs pursue quantitative, systems- and design-oriented research in and for the life sciences, both to better understand complex biological and physiological networks as well as through the development of (bio)molecules, techniques, or devices that in many cases translate into novel therapeutics and diagnostics. The IBI is situated in both the School Life Science (SV) and the School of Engineering (STI). This dual affiliation allows great diversity in hiring faculty from different backgrounds and with different research perspectives. 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. After 10 years under the founding leadership of Jeffrey Hubbell, Melody Swartz became the new Institute Director in 2012 when Prof. Hubbell became the Dean of the School of Life Sciences. Among other notable events were the promotion of Prof. Felix Naef to Associate Professor, the success of our annual “IBI Day” (this year’s theme was Systems/Computational Bioengineering), and the launch and first meeting of a Scientific Advisory Board, which will convene regularly in the future. In addition, several IBI faculty were honored in 2012 and are highlighted in the introduction of this SV Annual Report (p. 7).

IBI - Institute of Bioengineering

On the educational side, 20 new PhDs were awarded in IBI-affiliated labs, and 35 graduates received their MSc in Bioengineering. This includes the first 4 Bertarelli Fellows, whose thesis work done partially at Harvard Medical School was featured at the 2nd Symposium of the Bertarelli Program on Translational Neuroscience and Neuroengineering (http://ptnn.epfl.ch), which is hosted by IBI. The Symposium was held at EPFL on Oct. 11-12. IBI’s continuing success is reflected in the Quantitative Ranking of Engineering Disciplines (http://sti.epfl.ch/ page-84929.html), a strictly bibliometric ranking which finds it in 3rd place worldwide and number 1 in Europe, as already in 2011. http://sv.epfl.ch/page-37989.html

EPFL School of Life Sciences - 2012 Annual Report

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

Johan Auwerx Full Professor Nestlé Chair in Energy Metabolism

Kristina Schoonjans Adjunct Professor Co-group Leader

Introduction

Johan Auwerx and Kristina Schoonjans use a systems physiology approach to understand metabolic homeostasis and the pathogenesis of common metabolic diseases. Their research 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, atherosclerosis, C.elegans, diabetes, genetics, genetically engineered mouse models, mitochondria, metabolism, mouse genetic reference populations, obesity, phenogenomics, transcription, transcription factors.

Results Obtained in 2012

Johan Auwerx received an M.D. (1982) and Ph.D. (Molecular Endocrinology; 1989) degree from the Katholieke Universiteit Leuven, Belgium. He performed post-doctoral training in Medicine and Genetics at the University of Washington, Seattle. He is certified in Endocrinology, Metabolism and Nutrition. Kristina Schoonjans obtained her Ph.D in Molecular Biology and Pharmacology from the University of Lille, France in 1995. After her postdoctoral training at the Pasteur Institute (Lille) in 1999, she moved to the IGBMC in Strasbourg and was appointed Research Director with INSERM in 2007. They both codirect the LISP lab at the EPFL since 2008.

Membrane and nuclear receptors in bile acid signaling and metabolism - Earlier studies in our lab established how the enterohepatic nuclear receptors - farnesoid X receptor (FXR), liver receptor homolog-1 (LRH-1) and short heterodimer partner (SHP) - govern hepatic lipid and bile acid metabolism, and regulate cell proliferation. We furthermore identified bile acids as endocrine regulators of energy expenditure and glucose homeostasis, 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 diabetes and sparked a paradigm shift that transformed bile acids, known to be lipid solubilizers in the gut, to versatile endocrine signals that impact various aspects of physiology. More recently, we have highlighted the role of macrophage TGR5 in the context of inflammationdriven metabolic diseases, such as atherosclerosis. TGR5 activation in macrophages by bile acid mimetics inhibits pro-inflammatory cytokine production and reduces atherosclerosis via cAMP-dependent interference of p65 nuclear translocation.

Cofactors and fine-tuning of energy homeostasis - The role of transcriptional cofactors in the control of metabolic homeostasis, in general, and of mitochondrial function, in particular, is still poorly understood. We have established that a yin-yang between corepressors - NCoR1 and the sirtuin family of deacetylases - and co-activators - PGC1α, 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-1α, 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 AMPK 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. This work has established that complex transcriptional networks convert signals associated with caloric intake and cellular energy status into changes of chromatin state and transcription. The BXD Genetic Reference Population as a resource to study metabolism - A cohort of 42 strains of BXDs has recently been pushed through an extensive metabolic phenotyping program. This study focused on differential effects of diet as well as exercise, weight gain, fat deposition, gene expression, and many classic metabolic traits. More than 400 metabolic phenotypes related to mitochondrial function were measured. This program is an expansion of an earlier pilot study that focused on sex differences in 140 metabolic traits on BXD cohorts. We have observed striking variation in the response of body weight to diet and exercise among BXD strains. These ongoing experiments further validate the BXD family as an excellent resource for the genetic dissection of metabolic networks.

EPFL School of Life Sciences - 2012 Annual Report

Selected Publications

C. Canto, R.H. Houtkooper, E. Pirinen, D.Y. Youn, M.H. Oosterveer, P.J. Fernandez-Marcos, H. Yamamoto, P.A. Andreux, P. Cettour-Rose, K. Gademann, C. Rinsch, K. Schoonjans, A. A. Sauve, J. Auwerx. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet induced obesity. Cell Metabolism, 2012, 15, 838-847. P.A. Andreux, E.G. Williams, H. Koutnikova, R.H. Houtkooper, M.F. Champy, H. Henry, K. Schoonjans, R.W. Williams, J. Auwerx. Systems genetics of metabolism – the use of the BXD murine reference panel for multiscalar integration of traits. Cell 2012, 150, 1287-1299. P. Bai, C. Canto, H. Oudart, A. Brunyánszki, Y. Cen, C. Thomas, H. Yamamoto, A. Huber, B. Kiss, R.H. Houtkooper, K. Schoonjans, V. Schreiber, A.A. Sauve, J. Menissier-de Murcia, J. Auwerx PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metabolism, 2011, 13, 461-468. P. Bai, C. Canto, A. Brunyánszki, A. Huber, M. Szanto, Y. Cen, H. Yamamoto, S. Houten, B. Kiss, H. Oudart, P. Gergely, V. Schreiber, J. Menissier-de Murcia, A.A. Sauve, J. Auwerx. PARP-2 regulates SIRT1 expression and whole body energy expenditure. Cell Metabolism, 2011, 13, 450-460. J. Du, Y. Zhou, X. Su, J. J. Yu, S. Khan, H. Jiang, J. Kim, J. Woo, J. H. Kim, B. H. Choi, B. He, W. Chen, S. Zhang, R. A. Cerione, J. Auwerx, Q. Hao, H. Lin. Sirt5 Is an NAD-Dependent Protein Lysine Demalonylase and Desuccinylase. Science, 2011, 334, 806-809. H. Yamamoto, E.G. Williams, L. Mouchiroud, C. Canto, W. Fan, M. Downes, C. Heligon, G.D. Barish, B. Desvergne, R.M. Evans, K. Schoonjans, J. Auwerx. NCoR1 is a conserved physiological modulator of muscle mass and oxidative function. Cell, 2011, 147, 827-839. T.W.H. Pols, M. Nomura, T. Harach, G. Lo Sasso, M.H. Oosterveer, C. Thomas, G. Rizzo, A. Gioiello, L. Adorini, R. Pelliciari, J. Auwerx, K. Schoonjans. TGR5 activation inhibits atherosclerosis by reducing macrophage infiltration and lipid loading. Cell Metabolism, 2011, 14, 747-757.

Team Members Postdoctoral Fellows Taoufiq Harach Jo YoungSuk Giuseppe Lo Sasso Adriano Maida Laurent Mouchiroud Maaike Oosterveer Eija Pirinen Thijs Pols Sooraj Ratnakumar Dongryeol Ryu Matthias Stein Hiroyasu Yamamoto PhD Students Pénélope Andreux Virginija Jovaisaite Elena Katsyuba Mitsonura Nomura Evan Williams Pan Xu Julien Zaldivar Hongbo Zhang Master’s Student Adrienne Mottis Technicians Sabrina Bichet Thibaud Clerc Amandine Moriot-Signorino-Gelo Norman Moullan Administrative Assistant Valérie Stengel

IBI - Institute of Bioengineering

Oosterveer MH, Mataki C, Yamamoto H, Harach T, Moullan N, van Dijk TH, Ayuso E, Bosch F, Postic C, Groen AK, Auwerx J, Schoonjans K. LRH-1-dependent glucose sensing determines intermediary metabolism in liver. J. Clin. Invest, 2012, 122, 2817-2826.

Mice treated with resveratrol are protected from obesity.

EPFL School of Life Sciences - 2012 Annual Report

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

Steinunn Baekkeskov Visiting Professor

Introduction

The Baekkeskov group studies how and why the pancreatic beta cell becomes a target of autoimmunity resulting in beta cell destruction and development of type 1 diabetes. Current research aims at elucidating the early events leading to autoimmunity towards the beta cell and how the process can be blocked or prevented.

Keywords

Type 1 diabetes, autoimmunity, beta cell autoantigens, intracellular membrane proteins, protein targeting, protein trafficking, endoplasmic reticulum stress, GAD65, GAD67, GABA.

Results Obtained in 2012

Research in the Baekkeskov laboratory seeks to understand why the immune system erroneously mounts an immune response to some self proteins and how this process can be prevented. We study the autoantigen GAD65, which is targeted by the immune response associated with destruction of pancreatic beta cells and development of Type 1 Diabetes. GAD65, the smaller isoform of the GABA synthesizing enzyme, glutamic acid decarboxylase (GAD), is critical for fine tuning of GABA-ergic neurotransmission, while the highly homologous isoform of GAD, GAD67, synthesizes basic levels of GABA. GAD65 is unusually susceptible to becoming an autoantigen in the two cell types that express it, pancreatic beta cells and GABA-ergic neurons. Thus it is a primary autoantigen in both type 1 diabetes and a rare neurological disorder, stiff-man syndrome that affects GABA-ergic neurons. In contrast GAD67 is not an independent autoantigen in either disease. The two isoforms differ

mainly in the N-terminal region that controls membrane targeting and trafficking of the proteins. Our research focuses on elucidating the mechanisms of membrane association and trafficking pathways of GAD65 and how they differ for GAD67. A detailed understanding of the differences in the trafficking pathways of GAD65 and GAD67 may hold the key to why only GAD65 becomes a target of autoimmunity. While we know much about the mechanisms that mediate membrane association and trafficking of GAD65, more recently we have shown that two mechanisms govern membrane association of the GAD67. One mechanisms results in heterodimerisation with GAD65 and piggy-backing onto its the trafficking pathways, while the second mechanisms is independent of GAD65. Both mechanisms result in targeting of GAD67 to synaptic vesicle membranes. We have identified a sophisticated mechanism that controls the cycling of GAD65 between the Golgi compartment and the synaptic vesicle membranes, where it is needed for a rapid synthesis and secretion of GABA to meet a sudden increase in demand. This mechanism involves a cycle of palmitoylation/depalmitoylation of two cysteines, cys 30 and 45, in the N-terminal targeting domain, which are absent in GAD67. We have recently shown that induction of mild oxidative stress in beta cells results in GAD65 being excluded from its normal trafficking pathway. Thus the protein is blocked from entering the vesicular membrane pathway to synaptic vesicles. If beta cell stress continues, GAD65 can form large aggregates. We hypothesize that such aggregates would be highly immunogenic if released from damaged and/or apoptotic beta cells.

EPFL School of Life Sciences - 2012 Annual Report

Team Members

• What is the functional relevance of the acylation cycle in GAD65 for control of GABA-ergic mechanisms in neurons and pancreatic beta cells? • What is the mechanism involved in accumulation of GAD65 in conditions of beta cell oxidative stress? Is the block in the trafficking pathway to synaptic vesicle membranes due to oxidation of cys 30 and 45 to form a disulfide bridge and/ or inhibition of the palmtoylation transferase involved in palmitoylation of GAD65? Does a block in the acylation cycle due to accumulation of oxidized and aggregated GAD65 contribute to beta cells stress? Does aggregation of GAD65 increase its immunogenicity?

Postdoctoral Fellow Ed Phelps Lab Manager Miriella Pasquier

Administrative Assistant Marisa Marciano Wynn

IBI - Institute of Bioengineering

Current Questions:

Large dense core insulin secretory vesicles are visualized in primary rat beta cells by immunofluorescence staining and confocal microscopy. The diabetes autoantigen GAD-65 is found in vesicles separate from the insulin secretory system. Insulin (magenta), GAD-65 (green), and DNA (blue).

EPFL School of Life Sciences - 2012 Annual Report

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

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 since 2002. He has made major contributions in basic epithelial stem cell biology and in stem cell therapy. Prof. Barrandon is a member of the EMBO and the Academia Europaea. He is also a member of the EPFL research committee, EPFL Ethical committee and of the Canton de Vaud Ethical committee. He was elected twice best teacher in Life Sciences at EPFL. In 2011, he co-founded gymetrics SA. Since 2012, he is “Initiative director” for the doctoral training cooperation initiative signed between the EPFL and A*Star Singapore.

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 has three main objectives that aim at improving cell and gene therapy using epithelial stem/progenitor cells: first, the laboratory would like to decipher the relationship between stem/progenitors cells of stratified epithelia, second to understand the impact of the physical 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 cell, plasticity, reprogramming, microenvironment, skin, epidermis, whisker, hair follicle, thymus, cornea, gene and cell therapy, translational medicine, regenerative medicine.

Results Obtained in 2012

Skin stem cells (epithelial and mesenchymal) can be extensively cultured and cloned, genetically manipulated and transplanted. 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 homeostatic situation, these decisions are tightly controlled and influenced by the

microenvironment (the niche). In a disease, the microenvironment may be abnormal, damaged by a preconditioning treatment or even completely missing as in third degree burns of the skin or corneal deficiency. Hence, transplanted cultured stem cells in regenerative medicine have to adjust to an environment that is far from ideal, if not hostile. Surprisingly, little is known on how stem cells respond to a non-homeostatic microenvironment and engraftment mostly remains an uncontrolled process. Using the minipig as a model system, we have cultured autologous epidermal stem cells and transplanted them onto granulation tissue formed in response to skin surgical wounds excised to muscular fascia. We have demonstrated that the cultured autologous stem cells respond to the microenvironment of the grafting bed by favoring differentiation rather self-renewal or death. We are now screening for small molecules and factors that favor renewal of transplanted stem cells to improve engraftment. The laboratory of Stem Cell Dynamics is also using state-of-the art architecture, microtechnology, informatics and visualization technology to construct models that permit to virtually manipulate the microenvironment and predict the consequences of theses manipulations on stem cell behavior and organ function using the skin, the thymus and the cornea as model systems.

EPFL School of Life Sciences - 2012 Annual Report

Selected Publications

Hirata-Tominaga, K., Nakamura, T., Okumura, N., Kawasaki, S., Kay, E.P., Barrandon, Y., Koizumi, N, and Kinoshita, S. (2013). Corneal endothelial cell fate is maintained by LGR5 via the regulation of hedgehog and Wnt pathway. Stem Cells. Apr 3. doi: 10.1002/stem.1390. [Epub ahead of print]

Team Members

Senior scientists Rochat Ariane

Smith, E., Claudinot, S., Lehl, R., Pellegrinet, L., Barrandon, Y., and Radtke, F. (2012). Generation and Characterization of a Notch1 Signaling-Specific Reporter Mouse Line. Genesis. 50(9):700-10.

Postdoctoral Fellows Amici Alessandro Caillier-Veron Maïa Claudinot Stéphanie Droz-Georget Stéphanie Gonneau Christèle Grasset Nicolas Kanemitsu Michiko Maggioni Melissa Wasnick Roxana PhD Students Arlabosse Tiphaine Gorostidi François Graber Julien Maggioni Melissa Manti Pierluigi Mosig Johannes Muller Georges Pluchinotta Matteo Zaffalon Andrea

Rochat, A., Grasset, N., Gorostidi, F., Lathion Droz-Georget, S., and Barrandon, Y. (2012) Regeneration of epidermis from adult human keratinocyte stem cells. In Handbook of stem cells 2nd ed. Atalla and Lanza editors Elsevier. Vol 2 pp. 767-777.

Master’s Students De Lageneste Marine Hémon Diane Lai Quiwen Perseguers Marie-Noëlle

Bonfanti, P., Barrandon, Y., and Cossu, G. “Hearts and Bones”: (2012) The Ups and Downs of “Plasticity” in Stem Cell Bioloy EMBO Mol. Med. 4(5):353-61.

Visiting Student Tyler Haynes

Bonfanti, P., Claudinot, S., Amici, A.W., Farley, A., Blackburn, C.C, and Barrandon, Y. (2010). Microenvironmental reprogramming of thymic epithelial cells to skin multipotent stem cells. Nature 466(7309):978-82. (Press release) Commentary in Bilousova and Roop Cell Stem Cell 2010, 7: 419-420.

Technicians Burki Marco De Souza Olga Mercier Louis Savoy Dorinne

Nanba, D., Toki, F., Matsushita, N., Matsushita, S., Higashiyama, S. and Barrandon, Y. (2013). Actin Filament Dynampacts Keratinocyte Stem Cell Maintainance EMBO Mol. Med. 5(4):640-53. Barrandon, Y., Grasset, N., Zaffalon, A., Gorostidi, F., Claudinot, S., DrozGeorget, S.L., Nanba, D., and Rochat, A. (2012). Capturing epidermal stemness for regenerative medicine. Semin. Cell Dev. Biol. 23(8):937-944. Shakhova, O., Zingg, D., Schaefer, S.M., Hari, L., Civenni, G., Blunschi, J., Claudinot, S., Okoniewski, M., Beermann, F., Mihic-Probst, D., Moch, H., Wegner, M., Dummer, R., Barrandon, Y., Cinelli, P., and Sommer, L. (2012). Sox10 promotes the formation and maintenance of giant congenital naevi and melanoma. Nature Cell Biol. 14(8):882-90.

IBI - Institute of Bioengineering

Administrative Assistants Guex Nathalie Savioz-Dayer Emmanuelle

Generation of epidermis, hair follicles and sebaceous glands from a serially cultured progeny of a single multipotent stem cell isolated from the upper constant region of a whisker follicle of an adult GFP rat. Cells were transplanted onto the back skin of a DsRed mouse pup and biopsy was obtained and sectioned 90 days later. Bar = 100 microns.

EPFL School of Life Sciences - 2012 Annual Report

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

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 and integrated with experimental inputs 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 also 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.

Results Obtained in 2012

The seamless integration of computational techniques and biophysical/biochemical measurements is an emerging and efficient strategy to extend our knowledge of biological function at the molecular level shedding light on features that are often experimentally inaccessible. Biomolecules assemble and cooperate in large complexes to achieve specific biological tasks. Owing to their size and complexity, their structure and dynamics are difficult to be investigated at atomistic resolution with current in vitro/in vivo methods. To enhance the effective resolution of molecular architecture and mechanism, we have recently introduced a new approach called Protein Optimization Workbench - POW (available at http://lbm.epfl.ch/resources) that uses a Particle Swarm Optimization (PSO) search guided by experimental-based restraints to characterize protein quaternary structure. Importantly, within this scheme it is possible to take into account the native flexibility of each protein subunit as extracted from molecular dynamics simulations. This is a key ingredient for the prediction of biologically functional assemblies when, upon oligomerization, subunits explore activated states undergoing significant conformational changes. We expect that, with the ever-growing sampling capabilities of current molecular dynamics simulations, this hybrid strategy will offer in the future an un-

precedented, robust and efficient way to address molecular assembly through dynamic modeling. During this year, we have worked at extending and improving our framework with new optimization engines, new experimentally based fitness functions and new applications to molecular assembly. Following this same integrative dynamic strategy, we have completed the modeling of the transmembrane (TM) core of the PhoQP two-component system, a signaling complex essential for bacterial virulence and cationic antimicrobial peptide resistance (see Figure 1). PhoQ is the histidine kinase chemoreceptor of this tandem machine and assembles in a homodimer conformation spanning the bacterial inner membrane. We obtained an atomistic model of the key TM domain assembled by using molecular simulations, validated by experimental cross-linking data (Figure 1A,B). A concerted displacement of the TM helices at the periplasmic side is found to modulate a rotation at the cytoplasmic end (Figure 1C), supporting the transduction of the chemical signal through a combination of scissoring and rotational movement of the TM helices. This mechanism is the key to understanding how the chemical stimuli sensed by the periplasmic sensor domain trigger, via the relay of the HAMP domain, the histidine auto-phosphorylation and kinase/phosphatase activity at the cytoplasmic end (Figure 1D) (PLoS Comput Biol 9(1): e1002878). PhoQ is embedded in the inner bacterial membrane. Therefore, interaction with anionic lipids, such as phosphophatidylglycerol and cardiolipin, is supposed to play a key role in the activity of PhoQ TCS and other membrane proteins interacting with at the bacterial membrane. In particular, cardiolipins have a unique dimeric structure for which we have developed an ab initio parameterization for molecular simulation consistent with commonly used force fields. The proposed models will contribute to study the assembly of more realistic bacterial and mitochondrial membranes and the investigation of the role of cardiolipins for the biophysical and biochemical properties of membranes and membrane-embedded proteins (J. Chem. Theory Comput., 2013, 9 (1), 670).

EPFL School of Life Sciences - 2012 Annual Report

Selected Publications

T. Lemmin, C. Soto, G. Clinthorne, W.L. DeGrado, M. Dal Peraro (2013), Assembly of the Transmembrane Domain of E. coli PhoQ Histidine Kinase: Implications for Signal Transduction from Molecular Simulations, PLoS Comp. Biol., 9(1): e1002878. G. Palermo, M. Stenta, A. Cavalli, M. Dal Peraro, M. De Vivo (2013) Molecular Simulations Highlight the Role of Metals in Catalysis and Inhibition of Type II Topoisomerase, J. Chem. Theory Comput., 9 (2), 857. T. Lemmin, C. Bovigny, D. Lançon, M. Dal Peraro. (2013) Cardiolipin Models for Molecular Simulations of Bacterial and Mitochondrial Membranes, J. Chem. Theory Comput., 9 (1):670–678. T. Hofmeyer, S. Schmelz, M. T. Degiacomi, M. Dal Peraro, M. Daneschdar, A. Scrima, J. van den Heuvel, D.W. Heinz and H. Kolmar (2013) Arranged Sevenfold: Structural Insights into the C-Terminal Oligomerization Domain of Human C4b-Binding Protein, J. Mol. Biol. 425, 1302–1317

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

S. Ittig, B. Lindner, M. Stenta, P. Manfredi, E. Zdorovenko, Y.A. Knirel, M. Dal Peraro, G.A. Cornelis and U. Zähringer (2012) The Lipopolysaccharide from Capnocytophaga canimorsus Reveals an Unexpected Role of the Core-Oligosaccharide in MD-2 Binding, PLoS Pathogens, 8(5):e1002667. A. Lakkaraju, L. Abrami, T. Lemmin, B. Kunz, S. Blaskovic, A. Kihara, M. Dal Peraro, F.G. van der Goot FG (2012) Palmitoylated calnexin is a key component of the ribosome-translocon complex, EMBO J, 7;31(7):1823-35. J. Sgrignani, A. Magistrato, M. Dal Peraro, et al. (2012) On the active site of mononuclear B1 metallo beta-lactamases: a computational study, J. Comp-Aided Mol. Des. 26(4): 425-435. 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.

IBI - Institute of Bioengineering

E. Khurana, R. Devane, M. Dal Peraro, M.L., Klein (2011) 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.

Assembly of the Transmembrane Domain of E. coli PhoQ Histidine Kinase. (A,B) Structural validation using disulfide cross-linking scanning of MD-derived conformation of TM1-TM2 tetramer (see structural model in D). In the inset the correlation between the cross-linking (1-efficiency) (in black) and the MD-averaged Cα distance measured for the TM model structure (in red) is reported. (C) The free energy landscape defined by sampling interhelical distances between TM1 C-termini and TM2 N-termini is reported. The conformational change observed in the unbiased MD simulations (orange points) occurs along a free energy valley, which connects a main equilibrium state (F0) and a high-energy conformation, which can be associated with relevant states during the signaling process (F1, ~5 kcal/mol higher in free energy). (D) PhoQ TM1-TM2 assembly equilibrated in an all-atom membrane bilayer. PLoS Comp. Biol., 9(1): e1002878.

EPFL School of Life Sciences - 2012 Annual Report

Deplancke Lab http://deplanckelab.epfl.ch/

Bart Deplancke received his M.Sc. in bio-engineering from Ghent University (Belgium), and his PhD from the University of Illinois (Urbana-Champaign, USA). After a postdoc at Harvard Medical School and then the University of Massachusetts Medical School, he moved to the EPFL at the end of 2007 as a tenure-track assistant professor where his group uses integrative and population genomics approaches to study the gene regulatory properties of the metazoan genome. He is currently also guest professor at Ghent University and co-founded the software company Genohm SA.

Bart Deplancke Tenure Track Assistant Professor

Introduction

The LSBG is developing and using high-throughput sequencing, microfluidics, large-scale yeast screening, and computational approaches to characterize the regulatory code in Drosophila and mammals and to examine how variations in this code affect molecular and organismal diversity.

Keywords

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

Results 2012

Genomic variation and its impact on gene expression in Drosophila melanogaster - One of the principal challenges in current biology is to understand the relationship between genetic and phenotypic variation. Despite its excellent track record as a premier model to understand genome function, no genome-wide variation data beyond single-nucleotide variants and microsatellites are currently available for D. melanogaster. Our lab therefore set out to generate a comprehensive, nucleotide-resolution catalogue of variants of various types (single-nucleotide, multi-nucleotide, and structural variants) using high-throughput sequencing for 39 wild-derived inbred D. melanogaster lines. For this purpose, we used our in-house developed algorithm, PrInSeS-G, which uses de novo local assembly to detect both SNP and non-SNP variants (1 bp-~10 kb) at single nucleotide resolution (Massouras et al., Nature Meth., 2010). We identified more than 2.8 million SNPs across all analyzed inbred fly lines. In addition, we detected 0.6 million indels (i.e. insertions or deletions), and 0.2 million complex variants, together accounting for more than half of the observed genomic variation (see Figure below). We used our variant data to provide novel insights into the regulatory architecture of gene expression variation in adult flies by mapping cis-expression quantitative trait loci (cis-eQTLs) for more than 2,000 genes. Interestingly, most associations are sexspecific, providing evidence for a decoupling of the genomic, regulatory architecture between males and females.

Absolute quantification of transcription factors during cellular differentiation using multiplexed targeted proteomics - The accurate and reproducible quantification of proteins within pathways or biological networks has been described as an essential requirement in life sciences or clinical research (Picotti and Aebersold, Nature Methods, 2012). For example, the biochemical and regulatory properties of transcription factors (TFs) which control gene expression within gene regulatory networks are largely dictated by their cellular (nuclear) abundance. Deriving absolute TF values is therefore of crucial importance to understand TF function. However, accurate TF copy number information has been notoriously difficult to acquire, owing to the low cellular concentration of many TFs. Consequently, only a handful of studies have so far provided estimates on the absolute in vivo abundance of animal TFs. Among the novel proteomic approaches enabling targeted, quantitative analyses, Selected Reaction Monitoring (SRM) has emerged as a powerful, analytical tool. Over the course of the last three years, our lab, together with the EPFL Proteomics Core Facility, has therefore invested significant efforts to develop a novel and sensitive SRM-based mass spectrometry assay, allowing the simultaneous measurement of copy numbers of up to 10 TFs. We applied this approach to profile the levels of key TFs in our model system of interest: adipogenesis. Specifically, we revealed that TF abundance differs dramatically (from 250 to >300,000 copies per nucleus), but that their dynamic range during fat cell differentiation varies at most five-fold. In collaboration with the Naef lab here at the EPFL, we also formulated a genome-wide TF DNA binding model to explain the significant increase in binding sites of the adipogenic master regulator PPARÎł during the final differentiation stage, despite a concurrent saturation in PPARÎł copy number. This model provides unique, quantitative insights into the relative contributions of binding energetics, copy number, and chromatin state in dictating TF DNA occupancy profiles.

EPFL School of Life Sciences - 2012 Annual Report

Selected Publications

Team Members

Raghav*, S.K., Waszak*, S.M., Krier, I., Isakova, A., Gubelmann, C., Mikkelsen, T.S., and Deplancke, B. (2012). Integrative genomics identifies SMRT as a gatekeeper of early adipogenesis through the transcription factors C/EBPβ and KAISO, Molecular Cell, 46:335-50. (*, first author)

PhD Students Carine Gubelmann Alina Isakova Irina Krier Andreas Massouras Rachana Pradhan Sebastian Waszak

Simicevic*, J., Schmid*, A.W., Gilardoni*, P., Zoller, B., Raghav, S.K., Krier, I., Gubelmann, C., Lisacek, F., Naef, F., Moniatte#, M., Deplancke#, B. Absolute copy number analysis of transcription factors during cellular differentiation using multiplexed targeted proteomics, Nature Methods, in press. (*, first author; #, corresponding author)

Deplancke#, B., Verstrepen#, K.J. (2012). Variable outcome of mutations. Science, 335:44-45. (#, corresponding author) LeMartelot*, G., Canella*, D., Symul*, L., Migliavacca*, E., Gilardi, F., Liechti, R., Martin, O., Harshman, K., Delorenzi, M., Desvergne, B., Herr, W., Deplancke, B., Schibler, U., Rougemont, J., Guex#, N., Hernandez#, N., Naef#, F., and the CycliX consortium. (2012) Genome-wide profiling of RNA polymerase II occupancy, associated histone marks, and mRNA accumulation reveal transcriptional and post-transcriptional mechanisms underlying circadian gene expression, PLoS Biology, 10:e1001442. (*, first author; #, corresponding author)

Postdoctoral Fellows Monica Albarca Paola Gilardoni Sunil Raghav Petra Schwalie

Scientific Assistants Jean-Daniel Feuz Wiebke Westphal Administrative assistant Marie-France Radigois

Schröter, C., Ares, S., Morelli, L.G., Isakova, A., Hens, K., Soroldoni, D., Gajewski, M., Jülicher, F., Maerkl, S.J., Deplancke, B., Oates, A.C. (2012). Topology and dynamics of the zebrafish segmentation clock core circuit, PLoS Biology, 10:e1001364. Hens, K., Feuz, J., Isakova, A., Iagovitina, A., Massouras, A., Bryois, J., Callaerts, P., Celniker, S.E., Deplancke, B. (2011). Automated protein-DNA interaction screening of Drosophila regulatory elements. Nature Methods, 8:1065-70. Perspective: Ozdemir, A., Stathopoulos, A. (2011). Exciting times: bountiful data to facilitate studies of cis-regulatory control. Nature Methods, 8:1016-17. Gubelmann, C., Gattiker, A., Massouras, A., Hens, K., Decouttere, F., Rougemont, J., Deplancke, B. (2011). GETPrime: a gene- or transcript-specific primer generator for qPCR. Database, bar040.

IBI - Institute of Bioengineering

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

Number of base pairs affected by variants discovered per fly inbred line, with lines ordered by depth of coverage (green dotted line). The line “Berkeley” is the reference line. SNPs are shown in black/grey, insertions in red, deletions in blue, and complex variants in orange. (From Massouras et al., 2012)

EPFL School of Life Sciences - 2012 Annual Report

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

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 Dean of the School of Life Sciences Merck-Serono Chair in Drug Delivery

Introduction

We design novel materials for applications in medicine such as drug delivery, regenerative medicine, vaccination and tolerogenic vaccination. We focus on examples where novel materials or biomolecules are necessary to solve the problem, thus working at the interface between molecular science and biology.

Keywords

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

Results Obtained in 2012

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 determined that display of growth factors, for example for inducting angiogenesis, proximal to adhesion promoting domains can induce synergistic signaling between the ligated growth factor receptor and the ligated adhesion receptor. We have used this concept to design second generation variants of a number of growth factors, for example for inducing angiogenesis, skin repair and bone repair, such that the variants display super-affinity for extracellular matrix molecules. We have shown that these engineered growth factors can induce more potent tissue repair and regeneration then their wildtype homologs. 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. Tolerogenic vaccination - In addition to effector immune responses, we are also keenly interested in protein engineering approaches to tolerize versus cellular immunity, harnessing the tolerogenic antigen presentation that occurs with antigen from apoptotic cells yet using simple engineered antigen forms that are clinically tractable. We 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. We are exploring this technology in inducing tolerance to protein drugs, for example in protein replacement therapies in rare diseases, and to autoimmune antigens, most notably type-1 diabetes antigens.

EPFL School of Life Sciences - 2012 Annual Report

Selected Publications

Martino, M.M., Briquez, P.S., Ranga, A., Lutolf, M.P. & Hubbell, J.A. Heparinbinding domain of fibrin(ogen) binds growth factors and promotes tissue repair when incorporated within a synthetic matrix. Proc. Natl. Acad. Sci. U. S. A. 110, 4563-4568 (2013). Garcia-Cordero, J.L., Nembrini, C., Stano, A., Hubbell, J.A. & Maerkl, S.J. A high-throughput nanoimmunoassay chip applied to large-scale vaccine adjuvant screening. Integrative biology : quantitative biosciences from nano to macro 5, 650-658 (2013). Vasdekis, A.E., Scott, E.A., O’Neil, C.P., Psaltis, D. & Hubbell, J.A. Precision intracellular delivery based on optofluidic polymersome rupture. ACS nano 6, 7850-7857 (2012). Swartz, M.A., Hirosue, S. & Hubbell, J.A. Engineering approaches to immunotherapy. Sci Transl Med 4, 148rv149 (2012). Stano, A., Nembrini, C., Swartz, M.A., Hubbell, J.A. & Simeoni, E. Nanoparticle size influences the magnitude and quality of mucosal immune responses after intranasal immunization. Vaccine 30, 7541-7546 (2012). Scott, E.A. et al. Dendritic cell activation and T cell priming with adjuvant- and antigen-loaded oxidation-sensitive polymersomes. Biomaterials 33, 6211-6219 (2012). Hubbell, J.A. & Chilkoti, A. Chemistry. Nanomaterials for drug delivery. Science 337, 303-305 (2012). 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). 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).

Team Members

Postdoctoral Fellows Amiguet-Vercher Sandra Brubaker Carrie De LaPorte Laura Dane Karen Engelhardt, Eva-Maria Kontos Stephane Kourtis Iraklis Larsson Mattias Lorentz Kristen Mahou Redouan Rice Jeffrey Sancho Oltra Nuria Scott Evan Alexander Tortelli Federico Wilson David Scott

PhD Students Ahmadloo Hamideh Briquez Priscilla Damo Martina De Titta Alexandre Eby Jackson Grimm Alizée Julier Ziad Panagiotou Vasiliki Raghunathan Sandeep Stano Armando Vardar Elif Master Students Djahanbakhsh Rafiee Sarah Liu Alexandra Sibylle Fallet Léa Maillat Hasani-Sadrabadi Mohammad Mahdi Bachelor Students Kayser Stephanie Leahu Teodor Marchand Cynthia Internships Marion Boursier, France David Allen Roberts, USA 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.

EPFL School of Life Sciences - 2012 Annual Report

Jensen Lab http://jensenlab.epfl.ch/

Jeff Jensen is a population geneticist, broadly interested in the study of adaptation in natural populations. He received a BS / BA from the University of Arizona in 2002 in Evolutionary Biology and Biological Anthropology, respectively, and was co-advised by Michael Nachman and Brian Charlesworth. Prof. Jensen earned his PhD in Molecular Biology & Genetics at Cornell University in 2006, co-advised by Charles Aquadro and Carlos Bustamante. He did his postdoc work as an NSF Bioinformatics Fellow at UCSD and UC Berkeley advised by Doris Bachtrog, Peter Andolfatto, and Rasmus Nielsen. He founded the Jensen Lab at the University of Massachusetts in 2009, and relocated the lab to EPFL in the Fall of 2011.

Jeffrey Jensen Tenure Track Assistant Professor

Introduction

The primary research theme of our group is centered around drawing statistical inference from DNA polymorphism data - specifically, describing the processes that determine the amount and distribution of genetic variation within and between natural populations, and between species. Under this over-arching theme, specific projects range from the development of Bayesian statistics for the estimation of demographic parameters, to Neanderthal genomics, to directly inferring the distribution of fitness effects of new mutations from experimental yeast data. Lab members work on both applied and theoretical problems in fields ranging from population genomics to medical genetics.

Keywords

Population genetics, molecular evolution, computational biology.

Results Obtained in 2012

In the molecular age, the relationship between gene sequence and selective effect has provided the fundamental link between genotype and phenotype with the notion of Darwinian fitness. Yet, despite great strides in molecular technologies, remarkably little is known about the genetic basis of phenotypic evolution, or of how selective pressures act to shape phenotypes. And thus questions fundamental to all of evolution biology remain largely unanswered: How many sites in the genome encode functions that are strongly maintained? Do most adaptive changes have a large effect on fitness, or is adaptation accomplished through many small steps? How many changes underlie adaptation to a novel selective pressure? And, indeed, what proportion of new, segregating, and fixed mutations are deleterious, neutral or beneficial? While lab members work on a variety of topics spanning population genetic theory, ecological genetics, and medical genomics, all united by the above questions - we highlight here three general themes of current focus.

Statistical inference in population genetics This line of research aims to identify adaptively important regions of the genome in an unbiased manner based on patterns of genetic variation - offering a genotype-first approach to identifying the action of positive selection. We design maximum likelihood and approximate Bayesian based methodology, with an interest towards both the identification of specific beneficial mutations as well as the estimation of the distribution of fitness effects - all with a particular focus on distinguishing selective from demographic forces. The evolution of cryptic coloration In collaboration with the Hoekstra Lab (Harvard University), we seek to investigate the evolutionary consequences of cryptic coloration in wild mouse populations. Pelage of the deer mouse, Peromyscus maniculatus, closely matches its substrate throughout its range, driven by natural selection for crypsis. This project takes advantage of a system in which the ecological context of phenotypic variation is well understood, and in which the genetic basis of the quantitative phenotype is largely controlled by a single gene of major effectâ&#x20AC;&#x201D;Agouti. This system represents an ideal scenario in which to address the long-standing debate regarding the means by which selection shapes natural populations following the advent of a novel selective pressure. Experimental dissection of fitness landscapes In collaboration with Dan Bolon (University of Massachusetts Medical School), we seek to systematically determine the fitness effects of all individual single-codon substitutions in yeast, utilizing a newly developed high throughput sequencing technology. Rather than drawing inference from fixed or polymorphic differences as in Peromyscus above, this project seeks to measure selection coefficients directly from new mutations. Specifically, we can for the first time empirically describe the relative proportions of deleterious, neutral, and beneficial mutations.

EPFL School of Life Sciences - 2012 Annual Report

Selected Publications

Shulha, H.P.*, J. Crisci*, D. Reshetov*, J.S. Tushir*, I. Cheung, R. Bharadwaj, H.J. Chou, I. Houston, C.J. Peter, A.C. Mitchell, W-D. Yah, R.H. Myers, J-f. Chen, T.M. Preuss, E. Rogaev#, J.D. Jensen#, Z. Weng#, and S. Akbarian#, 2012. Humanspecific histone methylation signatures at transcription start sites in prefrontal neurons. PLoS Biology 10(11): e1001427. * authors contributed equally, #corresponding authors Pavlidis, P., J.D. Jensen, W. Stephan, and A. Stamatakis, 2012. A critical assessment of story-telling: GO categories and the importance of validating genomic scans. Molecular Biology & Evolution 29(10): 3237-48. Domingues, V., Y.-P. Poh, B. Peterson, P. Pennings, J.D. Jensen, and H.E. Hoekstra, 2012. Evidence of adaptation from ancestral variation in young populations of beach mice. Evolution 66: 3209-23. Crisci, J., Y.-P. Poh, A. Bean, A. Simkin, and J.D. Jensen, 2012. Recent progress in polymorphism-based population genetic inference. Journal of Heredity 103: 287-96. Sinha, P., A. Dincer, D. Virgil, G. Xu, Y.-P. Poh, and J.D. Jensen, 2011. On detecting recent adaptive events using single genomes. Front. Gene. 2: 85-90. Crisci, J., A. Wong, J. Good, and J.D. Jensen, 2011. On characterizing adaptive events unique to modern humans. Genome Biology & Evolution 3: 791-8. Jensen, J.D. and D. Bachtrog, 2011. Characterizing the influence of effective population size on the rate of adaptation: Gillespie’s Darwin Domain. Genome Biology & Evolution 3: 687-701.

Team Members Senior Scientists Greg Ewing Anna Ferrer-Admetlla Matthieu Foll Postdoctoral Fellows Claudia Bank Lisha Mathew Yu-Ping Poh Cornelia Pokalyuk Nick Renzette Daniel Wegmann PhD Students Angela Bean Jessica Crisci Louise Ormond Alfred Simkin Master Student Hyunjin Shim Bioinformatician Shivani Mahajan Administrative Assistant Sophie Barret

IBI - Institute of Bioengineering

Hietpas, R.T., J.D. Jensen, and D.N.A. Bolon, 2011. Experimental dissection of a fitness landscape. Proc Natl Acad Sci USA 108: 7896-901.

The observed distribution of fitness effects of mutations observed directly from experimental studies in yeast (described in project III). For comparison, a cartoon of historically proposed population genetic models is given above. As shown – empirical observations give a remarkable fit to the Nearly-Neutral Theory of molecular evolution.

EPFL School of Life Sciences - 2012 Annual Report

Lutolf Lab http://lscb.epfl.ch/ 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). From 2005 to 2007 and supported by fellowships from the Swiss National Science Foundation and Leukemia and Lymphoma Society, Lutolf was a Postdoc in the laboratory of Helen Blau at Stanford University, where he studied microenvironmental (â&#x20AC;&#x2DC;nicheâ&#x20AC;&#x2122;) regulation of adult stem cells. In 2007, Lutolf received a European Young Investigator (EURYI) award to start up his independent research at EPFL. Lutolf is associate editor of the new RSC Journal Biomaterials Science and editorial board member of the NPC Journal Scientific Reports.

Matthias P. Lutolf Tenure Track Assistant Professor

Introduction

Adult stem cells rapidly lose their potential when grown outside of their natural microenvironment, or niche, posing a substantial hurdle for their efficient clinical use. By interfacing stem cell biology, biomolecular engineering and microtechnology, a major goal in the Lutolf lab is to elucidate how niche signals control the behavior of adult stem cells, in particular hematopoietic stem cells. We address this question by developing functional artificial niches as tools to probe the biochemical and biophysical stem cell-niche cross-talk at the single cell level and in high-throughput.

Keywords

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

Results Obtained in 2012

One pertinent question the lab has been addressing is the regulation of mouse hematopoietic stem cell (HSC) fate decision-making. Despite a remarkable extent of knowledge regarding HSC biology, the mechanisms governing the long-term maintenance of their function are poorly understood. Compelling evidence shows that the 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 key 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. 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 pos-

sible to probe the effect of key microenvironmental 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 several 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. 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. We identified 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. LT-HSC culture on artificial niches displaying the identified cell-cell interaction proteins show delayed cell cycle entry and maintenance of long-term blood reconstitution.

EPFL School of Life Sciences - 2012 Annual Report

Selected Publications

Roccio M, Schmitter D, Knobloch M, Okawa Y, Sage D, Lutolf MP*, Predicting stem cell fate changes by differential cell cycle progression patterns, Development, 140 (2): 459-70 (2012) Kobel S, Burri O, Griffa A., Girotra M, Seitz A, Lutolf MP*, Automated analysis of single cells in microfluidic traps, Lab on a Chip, 12 (16): 2843-9 (2012) Bichsel C, Gobaa S, Kobel S, Secondini C, Thalmann GN, Cecchini MG, Lutolf MP*, Diagnostic microchip to assay 3D colony-growth potential of captured circulating tumor cells, Lab on a Chip, 12 (13): 2313-6 (2012) Vannini N, Roch A, Griffa A, Naveiras O, Kobel S, Lutolf MP*, Identification of in vitro HSC fate regulators by differential lipid raft clustering, Cell Cycle, 11(8): 1535-43 (2012) Roccio M, Gobaa S, Lutolf MP*, High-throughput fate analysis of single neural stem cells in microarrayed artificial niches, Integrative Biology, 4 (4), 391-400 (2012) Pataky K, Braschler T, Negro A, Renaud P, Lutolf MP*, Brugger J*, Microdrop printing of soft matter into 3D tissue-like geometries, Advanced Materials, 24(3): 391-396 (2012) 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, 8 (11): 949-55 (2011)

Team Members Postdoctoral Fellows Steffen Cosson Nikolce Gjorevski Samy Gobaa Olaia Naveiras Adrian Ranga Nicola Vannini

PhD Students Simone Allazetta Nathalie Brandenberg Mukul Girotra Sylke Hoehnel Laura Kolb Andrea Negro Yuya Okawa Adrian Ranga Aline Roch Yoji Tabata Master Student Jo’an Bardy Technician Vasco Campos Administrative Assistant Maria Fernandes Coelho

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)

IBI - Institute of Bioengineering

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

Automated high-throughput screening of cell fate in near-physiological 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.

EPFL School of Life Sciences - 2012 Annual Report

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

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 promoted as Associate Professor at the EPFL School of Life Sciences in 2012 and is currently a member of the Institute of Bioengineering (IBI).

Felix Naef

Associate Professor

Introduction

Our lab is interested in quantitative, computational, and systems biology. We work on various problems including circadian biology, developmental patterning, gene expression networks, and stochastic transcription in single cells. To study these systems we combined theoretical, computational and experimental methods.

Keywords

Gene regulation, circadian transcription, chronobiology, circadian clock precision, fluctuations and bursting in gene expression.

Results Obtained in 2012

Circadian gene regulation in mouse liver. Interactions of cell-autonomous circadian oscillators with diurnal cycles govern the temporal compartmentalization of cell physiology in mammals. To understand the transcriptional and epigenetic basis of diurnal rhythms in mouse liver genomewide, we generated temporal DNA occupancy profiles by RNA polymerase II (Pol II), as well as profiles of the histone modifications H3K4me3 and H3K36me3. We used these data to quantify the relationships of phases and amplitudes between different marks. We found that rhythmic Pol II recruitment at promoters rather than rhythmic transition from paused to productive elongation underlies diurnal gene transcription, a conclusion further supported by modeling. Moreover, Pol II occupancy preceded mRNA accumulation by three hours, consistent with mRNA half-lives. Both methylation marks showed that the epigenetic landscape is highly dynamic and globally remodeled during the 24 hour cycle. While promoters of transcribed genes had trimethylated H3K4 even at their trough activity times, trimethylation levels reached their peak, on average, one

hour after Pol II. Meanwhile, rhythms in tri-methylation of H3K36 lagged transcription by three hours. Finally, modeling profiles of Pol II occupancy and mRNA accumulation identified three classes of genes: one showing rhythmicity both in transcriptional and mRNA accumulation, a second class with rhythmic transcription but flat mRNA levels, and a third with constant transcription but rhythmic mRNAs. The latter class emphasizes widespread temporally gated post-transcriptional regulation in the mouse liver. Stochastic transcription in single mammalian cells in response to endogenous stimuli. Mammalian genes are often transcribed discontinuously in the form of short bursts of RNA synthesis followed by longer silent periods. However, how these ‘on’ and ‘off’ transitions, together with the burst sizes, are modulated in single cells to increase gene expression upon stimulation is poorly characterized. By combining single cell time-lapse luminescence imaging with stochastic analysis of the time traces, we quantified the transcriptional responses of the endogenous connective tissue growth factor (ctgf) gene to different physiological stimuli, serum and TGF-b1. Both stimuli caused an acute increase in bursting. While TGF-b1 showed prolonged transcriptional activation, serum stimulation resulted in a large and temporally tight first burst of transcription, followed by a refractory period in the range of hours. Our study thus reveals how different physiological stimuli can trigger kinetically distinct transcriptional responses on the same gene promoter.

EPFL School of Life Sciences - 2012 Annual Report

Selected Publications

G. Le Martelot, D. Canella, L. Symul, E. Migliavacca, F. Gilardi, R. Liechti, O. Martin, K. Harshman, M. Delorenzi, B. Desvergne, W. Herr, B. Deplancke, U. Schibler, J. Rougemont, N. Guex, N. Hernandez, F. Naef, “Genome-Wide RNA Polymerase II Profiles and RNA Accumulation Reveal Kinetics of Transcription and Associated Epigenetic Changes During Diurnal Cycles”. PLoS Biol 10, e1001442 (2012). J. Morf, G. Rey, K. Schneider, M. Stratmann, J. Fujita, F. Naef, U. Schibler, “Coldinducible RNA-binding protein modulates circadian gene expression posttranscriptionally”, Science 338, 379 (2012). M. Stratmann, D. Suter, N. Molina, F. Naef, U. Schibler, “Circadian Dbp transcription relies on highly dynamic BMAL1-CLOCK interaction with E-boxes and requires the proteasome”, Molecular Cell, 48, 277 (2012). 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).

Team Members Postdoctoral Fellows Teresa Ferraro Nacho Molina Bhaswar Ghosh Jingkui Wang PhD Students Johannes Becker Jonathan Bieler Simon Blanchoud Rosamaria Cannavo Julia Cajan Jerome Mermet Damien Nicolas Jonathan Sobel Laura Symul Benjamin Zoller Administrative Assistant Sophie Barret

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).

IBI - Institute of Bioengineering

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).

Figure 1. Pol II, H3K4me3, and H3K36me3 genomic profiles of core circadian clock genes measured around the clock. A. The density profiles of Pol II (red), H3K4me3 (green), and H3K36me3 (blue) are indicated for the Bmal1 gene, with the thin lines above the profiles indicating the position-specific temporal maxima. The gene structure (RefSeq transcripts) is shown below the panel. The dashed lines starting with a circle and the arrows represent minima and maxima, respectively, of gene body Pol II occupancy (red), promoter H3K4me3 occupancy (green), and gene body H3K36me3 occupancy (blue), as estimated by cosine fits. Maximal in Pol II, H3K4me23, and H3K36me3 densities are reached at ZT21, ZT23, and ZT2. B. As in A, but for the RevErba(Nr1d1) gene. Maximal Pol II, H3K4me23, and H3K36me3 densities are reached at ZT6, ZT9, and ZT9.

EPFL School of Life Sciences - 2012 Annual Report

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

Melody Swartz is a Professor and Director of the Institute of Bioengineering (IBI), with a joint appointment in Cancer Research (ISREC). She trained at Johns Hopkins (BS) and M.I.T. (PhD) in Chemical Engineering, and Brigham & Women’s Hospital (postdoc). She spent four years as Asst. Professor at Northwestern Univ. before moving to the EPFL in 2003. Her research focuses on the lymphatic system, integrating several fields to elucidate the functional regulation and immunobiology of lymphatic vessels. In 2012, she was named a MacArthur Fellow.

Melody A. Swartz Full Professor Director of IBI

Introduction

The lymphatic system is an important regulator of tissue homeostasis including fluid and solute balance, inflammation, and immunity. 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. Thus, we aim to build a more comprehensive understanding of how various aspects of lymphatic function are coupled, as well as to develop novel therapeutic strategies to target lymphatic vessels for immunomodulation, e.g., in vaccine design and cancer immunotherapy.

Keywords

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

Results Obtained in 2012

In 2012, we demonstrated an essential role of peripheral lymphatics in eliciting the timing and the quality of the immune response (Thomas et al, J. Immunol). Specifically, we found that humoral (antibody) responses, but not cellular immune responses, critically depends on dermal lymphatic drainage, and furthermore that adaptive tolerance following challenge could not be induced without lymphatics. We suggest that lymphatic drainage of fluid and antigens is critical to B cell immunity and maintenance of peripheral tolerance. We also discovered a new mechanism by which lymphatic endothelial cells (LECs) themselves can promote immunological tolerance, specifically in the context of cancer (Lund et al, Cell Rep.). In collaboration with Stephanie Hugues’ lab at the University of Geneva, we demonstrated that tumor-associated LECs can scavenge tumor antigens and cross-present them to T cells for subsequent deletional

tolerance. In this way, lymphatic vessels may limit the efficacy of immunotherapy aimed to activate host immunity against the tumor. These studies, among other recent reports, are helping to define the immunomodulatory roles of lymphatic vessels as well as the immunological functions of inflammationassociated lymphangiogenesis. Of course, these results bring interesting 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 as compared with non-draining lymph nodes, presumably by replacing the tumor-primed, tolerogenic milieu of the 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. Also in 2012, we continued to bring new fundamental understanding of how the lymphatic microenvironment affects interstitial function by virtue of driving interstitial flow. We explored how dendritic cells (DCs) interpret different types of cues in such a biomechanically complex environment, and demonstrated the importance of flow-mediated signals on lymphatic function; namely, its active transport mechanisms for water, solutes, proteins, and nanoparticles. We also furthered our understanding of autologous chemotaxis, a concept that our laboratory has put forth, in a model of glioma with CXCL12/CXCR4 signaling (Munson et al, Cancer Res.).

EPFL School of Life Sciences - 2012 Annual Report

Selected Publications

JM Munson, R.V. Bellamkonda, and M.A. Swartz (in press). Interstitial flow in a 3D microenvironment increases glioma invasion by a CXCR4-dependent mechanism. Cancer Res. (epub ahead of print). MA Swartz, S Hirosue, JA Hubbell (2012). Engineering approaches to immunotherapy. Sci. Transl. Med. 4:148rv9. SN Thomas, JM Rutkowski, M Pasquier, EL Kuan, K Alitalo, GJ Randolph, and MA Swartz (2012). Weak humoral immunity and acquired autoimmunity in mice with impaired dermal lymphatic drainage. J. Immunol. 189(5):2181-90. AW Lund, F.V. Duraes, S. Hirosue, S.N. Thomas, C. Nembrini, S. Hugues, and M.A. Swartz (2012). Tumor VEGF-C promotes immune tolerance and tumor antigen cross-presentation by lymphatics. Cell Reports 1(3): 191 - 199. Comment: Cancer Res. 72:1589-90, 2012; named “Best of Cell Reports 2012”. MA Swartz and AW Lund (2012). Lymphatic and interstitial flow in the tumor microenvironment: Linking tumor mechanobiology with lymph node immunity. Nature Rev. Cancer 12:210-219. 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. 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.

Team Members Postdoctoral Fellows Dan Bonner Francesca Capotosti Catherine Card Witold Kilarski Amanda Lund Alexandra Magold Jennifer Munson Scott Ryan Oliver Edward Phelps

PhD Students Marie Ballester Alexandre de Titta Manuel Fankhauser Esra Güç Laura Jeanbart Iraklis Kourtis Marco Pisano Sandeep Raghunathan Marcela Rincon-Restrepo Valentina Triacca Ingrid van Mier Efthymia Vokali Master’s Students Sabrina Riedl (Erasmus) Lambert Potin Iro Oikonomidi Research Associate Sachiko Hirosue Technicians Véronique Borel Patricia Corthésy Henrioud Pasquier Miriella Interns/Trainees Luis Alonso Natacha Bordry Kathryn Hockemeyer Renata Mezyk-Kopecm PhD Le Thanh Tu Nguyen Amy Sessions Katherine Tschudi

IBI - Institute of Bioengineering

Administrative Assistant Ingrid Margot

In vitro 3D lymphangiogenesis assay showing lymphatic endothelial cells sprouting from dextran beads embedded within a fibrin gel (Image by Esra Guç).

EPFL School of Life Sciences - 2012 Annual Report

Wurm Lab http://lbtc.epfl.ch/

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, he 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 he was appointed Visiting Professor at Jinan University in Guangzhou, China in 2008. He has published over 200 scientific papers and holds several 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 (r-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 r-proteins. The major goal of the LBTC is the development of novel and/or improved tools for gene transfer to cultured mammalian cells and subsequent high-level expression of r-proteins from such cells in new and scalable production systems (bioreactors).

Keywords

Recombinant protein expression, mammalian cell culture, orbital shaking bioreactor, bioprocess control, gene transfer, DNA integration, stable cell line development, HEK293, CHO, insect cell culture.

Results Obtained in 2012

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. The main results obtained in 2012 are summarized below. Transient gene expression and stable transgene integration. The transient transfection approach allows the expression of a fully glycosylated r-protein at high titres (up to 1 g/L for IgGs) only 1-2 weeks after gene cloning. Through a detailed analysis of the cellular uptake and disassembly of PEI-DNA complexes we were able to increase r-protein productivity from transiently transfected cells by maximizing the relative amount of plasmid DNA delivered at transfection. This knowledge allowed us to develop an optimized transfection protocol that sensibly reduces the overall production costs for r-proteins by transient expression. In collaboration with Prof. H.A. Klok, we evaluated a promising new polylysine-based polymer for gene delivery

in animal cells. In collaboration with Prof. Y. Tsybin, we characterized recombinant antibodies produced by transient gene expression and compared the glycosylation patterns with the same protein produced in stable cell lines. Stable integration of recombinant genes into the genome of a host cell was studied in the widely-used cell line Chinese hamster ovary (CHO). We investigated the cytogenetics of CHO-derived stable cell lines generated using different DNA delivery techniques, including transposonand lentivirus-mediated gene integration. Understanding transgene integration will allow us to develop strategies to prevent the widely-observed phenomenon of gene silencing, which lowers productivity in stable cell lines over time. We demonstrated that transposon-mediated DNA delivery is a very efficient method to obtain high-producing CHO cell lines, superior to cell lines generated by standard transfection. More recently, we extended our research to insect cell-based expression systems, and we are developing nonviral, scalable gene delivery methods for these hosts. The orbitally shaken bioreactor (OSR) technology for mammalian cell cultivation, designed in our lab has been scaledup to 1000 L. The fluid dynamics in orbitally shaken cylindrical vessels (with nominal volumes from 50 mL to 250 L) were studied in collaboration with Prof. A. Quarteroni (Chair of Modelling and Scientific Computing) and Dr. M. Farhat of the Hydraulic Machines Laboratory. A fluid dynamics model of the OSRs could be determined and tested. Further characterization of the OSR system and confirmation of the numerical simulation is ongoing. Overall, our research provided useful insights for understanding cell cultivation in suspension, gene integration and protein expression. These studies are of interest both in basic cellular biology and for their application in pharmaceutical biotechnology for the production of recombinant therapeutic proteins. Several products (tools and bioreactor systems) are on the market since a number of years that have been inspired, invented and generated by and with contributions of LBTC scientists.

EPFL School of Life Sciences - 2012 Annual Report

Selected Publications

Michel PO, Degen C, Hubert M, Baldi L, Hacker DL, Wurm FM. (2012) A NanoDrop-based method for rapid determination of viability decline in suspension cultures of animal cells. Anal Biochem 430(2):138–40. Kadlecova Z, Baldi L, Hacker D, Wurm FM, Klok H-A. (2012) Comparative study on the in vitro cytotoxicity of linear, dendritic, and hyperbranched polylysine analogues. Biomacromolecules 13(10):3127–37. Rajendra Y, Kiseljak D, Manoli S, Baldi L, Hacker DL, Wurm FM. (2012) Role of non-specific DNA in reducing coding DNA requirement for transient gene expression with CHO and HEK-293E cells. Biotechnol Bioeng 109(9):2271–8. Zagari F, Jordan M, Stettler M, Broly H, Wurm FM. (2012) Lactate metabolism shift in CHO cell culture: the role of mitochondrial oxidative activity. N Biotechnol 30(2):238-45. Kadlecova Z, Nallet S, Hacker DL, Baldi L, Klok H-A, Wurm FM. (2012) Poly(ethyleneimine)-Mediated Large-Scale Transient Gene Expression: Influence of Molecular Weight, Polydispersity and N-Propionyl Groups. Macromol Biosci 12(5):628–36. Rajendra Y, Kiseljak D, Baldi L, Hacker DL, Wurm FM. (2012) Reduced glutamine concentration improves protein production in growth-arrested CHODG44 and HEK-293E cells. Biotechnol Lett 34(4):619–26.

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 Francesca Zagari Master Students Archita Chaudhary Fabrizio De Angelis Saroj Ghimire Bachelor/Project students Christophe Degen Ana Pitol Garcia Anne Catherine Portman Laboratory Support Veronika Knapkova

Tissot S, Michel PO, Hacker DL, Baldi L, De Jesus M, Wurm FM. (2012) k(L)a as a predictor for successful probe-independent mammalian cell bioprocesses in orbitally shaken bioreactors. N Biotechnol 29(3):387–94.

Trainees Mélanie Hubert Mélissa Vona

Discacciati M, Hacker D, Quarteroni A, Quinodoz S, Tissot S, Wurm FM. (2012) Numerical simulation of orbitally shaken viscous fluids with free surface. Int J Numer Meth Fluids 71(3): 294-315.

Technical Assistants Virginie Bachmann Ione Gutscher

IBI - Institute of Bioengineering

Administrative Assistant Fabienne Rudin

We studied the structure-activity relationship for various lots of linear poly(ethyleneimine) (PEI), a commonly used transfection reagent for the production of r-proteins by transient gene expression. PEI’s polydispersity and N-propionyl side groups contribute to its high transfection efficiency.

Co-affiliated Research Groups EPFL School of Life Sciences - 2012 Annual Report

Aminian Lab

- coaffiliated

http://lmam.epfl.ch/ Kamiar Aminian received his PhD degree in biomedical engineering in 1989 from Ecole Polytechnique Fédérale de Lausanne (EPFL). He is currently Professor of medical instrumentation and the director of the Laboratory of Movement Analysis and Measurement of EPFL. His research interests include methodologies for human movement monitoring and analysis in real world conditions mainly based on wearable technologies and inertial sensors with emphasis on gait, physical activity and sport. He is currently the president of the 3D Analysis of Human Movement group on the International Society of Biomechanics. He is author of more than 350 scientific publications and holds more than 8 patents related to medical devices.

Kamiar Aminian

Adjunct Professor School of Engineering (STI)

Research Interests

The Laboratory of Movement Analysis and Measurement investigates human movement, physical activity and locomotion associated with 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. In 2012, we performed gait analysis in more than 1800 subjects (elderly, Parkinson’s disease, cerebral palsy) with our foot worn system and defined a new concept of “foot signature” to classify diseases based on foot trajectories. We quantified the effect of soft tissue artifact on the actual 3D kinematics of the knee and to avoid this artefact we proposed a smart knee implant with internal kinematics sensors and evaluated its performance with a customised actuated knee simulator. We designed an inertial sensor based wearable system to quantify daily upper limbs mobility in patients with the cervical and shoulder disease. In sport, we proposed instrumented suits to estimate and validate kinematics, kinetics and coordination in ski jump and swimming which allowed further evaluations with Swiss Ski team and Lausanne Swimming Club. Our group participated also in measurements during the world alpine ski championship to evaluate the risk of injury by movement quantification. Finally, the patterns of physical activity were investigated in patients with pain and a new approach based on barcoding of physical activity was proposed to show the decrease of complexity of mobility pattern with pain. Based on the same approach we started to study the change of complexity in lifestyle activity of stroke patients and elderly subjects with fall risk.

Keywords

Human movement, biomechanics, sport performance, rehabilitation, clinimetry, wearable systems, daily activity, gait analysis, data mining, pain treatment, fall prevention, Parkinson disease, orthopaedics, stroke.

Selected Publications

Paraschiv-Ionescu A., Perruchoud C., Buchser E., Aminian K., (2012) Barcoding Human Physical Activity to Assess Chronic Pain Conditions, PLoS ONE 7(2), e32239. doi:10.1371/journal.pone.0032239.

Bagalà F., Becker C., Cappello A., Chiari L., Aminian K., Hausdorff JM., Zijlstra W., Klenk J., (2012) Evaluation of Accelerometer-Based Fall Detection Algorithms on Real-World Falls, PLoS ONE 7(5), e37062. doi:10.1371/journal. pone.0037062. Ganea, R., Paraschiv-Ionescu, A., Aminian, K. (2012) Detection and Classification of Postural Transitions in Real-World Conditions, IEEE Transactions on Neural Systems and Rehabilitation Engineering, 20(5), 688-696. Arami, A., Miehlbradt, J., Aminian, K. (2012) Accurate Internal-External Rotation Measurement in Total Knee Prosthesis: a magnetic solution, Journal of Biomechanics, 45(11), 2023-2027. Dadashi, F., Crettenand, F., Millet, G., Aminian, K. (2012) Front-crawl Instantaneous Velocity Estimation Using a Wearable Inertial Measurement Unit, Sensors, 12, 12927-12939. Chardonnens, J., Le Callennec, B., Favre, J., Cuendet, F., Gremion, G., and Aminian, K. (2012) Automatic measurement of key ski jumping phases and temporal events with a wearable system, Journal of Sports Sciences, 30(1), 53-61.

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 Administrative assistant Danielle Alvarez

EPFL School of Life Sciences - 2012 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 Ernest Fantner Tenure Track Assistant Professor School of Engineering (STI)

Research Interests

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

Erickson, B. W., Coquoz, S., Adams, J. D., Burns, D. J., & Fantner, G. E. (2012). Large-scale analysis of high-speed atomic force microscopy data sets using adaptive image processing. Beilstein journal of nanotechnology, 3, 747–58. doi:10.3762/bjnano.3.84. Huth, M., Porrati, F., Schwalb, C., Winhold, M., Sachser, R., Dukic, M., Adams, J., et al. (2012). Focused electron beam induced deposition: A perspective. Beilstein journal of nanotechnology, 3, 597–619. doi:10.3762/bjnano.3.70. Leitner, M., Fantner, G. E., Fantner, E. J., Ivanova, K., Ivanov, T., Rangelow, I., Ebner, A., et al. (2012). Increased imaging speed and force sensitivity for bio-applications with small cantilevers using a conventional AFM setup. Micron (Oxford, England : 1993), 43(12), 1399–407. doi:10.1016/j.micron.2012.05.007. Burns, D., Fantner, G. E., & Youcef-Toumi, K. (2012). Automatic lateral resonance identification from cantilever deflection information in high speed atomic force microscopy. ACC, 3240–3246. Retrieved from http://ieeexplore.ieee. org/xpls/abs_all.jsp?arnumber=6315085. 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. 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.

High speed atomic force microscopy, lipid membranes, MEMS, NEMS, Superresolution microscopy/AFM, microfluidics, bone, single molecule force spectroscopy, antimicrobial peptides, live cell imaging.

IBI - Co-affiliated Research Groups

Keywords

Team Members Postdoctoral Fellows Jonathan Adams Blake Erickson

PhD Students Farnaz Behroozi Maja Dukic Nahid Hosseini Adrian Pascal Nievergelt Pascal Damian Odermatt Oliver Peric Administrative Assistant Ruth Fiaux

EPFL School of Life Sciences - 2012 Annual Report

Guiducci Lab

- coaffiliated

http://clse.epfl.ch/ 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) since 2007. In 2006 she presented with Infineon Technologies the first CMOS chip for label-free electrical detection of DNA. In 2009, she joined the Institute of Bioengineering at EPFL as a Tenure-Track Assistant Professor. She is also affiliated to the EPFL Institute of Electrical Engineering. She is Associate Editor of the ACM JETC and reviewer of the main journals in the biosensor/ biochip field. She has 500 citations of her scientific work.

Carlotta Guiducci

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

Research Interests

The Laboratory of Life Sciences Electronics (CLSE) is committed to provide new fabrication solutions for heterogeneous integration and new sensing technologies to for the life science domain. At present, successful integration and miniaturization of e-biochips are hindered by the several issues, namely, the lack of cost-effective solutions for biochip-on chip stacking, the limited compatibility of standard microelectronic processes with chemical surface treatments and the lack of universal robust molecular probes to be coupled yet functional on solid-state surface. The group of Prof. Guiducci recently provided an innovative solution for the 3D integration of a disposable sensing microchip on a CMOS stack and developed a set of processes for the protection of the underlying electronics and for the improved robustness of the exposed biochip features. The research activity is also dedicated to the development and characterization of electronic micro and nanotransducers for label-free chemical and biological sensing such as hybrid field effect devices (electrochemical silicon and gold nanowires) and 3D microelectrodes for particles detection and characterization by electrical techniques (impedance sensing and electrorotation for application in the study of cell-protein interaction and cell characterization). Prof Guiducci is coordinator of the ISyPeM Nano-tera.ch project on therapeutic drug monitoring for personalized medicine. In this framework, the group develops aptamerbased label-free sensing approaches for the detection of small drug molecules such as efavirenz and imatinib.

Keywords

Drug monitoring, lab-on-a-chip, e-biochips, vertical silicon surfaces, nanosensors, microarrays, SPR micrfabrication, heterogeneous integration, aptamers, electrochemical impedance spectroscopy, nanowires.

Selected Publications

Temiz, Y., Ferretti, A., Leblebici, Y., Guiducci, C. (2012). A Comparative Study on Fabrication Techniques for On-Chip Micro- electrodes. Lab Chip. (12): 4920–4928.

Cagnin, S., Cimetta, E., Guiducci, C., Martini, P., Lanfranchi, G. (2012). Directly detect biological effects: overview on micro- and nano-technology tools for stem cells applications. Sensors 12(11): 15947-15982. Temiz, Y., Guiducci, C., Leblebici, Y. (2013). Post-CMOS Processing and 3D Integration Based on Dry-Film Lithography. Proc. IEEE Compon., Pack. and Manufact. Techno. (99): 1. Balasubramaniany, V., Ruediy, P.-F., Temiz, Y., Ferretti, A., Guiducci, C., Enz, C. (2013). A 0.18μm Biosensor Frontend based on 1/f Noise, Distortion Cancelation and Chopper Stabilization Techniques. Proc. IEEE Biomed. Circuits and Syst. (99): 1-14. Cappi, G., Accastelli, E., Cantale, V., Rampi, M. A., Benini, L., Guiducci, C. (2013). Peak Shift Measurement of Localized Surface Plasmon Resonance by a Portable Electronic System. Sensors and Actuators B: Chem. 176: 225-231. Bianchi, E., Rollo, E., Kilchenmann, S., Bellati, F. M., Accastelli, E., Guiducci, C. (2012). Detecting Particles Flowing through Interdigitated 3D Microelectrodes. Proc. IEEE EMBC: 5002-5005. Temiz, Y., Zervas, M., Guiducci, C., Leblebici, Y. (2011). Die-level TSV fabrication platform for CMOS-MEMS integration. Proc. Solid-State Sensors, Actuators and Microsyst. Conf. (TRANSDUCERS): 1799-1802. Temiz, Y., Kilchenmann, S., Leblebici, Y., Guiducci, C. (2011). 3D integration technology for lab-on-a-chip applications. Electr. Letters. 47(26): S22-S24.

Team Members Postdoctoral Fellows Elena Bianchi Fabio Spiga

PhD Students Enrico Accastelli Giulia Cappi Anna Ferretti Samuel Kilchenmann Enrica Rollo Interships Sarah Rafiee Djahanbakhsh Master’s Students Ketki Chawla Tania Palmieri Nadia Sarait Vertti Quintero Administrative Assistant Homeira Salimi

EPFL School of Life Sciences - 2012 Annual Report

Hatzimanikatis Lab

- coaffiliated

http://lcsb.epfl.ch/

Associate Professor School of Basic Sciences (SB)

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. We develop 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. Our research 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.

Keywords

Systems biotechnology, metabolic engineering, metabolism, proteomics, lipidomics.

Selected Publications

Racle J, Overney J and Hatzimanikatis V. (2012) A computational framework for the design of optimal protein synthesis. Biotechnol Bioeng. 109(8): 2127-2133. Soh KC, Miskovic L and Hatzimanikatis V. (2012) From network models to network responses: integration of thermodynamic and kinetic properties of yeast genome-scale metabolic networks. FEMS Yeast Res. 12(2):129-143. Brunk E, Neri M, Tavernelli I, Hatzimanikatis V and Rothlisberger U. (2012) Integrating computational methods to retrofit enzymes to synthetic pathways. Biotechnol Bioeng, 109(2): 572-582. Miskovic L and Hatzimanikatis V. (2011) Modeling of uncertainties in biochemical reactions. Biotechnol Bioeng. 108(2): 413-423. Singh A, Soh KC, Hatzimanikatis V and Gill RT. (2011) Manipulating redox and ATP balancing for improved production of succinate in E. coli. Metabol Eng. 13(1): 76-81.

Team members Postdoctoral Fellows Anirikh Chakrabarti Alexandros Kiparissides Georgios Savoglidis Marianne Seijo Katerina Zisaki PhD Students Stefano Andreozzi Meric Ataman 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. Dr. Hatzimanikatis has received many awards including: 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 Administrative Assistant Christine Kupper

EPFL School of Life Sciences - 2012 Annual Report

Ijspeert Lab

- coaffiliated

http://biorob.epfl.ch/ 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 gain 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.

Keywords

Robotics, computational neuroscience, control of locomotion, central pattern generators, nonlinear dynamical systems, exoskeletons.

Selected Publications

A. J. Ijspeert, J. Nakanishi, H. Hoffmann, P. Pastor and S. Schaal. Dynamical Movement Primitives: Learning Attractor Models for Motor Behaviors, in Neural Computation, vol. 25, num. 2, p. 328-373, 2013. Crespi, A.; Karakasiliotis, K.; Guignard, A.; Ijspeert, A. J., “Salamandra Robotica II: An Amphibious Robot to Study Salamander-Like Swimming and Walking Gaits,” IEEE Transactions on Robotics, vol. 29 (2), p. 308 – 320, 2013. 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. 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. Ijspeert A.J., Central pattern generators for locomotion control in animals and robots: a review. Neural Networks, 21(4):642-653, 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.

Team Members

Postdoctoral Fellows Crespi Alessandro Gams Andrej Guyot Luc Karakasiliotis Konstantinos Möckel Rico Morel Yannick PhD Studnets Ajallooeian Mostafa Bicanski Andrej Bonardi Stéphane Gay Sébastien Knüsel Jérémie Pouya Soha Thiandackal Robin Tuleu Alexandre van den Kieboom Jesse Vespignani Massimo Administrative Assistant Fiaux Sylvie

EPFL School of Life Sciences - 2012 Annual Report

Johnsson Lab

- coaffiliated

http://lip.epfl.ch/

Kai Johnsson

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

C. Trefzer, H. S’kovierova, S. Buroni, A. Bobovska, S. Nenci, E. Molteni, F. Pojer, M. R. Pasca, V. Makarov, S. T. Cole, G. Riccardi, K. Mikusova, K. Johnsson, Benzothiazinones are suicide inhibitors of mycobacterial decaprenylphosphoryl-ß-D-ribofuranose 2’-oxidase (DprE1)” in J Am Chem Soc. (2012), vol. 134, pp. 912-915. A. Masharina, L. Reymond, D. Maure, K. Umezawa, K. Johnsson, A Fluorescent Sensor for GABA and Synthetic GABA(B) Receptor Ligands. J Am Chem Soc 134, 19026 (Nov 21, 2012). M. A. Brun, K. T. Tan, R. Griss, A. Kielkowska, L. Reymond, K. Johnsson, A Semisynthetic Fluorescent Sensor Protein for Glutamate. J Am Chem Soc 134, 7676 (May 9, 2012). C. Chidley, H. Haruki, M. G. Pedersen, E. Muller, K. Johnsson, A yeast-based screen reveals that sulfasalazine inhibits tetrahydrobiopterin biosynthesis. Nature Chem Biol 7, 375 (Jun, 2011). M. A. Brun, R. Griss, L. Reymond, K. T. Tan, J. Piguet, R. J. R. W. Peters, H. Vogel, K. Johnsson, Semisynthesis of Fluorescent Metabolite Sensors on Cell Surfaces. J Am Chem Soc 133, 16235 (Oct 12, 2011).

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.

Keywords

Chemical biology, fluorescent protein sensors, drug target deconvolution, protein chemistry, protein engineering.

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

EPFL School of Life Sciences - 2012 Annual Report

Jolles-Haeberli Lab

- coaffiliated

http://cbt.epfl.ch/

Brigitte Jolles-Haeberli

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

Brigitte Haeberli-Jolles graduated from the EPFL with a MSc Diploma of Professional Engineer in Microtechnology in 1990. In 1995 she obtained her MD, Swiss Federal Diploma of Medicine and her Doctoral thesis in Medicine with honors (UNIL). She then received the Diploma in Clinical Epidemiology in 2002 and successfully completed a Clinical Fellowship in Arthritis Surgery at the University of Toronto. She obtained also the FMH and Swiss Federal Diploma of Specialist in Orthopaedic Surgery and Traumatology. She was nominated Master of Teaching and Research (MER) in 2003 and in 2005, Assistant Professor (PD) at UNIL. In 2008 she was nominated Adjunct Professor (EPFL) where she heads the Interinstitutional Center of Translational Biomechanics (CBT). Dr. Jolles-Haeberli was nominated Associate Professor (UNIL) in 2010 where she is the Team leader for Knee Arthroplasty Surgery (CHUV-UNIL).

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. The center also carries 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.

Keywords

Selected Publications

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. Jolles BM, Bogoch ER. Juvenile arthritis patients report favorable subjective outcomes of hip arthroplasty despite poor standard outcome scores. J Arthroplasty. 2012 Oct;27(9):1622-8. doi: 10.1016/j.arth.2012.02.024. Pichonnaz C, Bassin JP, Currat D, Martin E, Jolles BM. Bioimpedance for Oedema Evaluation after Total Knee Arthroplasty. Physiother Res Int. 2012 Nov 27. doi: 10.1002/pri.1540 Roshan-Ghias A, Terrier A, Jolles BM, Pioletti DP. Translation of biomechanical concepts in bone tissue engineering: from animal study to revision knee arthroplasty. Comput Methods Biomech Biomed Engin. 2012 Sep 17. Rouhani H, Favre J, Crevoisier X, Jolles BM, Aminian K. A comparison between joint coordinate system and attitude vector for multi-segment foot kinematics. J Biomech. 2012 Jul 26;45(11):2041-5. doi: 10.1016/j.jbiomech.2012.05.018. Jolles BM, Grzesiak A, Eudier A, Dejnabadi H, Voracek C, Pichonnaz C, Aminian K, Martin E. A randomised controlled clinical trial and gait analysis of fixedand mobile-bearing total knee replacements with a five-year follow-up. J Bone Joint Surg Br. 2012 May; 94(5):648-55. doi: 10.1302/0301-620X.94B5.27598.

Center Groups

Orthopaedic engineering, translational research, numerical modelling, biomechanical analysis, surgery outcome evaluation, sport performance evaluation, regenerative therapy.

Aminia Lab (LMAM) p. 72 Pioletti Lab (LBO) p. 84

Administrative Assistant Sabrina Martone

EPFL School of Life Sciences - 2012 Annual Report

Lacour Lab

- coaffiliated

http://lsbi.epfl.ch/ Stéphanie P. Lacour (PI) is the Bertarelli Foundation Chair in Neuroprosthetic Technology at the School of Engineering at the Ecole Polytechnique Fédérale de Lausanne. 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. Her research focuses on the materials, technology and integration of soft bioelectronic interfaces including artificial skin, ultra-compliant neural electrodes for in vitro platforms as well as in vivo implants.

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 in order to provide improved biocompatibility and enhanced functionality of these hybrid interfaces. Tactile sensory skin - In 2012, we have optimized the design of a skin-like substrate, which can host microfabricated tactile sensor circuits. The engineered substrates can stretch and relax reversibly like human skin yet provide “safe” mechanical platforms for the most fragile electronic devices. The substrate is made of elastomers and photosensitive plastics. We have also developed the technology to produce ultra-compliant pressure microsensors made of elastomeric microcellular polymers and thin film metallization. The sensors have unique conformability and can be tuned to detect the lightest touch but also full weight body load. Polymeric neural interfaces - In vitro, we are testing the hypothesis that the behavior of cells may be altered by modulating the local mechanical microenvironment at the surface of an implant. In vivo, we are developing a range of neural electrodes embedded in soft polymers. We have produced first prototypes of flexible auditory brainstem implants, stretchable spinal cord electrode implants and nerve-like regenerative electrode implants. Acute and chronic evaluation of the neural interfaces is on-going.

Keywords

Microelectrode arrays, neural interfaces, stretchability, sensory neurons, neuroprosthesis, tactile sensors, polymers, thin films, biocompatibility, thin film electronics, micro/ nanofabrication.

Selected Publications

Granger N, Chew D, Fairhurst P, Fawcett JW, Lacour SP, Craggs M, Mosse CA, Donaldson N, Jeffery ND (2013). Use of an implanted sacral nerve stimulator to restore urine voiding in chronic paraplegic dogs. Journal of Veterinary Internal Medicine, 27:99-105. Delivopoulos E, Chew D, Minev IR, Fawcett JW, Lacour SP (2012). Concurrent recordings of bladder afferents from multiple nerves using a microfabricated PDMS microchannel electrode array. Lab on Chip. 12:2540-2551. Huang YY, Terentjev E, Oppenheim T, Lacour SP, Welland ME (2012). Fabrication and electromechanical characterization of near-field electrospun composite fibers. Nanotechnology. 23:105305. Liu Q, Ford KL, Langley RL, Robinson A, Lacour SP (2012). Elastic dipole antenna prepared with thin metal films on elastomeric substrate. Electronics Letters. 48:65-66. 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.

Team Members

IBI - Co-affiliated Research Groups

Research Interests

Postdoctoral Fellows Ivan Minev Kate Musick Hugues Vandeparre PhD Students Anna Cyganowski Amelie Guex Cedric Paulou Alessia Romeo Douglas Watson Master’s Student Amélie Guex

Visiting PhD Student Maria-Teresa Francomano Administrative Assistant Carole Weissenberger

EPFL School of Life Sciences - 2012 Annual Report

Maerkl Lab

- coaffiliated

microfluidics.epfl.ch/

Sebastian Maerkl

Tenure Track Assistant Professor School of Engineering (STI)

Sebastian Maerkl received a B.S. degree in Biology and a second B.S. degree in Chemistry from Fairleigh-Dickinson University. He then joined the Biophysics and Biochemistry Option at Caltech as a graduate student and contributed to the early development of microfluidic technology. For his PhD thesis, Prof. Maerkl was awarded the Demetriades-Tasfka-Kokalis prize for the best Caltech PhD thesis in the field of Biotechnology in 2008. He was awarded the 1st place at the Innovator’s Challenge, a competition amongst Stanford, UC Berkeley, and Caltech. Since 2008 Prof. Maerkl holds a position as an Assistant Professor at the EPFL in the Institute of Bioengineering and the School of Engineering and in 2012 received the EPFL Prix SSV-Ambition.

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. Here the lab recently developed a microfluidic platform capable of obtaining 768 parallel kinetic rate measurements of biological interactions. We are using synthetic biology approaches to synthesize and measure large promoter libraries, and we are interested in generating genetic networks in vitro. In diagnostics we have been developing microfluidic platforms able to measure biomarkers in hundreds to thousands of samples, reducing assay costs and increasing throughput by orders of magnitude compared to current state-of-the-art approaches.

Keywords

Microfluidics, systems biology, synthetic biology, diagnostics.

Selected Publications

Niederholtmeyer H. and Maerkl S.J. (2012). Real-time mRNA measurement during an in vitro transcription and translation reaction using binary probes. ACS Synthetic Biology, doi:10.1021/sb300104f. Rockel S., Hens K., Geertz M., Deplancke B. and Maerkl S.J. (2012). iSLIM: a comprehensive approach to mapping and characterizing gene regulatory networks. Nucleic Acids Research, doi:10.1093/nar/gks1323.

Garcia-Cordero J.L. and S.J. Maerkl. (2012). Multiplexed surface micropatterning of proteins with a pressure-modulated microfluidic button-membrane. Chem. Commun., doi:10.1039/C2CC37740C. Geertz M., Shore D., and Maerkl S.J. (2012). Massively parallel measurements of biomolecular interaction kinetics on a microfluidic device. Proc. Natl. Acad. Sci. USA, doi:10.1073/pnas.1206011109. Schroeter C., Ares S., Morelli L.G., Isakova A., Hens K.J.I., Gajewski M., Juelicher F., Maerkl S.J., Deplancke B. and Oates A. C. (2012). Ubiquitous dimerization and selective DNA binding determine the dynamics of the zebrafish segmentation clock’s core circuit. PLoS Biology, 10(7): e1001364. Rajkumar A.S. and Maerkl S.J. (2012). Rapid Synthesis Of Defined Eukaryotic Promoter Libraries. ACS Synthetic Biology, doi:10.1021/sb300045j. 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. PLoS Genetics, 8(3): e1002614. 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, e1002053. Fidalgo L.M. and Maerkl S.J. (2011). A software–programmable microfluidic device for automated biology. LOC, 11(9), 1612-9.

Team Members Postdoctoral Fellows Jose Garcia-Cordero

PhD Students Matthew Blackburn Henrike Niederholtmeyer Jean-Bernard Nobs Arun Rajkumar Francesca Volpetti Kristina Woodruff Co-Advised PhD Students Johannes Becker Zuzana Tatarova Amanda Verpoorte Administrative Assistant Helen Chong

EPFL School of Life Sciences - 2012 Annual Report

Mermod Lab -

coaffiliated

http://www.unil.ch/biotech/page16861_en.html

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 • Characterization and modeling of regulatory genomic regions in cancer • Development of more efficient and safer vectors for gene and stem cell-based therapies

Keywords

Molecular Biotechnology, epigenetics, genomics, cell biology, gene expression.

Selected Publications

Gaussin A., Modlich U., Bauche C., Niederländer N., Schambach A., Duros C., Artus A., Baum C., Cohen-Haguenauer O. and Mermod N. (2012). CTF/NF1 transcription factors act as a potent genetic insulator for integrating gene transfer vectors. Gene Ther., 19:15-24. Harraghy N., Farina M., Regamey A., Girod P.-A., and Mermod N. (2012). Using matrix attachment regions to improve recombinant protein production. Methods Mol. Biol., 801:93-110. Mernier G., Majocchi S., Mermod N. and Renaud P. (2012). In situ evaluation of single-cell lysis by cytosol extraction and observation through fluorescence decay and dielectrophoretic trapping time. Sensors Actuators B Chem., 166: 907-912 Buceta M., Galbete J.L., Kostic C., Arsenijevic Y., and Mermod N. (2011). Use of human MAR elements to improve retroviral vector production. Gene Ther. 18:7-13. Kerschgens J., Renaud S., Grasso L., Egener-Kuhn T., Delaloye J.F., Lehr H.A., Vogel H. and Mermod N. (2011). Detection and analysis of tumor suppressor AP2α DNA binding activity by protein-binding microarrays. PLOS One, 6:e22895.

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

Team Members Postdoctoral Fellows Niko Niederländer Stéphanie Renaud Stefania Puttini Niamh Harraghy Elena Aritonovska Maxime Albesa Solenne Bire PhD Students Ruthger van Zwieten Stefano Majocchi Deborah Ley Simone Edelmann Kaja Kostyrko Yaroslav Shcherba Matthias Contie Pavithra Iyer Research Fellow Xuan Luo Master’s student Arnaud Rivier Engineers, informaticians & bioinformaticians Thomas Junier Etienne Lançon Daniel Peter Technicians Yves Dusserre Jacqueline Masternak Armindo Texeira Ione Gutscher Apprentice Alessia Cochard Administrative Assistant Nassim Berberat

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. Prof. Mermod has authored a number of scientific publications and patents.

EPFL School of Life Sciences - 2012 Annual Report

Micera Lab

- coaffiliated

http://tne.epfl.ch/ Silvestro Micera is Associate Professor and Head of the Translational Neural Engineering Laboratory in the Center for Neuroprosthetics and the Institute of Bioengineering. He received the Laurea degree in Electrical Engineering from the University of Pisa and the PhD in Biomedical Engineering from the Scuola Superiore Sant’Anna. In 2009 he was the recipient of the “Early Career Achievement Award” of the IEEE Engineering in Medicine and Biology Society. Dr.Micera’s research interests include the development of hybrid neuroprosthetic systems (interfacing the nervous system with artificial systems) and of mechatronic and robotic systems for function and assessment restoration in disabled and elderly persons.

Silvestro Micera

Associate Professor Center for Neuroprosthetics School of Engineering (STI)

Research Interests

The goal of the Translational Neural Engineering (TNE) Laboratory is to develop implantable neural interfaces and robotic systems to restore sensorimotor function in people with different kind of disabilities (spinal cord injury, stroke, amputation, etc.). In particular, the TNE lab aim is to be a technological bridge between basic science and clinical environment. Therefore, TNE novel technologies and approaches are designed and developed also starting from basic scientific knowledge in the field of neuroscience, neurology and geriatrics with the idea that better understanding means better development of clinical solutions. The lab is currently working with the University Hospital of Geneva (Prof. Guyot) to develop and validate a novel neuroprosthesis to restore vestibular functions in disabled subjects. The TNE is responsible for the integration and the assessment of performance of this device and collaborates on the clinical and neurophysiological characterization with clinical team. TNE is deeply involved in the activities led by Courtine’s team to develop a novel neuroprosthesis to restore locomotion using epidural electrical stimulation (EES). TNE works on novel models to better understanding EES, on novel control strategies to improve the performance of EES, and in several experiments to characterize cortical activities using intracortical electrodes during locomotion.

Selected Publications

Van den Brand R, Heutschi J, Barraud Q, DiGiovanna J, Bartholdi K, Huerlimann M, Friedli L, Vollenweider I, Moraud EM, Duis S, Dominici N, Micera S, Musienko P, Courtine G (2012). Restoring voluntary control of locomotion after paralyzing spinal cord injury. Science. 336:1182-5. Raspopovic S, Capogrosso M, Badia J, Navarro X, Micera S (2012). Experimental validation of a hybrid computational model for selective stimulation using transverse intrafascicular multichannel electrodes. IEEE Trans Neural Syst Rehabil Eng. 20:395-404. Panarese A, Colombo R, Sterpi I, Pisano F, Micera S (2012). Tracking motor improvement at the subtask level during robot-aided neurorehabilitation of stroke patients. Neurorehabil Neural Repair. 26:822-33. Tombini M, Rigosa J, Zappasodi F, Porcaro C, Citi L, Carpaneto J, Rossini PM, Micera S (2012). Combined analysis of cortical (EEG) and nerve stump signals improves robotic hand control. Neurorehabil Neural Repair. 26:275-81. Raspopovic S, Capogrosso M, Micera S (2011). A computational model for the stimulation of rat sciatic nerve using a transverse intrafascicular multichannel electrode. IEEE Trans Neural Syst Rehabil Eng. 19:333-44. Carpaneto J, Umiltà MA, Fogassi L, Murata A, Gallese V, Micera S, Raos V (2011). Decoding the activity of grasping neurons recorded from the ventral premotor area F5 of the macaque monkey. Neuroscience. 188:80-94.

Team Members Postdoctoral Fellows Jack DiGiovanna Stanisa Raspopovic

Professor Micera’s team also prepared all the devices and algorithms for the implantation of intraneural peripheral electrodes on an amputee (will happen in Rome in 2013), in order to develop a real-time bidirectional control of hand prostheses.

PhD Students Marco Bonizzato Marco Capogrosso (visiting) Martina Coscia (visiting) Andrea Crema Vidhi H. Desai (visiting) T. Khoa Nguyen Eduardo Martin Moraud Elvira Pirondini

Keywords

Research Assistant Federica Aprigliano

Implantable neuroprostheses, rehabilitation robotics, wearable devices, neuro-controlled artificial limbs, reaching and grasping, locomotion, functional electrical stimulation.

Master’s Students Florian Gothey Edoardo D’Anna Matteo Mancuso Administrative Assistant Jennifer Dinkleldein

EPFL School of Life Sciences - 2012 Annual Report

Millán Lab -

coaffiliated

http://cnbi.epfl.ch/ Prof. José del R. Millán holds the Defitech Chair at the École Polytechnique Fédérale de Lausanne (EPFL). His research on brain-computer interfaces 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. He is the recipient of the IEEE Nobert Wiener Award 2011 for his seminal and pioneering contributions to non-invasive brain-computer interfaces. Dr. Millán is an IEEE SMC Distinguished Lecturer.

José del Rocio Millán

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

The Chair in Non-Invasive Brain-Machine Interface laboratory (CNBI) carries out research on the direct use of human brain signals to control devices and interact with our environment. In this multidisciplinary research, we are bringing together our pioneering work on the two fields of brain-machine interfaces and adaptive intelligent robotics. Our approach to design intelligent neuroprostheses balances the development of prototypes‚ where robust real-time operation is critical‚ and the exploration of new interaction principles and their associated brain correlates. A key element at each stage is the design of efficient machine learning algorithms for real-time analysis of brain activity that allow users to convey their intents rapidly. Our neuroprostheses are explored in cooperation with clinical partners and disabled volunteers for the purpose of motor restoration, communication, entertainment and rehabilitation. A major highlight of 2012 was the final stretch of the European TOBI project that we have been coordinating since 2008. Remarkably, an important aspect of the project was to allow potential end-users to test our brain-controlled devices either at the involved research laboratories or at rehabilitation centers. More than 100 users suffering from motor impairments -due to stroke, spinal cord injury or neurodegenerative diseases- tested the designed prototypes.

Keywords

Brain-computer interfaces, neuroprosthetics, statistical machine learning, human-robot interaction, adaptive robotics, neuroscience, EEG, mental imagery.

Selected Publications

Lew E., Chavarriaga R., Silvoni S. and Millán J. d. R. (2012). Detection of self-paced reaching movement intention from EEG signals. Frontiers in neuroengineering. 5:13. Tzovara A., Murray M., Bourdaud N., Chavarriaga R., Millán J. d. R. and De Lucia M (2012). The timing of exploratory decision-making revealed by singletrial topographic EEG analyses. Neuroimage. 4:1959-69. Chavarriaga, R., Bayati, H., and Millán, J.d.R. (2012). Unsupervised adaptation for acceleration-based activity recognition: robustness to sensor displacement and rotation. Journal of Personal and Ubiquitous Computing, doi: 10.1007/s00779-011-0493-y. Leeb, R., Sagha, H., Chavarriaga, R., and Millán, J.d.R. (2011). A hybrid BCI based on the fusion of EEG and EMG Activities. Journal of Neural Engineering, 8:025011.

Müller-Putz, G.R., Breitwieser.,C., Cincotti, F., Leeb, R., Schreuder, M., Leotta, F., Tavella, M., Bianchi, L., Kreilinger, A., Ramsay, A., Rohm, M., Sagebaum, M., Tonin, L., Neuper, C. and Millán, J.d.R. (2011). Tools for Brain-Computer Interaction: A General Concept for a Hybrid BCI. Frontiers in Neuroinformatics, 5:30. doi: 10.3389/fninf.2011.00030. Carlson T. E., Tonin L., Leeb R., Rohm M., Rupp R., Al-Khodairy A. and Millán J. d. R. (2012). BCI Telepresence: A Six Patient Evaluation. TOBI Workshop lll: Bringing BCIs to End-Users: Facing the Challenge, Würzburg, Germany, March 20-22. Khaliliardali Z., Chavarriaga R., Gheorghe L.A. and Millán J. d. R. (2012). Detection of Anticipatory Brain Potentials during Car Driving. The 34th Annual International Conference of the Engineering in Medicine and Biology Society, San Diego, USA, Aug 28-Sep 1.

Team Members Postdoctoral Fellows Ricardo Chavarriaga Robert Leeb Tom Carlson Maria Laura Blefari Aleksander Sobolewski Sarah Degallier PhD Students Andrea Biasiucci Luca Tonin Serafeim Perdikis Mohit Kumar Goel Hesam Sagha Sareh Saeedi Michele Tavella Zahra Khaliliardali Marija Ušcumlic ` ` Huaijian Zhang Lucian Gheorghe Pierluca Borsò Michael Pereira Nicolas Bourdaud Eileen Lew

IBI - Co-affiliated Research Groups

Research Interests

Research Staff Marco Creatura Nicolas Beuchat Alberto Molina Master’s Student Abdolreza Madi Administrative Assistant Najate Guechoul

EPFL School of Life Sciences - 2012 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.

Dominique P. Pioletti

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

Research Interests

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

Keywords

Biomechanics, orthopaedics, mechanobiology, implant, tissue engineering, translational research.

Selected Publications

Voge,l A., Pioletti, D.P. (2012). Damping properties of the nucleus pulposus. Clinical Biomechanics. 27, 861-865. Darwich, S., Scaletta, C., Raffoul, W., Pioletti, D.P., Applegate, L.A. (2012). Epiphyseal chondro-progenitors provide a stable cell source for cartilage cell therapy. Cell Medicine, 4, 23-32. Terrier, A., Brighenti, V., Pioletti, D.P., Farron, A. (2012). Importance of polyethylene thickness in total shoulder arthroplasty: a finite element analysis. Clinical Biomechanics, 27, 443-448. Roshan Ghias, A., Vogel, A., Rakotomanana, L., Pioletti, D.P. (2011) Prediction of spatio-temporal bone formation in scaffold by diffusion equation. Biomaterials, 32, 7006-7012. 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.

Team Members Group Leader Alexandre Terrier

Postdoctoral Fellow Xabier Larrea PhD Students Jérôme Hollenstein Salim Darwich Philippe Abdel-Sayed Ulrike Kettenberger Mohamadreza Nassajian Moghadam Sohrab Emami-naini Chrsitoph Engelhardt Adeliya Latypova Tanja Hausherr Valérie Malfroy Camine Lab Assistant Sandra Jaccoud Engineers Francesc Levrero Florencio Julien Ston Master’s Students Yannick Devaud Christoph Wenger Valérie Malfroy-Camine Mohsen Afshar Gilles Michel Guillaume Pierret Sara Molins Raphaël Obrist Serge Metrailler Anouk Grandgeorge Annick Baur Valérie Parvex Jules Bourgon Administrative Assistant Virginie Kokocinski

Gortchacow, M., Wettstein, M., Pioletti, D.P., Terrier, A. (2011). A new technique to measure micromotion distribution around a cementless femoral stem, J Biomechanics, 44, 557-560. Roshan Ghias, A., Lambers, F., Gholam-Rezaee, M., Müller, R., Pioletti, D.P. (2011). In vivo loading increases mechanical properties of scaffold by affecting bone formation and bone resorption rates. Bone, 49, 1357-1364.

EPFL School of Life Sciences - 2012 Annual Report

Psaltis Lab

- coaffiliated

http://lo.epfl.ch/ 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)

The Optics laboratory focuses on biological imaging and optofluidics. Biological imaging deals with a variety of topics: phase conjugation through multimode fibers and biological tissues, imaging through biological media and nonlinear optics for bioparticle characterization. With optofluidics, we are focusing on developing technologies for energy harvesting purposes by leveraging the advantages of microfluidic systems. Biological imaging at a glance. • imaging techniques are used to improve detection of the type of cochlear damage. In preliminary studies, two-photon fluorescence microscopy is used to detect the damage on individual hair cells. • a high-resolution, lensless endoscope, minimally invasive, based on digital scanning, using phase conjugation through a multimode fiber was developed. • second harmonic generation (SHG) from nanoparticles for new types of imaging applications was studied. The coherent nature of SHG allows us to capture the complex radiated field information, thus allowing for many novel imaging applications, such as scan-free three-dimensional (3D) imaging, focusing and imaging through scattering media. • nonlinear imaging through Kerr media and object reconstruction after distortion in a non-linear media were studied. • a scanning confocal microscopy technique based on digital holography was developed. The data collected in this way contains all the necessary information to digitally produce three-dimensional images. Optofluidics - An interdisciplinary subject between optics and microfluidics, optofluidics has made substantial progress towards the integration of versatile optical functions into lab-on-a-chip systems. Integration and reconfigurability are its two major advantages. By combining optical elements into microfluidic devices, optofluidic chips hold promise in

the portable devices for applications such as environment monitoring, medical diagnosis and point of care testing.

Keywords

Optofluidics, nanoparticles, holography, nonlinear optics, phase conjugation, endoscopy, solar energy, digital confocal microscope.

Selected Publications

Yang, X., Pu, Y., Hsieh, C.L., Ong, C.A., Psaltis, D., Stankovich, K. (2013). Two photon microscopy of the mouse cochlea in situ for cellular diagnosis. Journal of Biomedical Optics. 18 (3): 031104. Papadopoulos, I.N., Farahi, S., Moser, C., Psaltis, D. (2013). High-resolution, lensless endoscope based on digital scanning through a multimode optical fiber. Biomedical Optics Express. 4 (2): 260-270. Goy, A., Psaltis, D. (2012). Digital confocal microscope. Optics Express. 20 (20): 22720-22727. Vasdekis, A.E., Evan, S., O’Neil, C., Psaltis, D., Hubbell, J. (2012). Precision intracellular delivery based on optofluidic polymersome rupture. ACS Nano. 6 (9): 7850-7857. Song, W., Vasdekis, A.E., Psaltis, D. (2012). Elastomer based tunable optofluidic devices. Lab on a Chip. 12 (19): 3590-3597. Erickson, D., Sinton, D., Psaltis, D., (2012). Optofluidics for energy applications. Nature Photonics. 5 (10): 583-590. Grange, R., Lanvin, T., Hsieh, C.L., Pu, Y., Psaltis, D. (2012). Imaging with second-harmonic radiation probes in living tissue. Biomedical Optics Express. 2 (9): 2532-2539.

Team Members Postdoctoral Fellows Alexandre Goy Jae-Woo Choi Marcin Zielinski Salma Farahi Wuzhou Song Ye Pu

PhD Students Grégoire Laporte Ioannis Papadopoulos Julien Cuennet Mohammad Hashemi Nicolino Stasio Thomas Lanvin Xin Yang Administrative Assistant Carole Loeffen Berthet

IBI - Co-affiliated Research Groups

Research Interests

EPFL School of Life Sciences - 2012 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. There she earned her Doctor of Sciences degree in 2003. She then undertook postdoctoral study at the University of California, Berkeley. From July 2008 she is an assistant tenure tracked 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, single-molecule fluorescence, PhotoActivated Light microscopy PALM and nanofabricated structures to study biomolecular systems and advance new nanotechnology. 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. DNA nanotechnology. Our main focus is to implement DNA origami structures into nanoelectronics. We use grapheme nanoribbon templates onto which different DNA origami structures can self-assemble and would enable us to register individual molecular nanostructures, to electronically address them, and to integrate them into functional devices. Local probe studies of single biomolecules. For example RNA polymerase, DNA binding proteins, membrane proteins such G protein–coupled receptors (GPCRs).

Keywords

PALM, GPCRs, solid-state nanopores, single molecule, DNA sequencing, nanoelectrodes.

Cell-type-specific β2 adrenergic receptor clusters identified using photo-activated localization microscopy are not lipid raft related, but depend on actin cytoskeleton integrity, M. Scarselli, P.Annibale and A.Radenovic Journal of Biological Chemistry DOI 10.1074/jbc.M111.329912. Nonlinear Optical Response in Single Alkaline Niobate Nanowires, F. Dutto, C. Raillon, K.Schenk and A. Radenovic Nano Lett., 2011, 11 (6), pp 2517–2521. 5. Identification of clustering artifacts in photoactivated localization microscopy P. .Annibale, S. Vanni, M. Scarselli, U. Rothlisberger and A. Radenovic Nature Methods 8, 527–528 2011. Single-layer MoS2 transistors, B. Radisavljevic, A. Radenovic, J. Brivio, V. Giacometti, A. Kis1*, Nature Nanotechnology Volume:6,147–150 2011

Team Members Postdoctoral Fellows Traversi Floriano Steinbock Lorentz Ke Liu Hendrik Deschout

PhD Students Annibale Paolo Brando Serena Roman Bulushev Dutto Fabrizia Kayci Metin Raillon Camille Arun Shivanandan Roman Bulushev

Selected Publications

Master’s Students Garcia Cordero Erick Mattia Greco Michael Graf Swati Krishnan

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

Technician Lely Feletti

Controllable shrinking and shaping of glass nanocapilaries under electron irradiation, L.J. Steinbock, J.F. Steinbock and A. Radenovic Nano Letters 2013 DOI: 10.1021/nl400304y

Administrative Assistant Chong Helen

EPFL School of Life Sciences - 2012 Annual Report

Renaud Lab

- coaffiliated

http://lmis4.epfl.ch/ Philippe Renaud has a Ms in Theoretical Physics. He received his PhD in Physics in 1988 and did a postdoc at the University of California, Berkeley (1988-1989) and then at the IBM Research Laboratories in Zürich (1990-1991) on scanning probe microscopy and magnetism. In 1992, he move to the MEMS team of CSEM in Neuchâtel, developing microsensors. He was appointed in 1993 as professor at EPFL where he started research on microsystems and on BioMEMS. He is also Scientific Director of the EPFL Center of MicroNanotechnollogy (CMi).

Phillippe Renaud

Full Professor School of Engineering (STI)

The Renaud laboratory is doing research in BioMEMS, microfluidics, nanofluidics and bioelectronic implants. We use the diverse wafer-based microfabrication for the realization of our devices. We have a strong activity on microfluidics systems for handling, analyzing and culturing biological cells. We have studied novel methods in flow cytometry and cell sorting based on electrical impedance analysis and dielectric properties of the cells. We also develop micro-bioreactors for on-chip co-culture of cells in drug screening and toxicology applications. Research on basic nanofluidic phenomena is used for understanding molecular transport in nanochannels. The team is developing devices for bioelectronic implants such as micro-electrodes for neural recordings and stimulation, biomechanical sensors for eye pressure or articular implants.

Keywords

Biosensors, microfluidics, cell chips, microflow cytometry, medical devices.

Selected Publications

B. Eker, R. Meissner, A. Bertsch, K. Mehta and P. Renaud. Label-Free Recognition of Drug Resistance via Impedimetric Screening of Breast Cancer Cells, in PLoS ONE, vol. 8, num. 3, p. e57423.1-12, 2013. G. Mernier, R. Martinez Duarte, R. Lehal, F. Radtke and P. Renaud. Very High Throughput Electrical Cell Lysis and Extraction of Intracellular Compounds Using 3D Carbon Electrodes in Lab-on-a-Chip Devices, in Micromachines, vol. 3, num. 3, p. 574-581, 2012.

Position Synapses Heterogeneously in 3D Micropatterned Neural Cultures, in PLoS ONE, vol. 6, num. 10, p. e26187.1-12, 2011. N. Buffi, D. Merulla, J. Beutier, F. Barbaud and S. Beggah et al. Miniaturized bacterial biosensor system for arsenic detection holds great promise for making integrated measurement device, in Bioengineered Bugs, vol. 2, num. 5, p. 296-298, 2011. R. Meissner, B. Eker, H. Kasi, A. Bertsch and P. Renaud. Distinguishing druginduced minor morphological changes from major cellular damage via labelfree impedimetric toxicity screening, in Lab on a Chip, vol. 11, num. 14, p. 2352-2361, 2011.

Team Members Postdoctoral Fellows Jules Vandersarl Rodrigo Martinez Duarte Amélie Beduer Ludovica Colella Songmei Wu PhD Students David Bonzon Sophie Delasoie Fabien Wildhaber Yufei ren Pierre Joris Mojtaba Taghipoor Robert Meissner David Forcheler

L. Colella, C. Beyer, J. Froehlich, M. Talary and P. Renaud. Microelectrodebased dielectric spectroscopy of glucose effect on erythrocytes, in Bioelectrochemistry, vol. 85, p. 14-20, 2012.

Senior Scientists Arnaud Bertsch Harald van Lintel

A. Kunze, A. Valero, D. Zosso and P. Renaud. Synergistic NGF/B27 Gradients

Administrative Assistant Sylvie Clavel

IBI - Co-affiliated Research Groups

Research Interests

EPFL School of Life Sciences - 2012 Annual Report

Roke Lab

- coaffiliated

http://lbp.epfl.ch/ Sylvie Roke studied chemistry and physics at Utrecht University (NL, highest honors). She obtained a PhD degree from Leiden University (highest honors) in the field of nonlinear optics. She was awarded the LJ Oosterhoff prize 2003. In 2004 she graduated with highest honors and obtained an Alexander von Humboldt Fellowship. In 2005 she obtained a Max-Planck Group Leader position and Research Group. In 2006 she was awarded the Minerva Prize (FOM, NL) and in 2008 the Hertha Sponer prize (DPG, DE). In 2009 she obtained an ERC startup grant, 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).

Sylvie Roke

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. These examples illustrate the complexity of small biological systems. For living matter, 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 nano sciences to the life sciences becomes possible. Currently, our understanding of soft biological systems is mostly 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 that are chosen to increase both our fundamental understanding and our technological abilities. • Development of theory and instrumentation for nonlinear light scattering / microscopy techniques to understand fundamental light matter interaction processes. • Molecular understanding of processes and interfaces in liquids and turbid media: aqueous systems • The investigation of structure and properties of biologically and medically relevant interfaces • Nonlinear optics applied to living systems Ultimately we want to develop a toolbox for tomorrow’s diagnosis for biomedical research, and bring molecular foundations to the understanding of biomedical processes.

Keywords

Nonlinear optics, biological imaging, light scattering, nanodroplets & particles, interfaces, water, membranes, surfactants.

Selected Publications

R. Vacha, S. Roke, P. (2012). Sodium Dodecyl Sulfate at Water-hydrophobic Interfaces: A Simulation Study. J. Phys. Chem B, 116, 11936-11942, DOI: 10.1021/jp304900z. KC. Jena, R. Scheu, S. Roke, P. (2012). Surface Impurities Are Not Responsible For the Charge on the Oil/Water Interface: A Comment. Angew. Chem. Int. Ed, DOI: 10.1002/anie.201204662. H. B. de Aguiar, R. Scheu, K. C. Jena, A. G. F. de Beer, S. Roke, P. (2012). Comparison of scattering and reflection SFG: a question of phase-matching. Phys. Chem. Chem. Phys, 14, 6826-6832. S. Roke, G. Gonella, P. (2012). Nonlinear Light Scattering and Spectroscopy of Particles and Droplets in Liquids. Annu Rev. Phys. Chem 63, 2012 :353–378. A. G. F. de Beer, J-S Samson, W. Hua, Z. Huang, X. Chen, H. C. Allen, and S. Roke, P. (2012). 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. H. B. de Aguiar, J.-S. Samson and S. Roke, P. (2011). Probing nanoscopic droplet interfaces in aqueous solution with vibrational sum-frequency scattering: a study of the effects of path length, droplet density and pulse energy. Chem. Phys. Lett, 512, 2011, 76-80. R. Vacha, S. Rick, P. Jungwirth, A. G. F. de Beer, H. B. de Aguiar, J-S Samson, and S. Roke, P. (2011). The structure and charge of water around a surfactant free oil in water emulsion. J. Am. Chem. Soc, 133 (26),10204–10210.

Team Members Postdoctoral Fellows Nikolaos Gomopoulos Kailash C. Jena Carlos Macias-Romero PhD Students Yixing Chen Cornelis Luetgebaucks Ekaterina Rostova Rüdiger Scheu Nikolay Smolentsev Administrative Assistant Rebecca Veselinov

EPFL School of Life Sciences - 2012 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 140 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)

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.

Keywords

Cardiovascular mechanics, hemodynamics, atherosclerosis, hypertension, ocular mechanics and glaucoma filtration surgery, implantable devices.

Selected Publications

Yiallourou, T. I., Kroger, J. R., Stergiopulos, N., Maintz, D., Martin, B. A., & Bunck, A. C. (2012). Comparison of 4D phase-contrast MRI flow measurements to computational fluid dynamics simulations of cerebrospinal fluid motion in the cervical spine. PLoS One, 7(12), e52284. Villamarin, A., Roy, S., & Stergiopulos, N. (2012). Eye vessel compliance as a function of intraocular and arterial pressure and eye compliance. Invest Ophthalmol Vis Sci, 53(6), 2831-2836. Vardoulis, O., Papaioannou, T. G., & Stergiopulos, N. (2012). On the estimation of total arterial compliance from aortic pulse wave velocity. Ann Biomed Eng, 40(12), 2619-2626. Rezakhaniha, R., Agianniotis, A., Schrauwen, J. T., Griffa, A., Sage, D., Bouten, C. V., et al. (2012). Experimental investigation of collagen waviness and orientation in the arterial adventitia using confocal laser scanning microscopy. Biomech Model Mechanobiol, 11(3-4), 461-473.

Papaioannou, T. G., Vardoulis, O., & Stergiopulos, N. (2012). The “systolic volume balance” method for the noninvasive estimation of cardiac output based on pressure wave analysis. Am J Physiol Heart Circ Physiol, 302(10), H20642073. Martin, B. A., Reymond, P., Novy, J., Baledent, O., & Stergiopulos, N. (2012). A coupled hydrodynamic model of the cardiovascular and cerebrospinal fluid system. Am J Physiol Heart Circ Physiol, 302(7), H1492-1509.

Team Members Engineers & Technical Staff Christian Andrié Michel Bachmann Stephane Bigler Fabiana Fraga Laurent Mosimann

Scientific Collaborators & Postdoctoral Fellows Rodrigo Araujo Fraga Da Silva Bryn Martin Danielle Passos Silva Sylvain Roy PhD Students Aristotelis Agianniotis Thiresia Gialourou Orestis Vardoulis Adan Villamarin

IBI - Co-affiliated Research Groups

Research Interests

Masters Students Emilie Farine Maira Seidl Administrative Assistant Tamina Sissoko

EPFL School of Life Sciences - 2012 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. 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.

Keywords

Signal & image processing, neuroimaging, pattern recognition.

Selected Publications

Van De Ville, D., Jhooti, P., Haas, T., Kopel, R., Lovblad, K.-O. and Haller, S. (2013). Recovery of the Default Mode Network After Demanding Neurofeedback Training Occurs in Spatio-Temporally Segregated Subnetworks, NeuroImage, 63(4):1775-1781. Richiardi, J., Gschwind, M., Simioni, S., Annoni, J.-M., Greco, B., Hagmann, P., Schluep, M., Vuilleumier, P. and Van De Ville, D. (2013). Classifying Minimally Disabled Multiple Sclerosis Patients from Resting State Functional Connectivity, NeuroImage, 62(3):2021-2033. Boss, D., Hoffmann, A., Rappaz, B., Depeursinge, C., Magistretti, P. J., Van De Ville, D. and Marquet, P. (2012). Spatially-Resolved Eigenmode Decomposition of Red Blood Cells Membrane Fluctuations Questions the Role of ATP in Flickering. PLoS ONE, 7(8):e40667.

Gschwind, M.; Pourtois, G.; Schwartz, S.; Van De Ville, D. & Vuilleumier, P. (2012). White-Matter Connectivity between Face-Responsive Regions in the Human Brain. Cerebral Cortex, 22(7):1564-1576. Van De Ville, D. and Kocher, M. (2011). Non-Local Means with Dimensionality Reduction and SURE-Based Parameter Selection. IEEE Transactions on Image Processing, 20(9):2683-2690. Richiardi, J., Eryilmaz, H., Schwartz, S., Vuilleumier, P. and Van De Ville, D. (2011). Decoding Brain States from fMRI Connectivity Graphs, NeuroImage, 56(2):616-626. 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(11):5265-5274.

Team Members Affiliated Scientist Melissa Saenz

Postdoctoral Fellows Ivana Balic Yury Koush Jonas Richiardi Frank Scharnowski PhD Students Zafer Dogan Soheil Faridi Isik Karahanoglu Jeffrey Kasten Rotem Kopel Nora Leonardi Master’s Students Nicolas Gninenko Yannik Messerli Thomas Zuppetti Administrative Assistant Ruth Fiaux

EPFL School of Life Sciences - 2012 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 price of the Swiss Biomedical Technology Society.

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

The focus of the Medical Photonics Group at EPFL is on detecting and treating disease with the help of light. This is translational research and goes from the basic ideas to clinical tests, and in some cases introduction into the market. Our projects involve close collaboration between academic, clinical and industrial partners. Among others we have contributed significantly to the development of several drugs approved by the US FDA and the European medical authorities, such as VisudyneTM for the treatment of wet age-related macular degeneration (AMD) - with QLT and Novartis, and HexvixTM (Cysview) for the detection and removal of early stage bladder cancer – with Photocure and GE-Healthcare. We also developed an autofluorescence bronchoscope, DAFETM, for the detection of early lung cancer with Wolf GmbH. At present we are working on the optimization of drug mixtures using a stochastic method with an in vitro feedback loop. We are also developing several novel methods for drug delivery. The latter include a photodynamic leakage approach, which will soon enter clinical trials, and an approach with enzyme-activated nanoparticles, which is based on disease enhanced enzyme activity. Our preclinical tests are done in part on the chicken chorioallantoic membrane (CAM) model and using intravital microscopy on the nude mouse. 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.

Keywords

Fluorescence detection, translational research, drug development, drug delivery, combination strategies, cancer, neovascularization.

Selected Publications

Weiss, A., van den Bergh, H., Griffioen, A.W., Nowak-Sliwinska, P. (2012).Angiogenesis inhibition for improvement of photodynamic therapy; the revival of a promising idea. BBA Rev. Cancer, 1826(1):53-70. Nowak-Sliwinska, P., Weiss, A., van Beijnum, J.R., Wong, T., Lovisa, B., Ballini, J.P., van den Bergh, H., Griffioen, A.W. (2012). Angiostatic kinase inhibitors to sustain photodynamic angio-occlusion. J. Cell. Mol. Med., 16(7) :1553-62. Gabriel, D., Lange, D., Chobaz-Peclat, V., Zuluaga, M.F., Gurny, R., van den Bergh, H., Busso, H. Thrombin-sensitive dual fluorescence imaging and therapeutic agent for detection and treatment of synovial inflammation in murine rheumatoid arthritis. (2011). J Control Release 28;163(2): 178-86. Gabriel, D., Zuluaga, M.F., van den Bergh, H., Gurny, R. Lange, N. (2011). It is all about proteases: from drug delivery to in vivo imaging and photomedicine. Curr Med Chem.18(12) :1785-805. Nowak-Sliwinska, P., van Beijnum, J.R., Casini, A., Nazarov, A., van den Bergh, H., Wagnières, G., Dyson, P.J., Griffioen, A.W. Organomettalic ruthenium(II) arene compounds with anti-angiogenic activity. (2011). J. Med. Chem, 54:3895-3902. Debefve, E., Mithieux, F., Perentes, J.Y., Wang, Y., Cheng, C., Schaefer, S.C., Ruffieux, C., Ballini, J.P., Gonzalez, M., van den Bergh, H., Ris, H.B., Lehr, H.B., Krueger, T. (2011). Leukocyte-endothelial cell interaction is necessary for photodynamic therapy induced vascular permeabilization. Lasers Surg Med. 43(7):696-704.

Team Members Postdoctoral Fellows Sandrine Gay Veronika Huntosova Patrycja Nowak-Sliwinska Andreas Pitzschke Georges Wagnières Yaboo Wang Matthiau Zellweger

IBI - Co-affiliated Research Groups

Research Interests

Master’s Student Debora Bonvin Research Assistants Carla Martoccia Olivier Seydoux Andrea Weiss Administration Véronique Bauler