IBI - Annual Report 2014 by EPFL School of Life Sciences

EPFL School of Life Sciences IBI - Institute of Bioengineering Report 2014

EPFL School of Life Sciences - 2014 Annual Report

IBI

Institute of Bioengineering The Mission of the Institute of Bioengineering (IBI) is to perform world-class quantitative, systems- and design-oriented research in and for the life sciences. By breaking down the boundaries between engineering, physics, chemistry, computer science and the life sciences, IBI labs strive to better understand basic biological principles and transform this knowledge into innovative technology platforms and clinical applications.

The IBI’s research agenda has evolved into six main themes: biomechanics and neuroengineering, bio-optics and bio-imaging, nano- and micro-bioengineering, molecular, cell and tissue engineering, systems and computational biology, systems physiology and immunoengineering.

Mattias Lutolf - Director

2014 has witnessed a change in leadership at the IBI’s helm, with Melody Swartz passing the Director’s baton to Matthias Lutolf on April 1st. Other notable events in 2014 include: Olaia Naveira’s arrival as new (junior) member of the Institute (appointment shared with the Lausanne University Hospital CHUV) and Theo Lasser’s courtesy appointment in IBI, alongside his principal affiliation to the Institute of Microengineering; tenures obtained by Matteo Dal Peraro, Bart Deplancke and Matthias Lutolf (all three promoted to Associate Professor); the annual Bioengineering Day held for the first time at the new on-campus SwissTech Convention Center; the launch of an annual IBI-sponsored ‘Future Leader in Bioengineering Award’, the first recipient of which is Rudolf Griss, postdoc in Kai Johnsson’s lab; a faculty retreat held at nearby beautiful “Les Bois Chamblards” estate as well as the second meeting of the IBI’s Scientific Advisory Board. In addition, several IBI faculty were honored in 2014; they are highlighted in the introduction of this Annual Report (p. 5). http://bioengineering.epfl.ch

IBI - Institute of Bioengineering

The IBI sits at the interface of the life sciences and of engineering, being situated in both the School of Life Sciences and the School of Engineering. This dual affiliation allows great diversity in hiring faculty from different backgrounds and with different research perspectives. It also provides a rich educational environment, both at the Bachelor/Master’s and at the Doctoral levels. This partnership is especially demonstrated by IBI’s joint Master’s program in Bioengineering which is shared by the two Schools. In 2013, this joint program awarded 47 MSc diplomas to graduates, up from 35 in 2013. IBI-affiliated labs also awarded 35 doctoral diplomas in 2014 as opposed to 32 in 2013.

EPFL School of Life Sciences - 2014 Annual Report

Auwerx Lab Johan Auwerx

Full Professor - Nestlé Chair in Energy Metabolism

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

Introduction

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

The laboratory of Dr. Auwerx has been using molecular physiology and systems genetics to understand mitochondrial function and metabolism in health, aging and disease. Mitochondria are derived from endo-symbiotic α-proteobacteria that contain multiple copies of their own circular DNA (mtDNA), vestiges of bacterial DNA. The large majority of mitochondrial proteins, however, are encoded in the nuclear DNA (nDNA) and these proteins are after their translation in the cytoplasm, imported, processed, and assembled with the proteins encoded by mtDNA. Assembly of the complexes of the mitochondrial electron transport chain, responsible for energy harvesting, hence relies on a perfect synchrony between proteins encoded by nDNA and mtDNA through the convergence and coordinated expression of these two genomes. Much of the initial work of his team focused on understanding how mitochondrial function and metabolism is controlled by altering the activity of transcription factors and their associated cofactors. His work was instrumental for the development of agonists of nuclear receptors - a particular class of transcription factors - into drugs, which now are used to treat high blood lipid levels, fatty liver, and diabetes. Dr. Auwerx was also amongst the first to recognize that transcriptional cofactors, which fine-tune the activity of transcription factors, act as energy sensors/effectors that influence mitochondrial function. His research validated these cofactors as targets to treat metabolic diseases, and spurred the clinical use of natural compounds, such as resveratrol and NAD+ precursors, as modulators of these cofactor pathways.

Results Obtained in 2014

Whereas the initial work of Johan Auwerx (see lab introduction) was instrumental to elucidate how transcription factors and their associated transcriptional cofactors are involved in the antegrade control of mitochondrial activity, more recently, he elucidated a novel retrograde signaling pathway that emanates from the mitochondria to influence nuclear function, i.e. mitochondria→nucleus. Interference with mitochondrial translation⎯either through genetic (mutations and variation in expression of the mitochondrial ribosomal proteins) or pharmacological strategies (doxycycline and chloramphenicol)⎯reduces the production of mtDNA encoded ETC components, resulting into a mitonuclear imbalance between mtDNA and nDNA encoded ETC proteins, which subsequently activates the mitochondrial unfolded protein response (UPRmt). UPRmt is an adaptive response that restores mitochondrial function, which in the worm is linked with the extension of lifespan. He furthermore discovered that exposing mice, worms and cells to compounds, which activate mitochondrial biogenesis, such as well-known longevity compounds rapamycin and resveratrol, as well as compounds that boost NAD+ levels, also induce UPRmt. This work indicates that UPRmt is triggered both during mitochondrial biogenesis and mitonuclear proteostatic imbalance, and in each case has beneficial effects on mitochondrial function and organismal health.

The work of the laboratory has been trend-setting in the field and is highly cited by his peers (h-factor > 105).

Keywords

Aging, atherosclerosis, C. elegans, diabetes, genetics, mitochondria, metabolism, mouse genetic reference populations, obesity, phenogenomics, transcription, transcription factors.

EPFL School of Life Sciences - 2014 Annual Report

Team Members Visiting Professor Eduardo Rochete-Ropelle

Postdoctoral Fellows Taoufiq Harach Seiko Ishida Pooja Jha Jo Young Suk Giuseppe Lo Sasso Olli Matilainen Keir Menzies Pedro Moral Quiros Laurent Mouchiroud Eija Pirinen Dongryeol Ryu Vincenzo Sorrentino

PhD Students Pénélope Andreux Virginija Jovaisaite Elena Katsyuba Adrienne Mottis Evan Williams Hongbo Zhang

Technicians Sabrina Bichet Norman Moullan

Administrative Assistant Valérie Stengel

Internships Student Tiffany Amariuta Bachelor project Student Tarik Ouhmad

IBI - Institute of Bioengineering

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

Selected Publications » Houtkooper, R.H., Mouchiroud, L., Ryu, D., Moullan, N., Katsyuba, E., Knott, G., Williams, R.W., and Auwerx, J. (2013). Mitonuclear protein inbalance as a conserved longevity mechanism. Nature 497:451-457. » Mouchiroud, L., Houtkooper, R.H., Moullan, N., Katsyuba, E., Ryu, D., Canto, C., Mottis, A., Jo, Y.-S., Viswanathan, M., Schoonjans, K., Guarente, L., and Auwerx, J. (2013). The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154:430-441. » Pirinen, E., Canto, C., Jo, Y.-S., Morato, L., Zhang, H., Menzies, K., Williams, E., Mouchiroud, L., Moullan, N., Hagberg, C., Li, W., Timmers, S., Imhof, R., Verbeek, J., Pujol, A., van Loon, B., Viscomi, C., Zeviani, M., Schrauwen, P., Sauve, A., Schoonjans, K., and Auwerx, J. (2014). Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle. Cell Metabolism 19:1034-1041. » Williams, E.G., Mouchiroud, L., Frochaux, M., Pandey, A., Andreux, P.A., Deplancke, B., and Auwerx, J. (2014). An evolutionary conserved role for the aryl hydrocarbon receptor in the regulation of movement. Plos Genetics 10:e1004673. » Ryu, D., Jo, Y.-S., Lo Sasso, G., Stein, S., Zhang, H., Perino, A., Lee, J.U., Zeviani, M., Romand, R., Hottiger, M.O., Schoonjans, K., and Auwerx, J. (2014). A Sirt7-dependent acetylation switch of GABPbeta1 controls mitochondrial function. Cell Metabolism 20:856-869. » Wu, Y., Williams, E.G., Dubuis, S., Mottis, A., Jovaisaite, V., Houten, S.M., Argmann, C.A., Faridi, P., Wolski, W., Kutalik, Z., Zamboni, N., Auwerx, J.*, and Aebersold, R.* (*co-last and co-corresponding authors) (2014). Multilayered genetic and omics dissection of mitochondrial activity in a mouse genetic reference population. Cell 158:1415-1430.

EPFL School of Life Sciences - 2014 Annual Report

Baekkeskov Lab Steinunn Baekkeskov

Visiting Professor

Introduction

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

Type 1 Diabetes (T1D) in humans develops following an autoimmune destruction of pancreatic beta-cells in the islets of Langerhans. In earlier work, we and others identified three intracellular human beta cell membrane proteins which are targeted by the autoimmunity associated with beta cell destruction. These include GAD65, the smaller isoform of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD), a tyrosine phosphatase, IA-2, and a zinc transporter, ZnT8. Autoantibodies to those proteins can be detected in the blood several years before clinical onset of T1D and identify individuals at risk. However, although T1D can be prevented in animal models, no safe methods are currently available in humans. GAD65, IA-2, and ZnT8 are also expressed in CNS neurons, which are protected behind the blood brain barrier. However, GAD65 is also a target antigen in a rare neurological disorder, stiff-man syndrome that affects GABAergic neurons. In contrast, the highly homologous isoform, GAD67, is not a target antigen in either disease. The two isoforms differ mainly in the N-terminal region that controls membrane targeting and trafficking of the proteins. Pancreatic beta cells have a well developed, extensive, and highly active ER, reflecting their role in synthesizing and secreting large amounts of insulin. Beta cells are unusually sensitive to ER stress. There is evidence to suggest that induction of ER-stress and apoptosis by cytokines secreted by inflammatory cells plays a role in the loss of beta cells that precedes clinical onset of Type 1 diabetes. Current research in the Baekkeskov Lab, aims at elucidating the mechanisms of early events leading to autoimmunity towards the beta cell. We focus on i) understanding why the GAD65 isoform of GAD is so susceptible to become a target of autoimmunity in contrast to GAD67; and ii) testing the hypothesis that ER stress is an important factor in inducing autoimmunity to GAD65, IA2, and ZnT8.

Keywords

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

Results Obtained in 2014

Function and Membrane Trafficking of GAD65 and GAD67. GABA is a paracrine and autocrine signaling molecule regulating the function of islet endocrine cells. The localization of GAD65 and GAD67 to vesicular membranes is important for rapid delivery and accumulation of GABA for regulated secretion. While the membrane anchoring and trafficking of GAD65 is mediated by intrinsic hydrophobic modifications, GAD67 remains hydrophilic, and yet is targeted to vesicular membrane pathways and synaptic clusters in neurons by both a GAD65-dependent and a distinct GAD65-independent mechanism. We investigated the trafficking of the GAD isoforms in beta cells. While GAD65 membrane trafficking is similar to neurons, beta cells lack the neuronal mechanism for GAD65-independent membrane anchoring of GAD67. Thus, only GAD65:GAD65 homodimers and GAD67:GAD65 heterodimers, but not GAD67:GAD67 homodimers gain access to vesicular compartments in beta cells to facilitate rapid accumulation of newly synthesized GABA for regulated secretion and fine tuning of GABA-signaling in islets of Langerhans. Effect of ER stress on membrane trafficking of GAD65. ER stress is implicated in loss of beta cells during the pathogenesis of T1D. ER-stress may facilitate the formation and release of immunogenic forms of intracellular proteins into an inflammatory environment contributing to antigen presentation and induction of autoimmunity. Cytokine induced ER stress in primary beta cells results in accumulation of GAD65 in trans-Golgi membranes and a diversion from its postGolgi trafficking route. We are testing the hypothesis that such accumulated forms are highly immunogenic. Hippocampal neurons and islet endocrine cells can form synapses. Islet endocrine cells have developed a system of expression of neurotransmitters and their receptors for paracrine and autocrine regulation of hormone secretion and maintenance of glucose homeostasis. An additional level of regulation may be provided by both sympathetic and parasympathetic fibers innervating the pancreas. A complete picture integrating neuronal and endocrine regulation is lacking. We developed a protocol for co-culturing primary rat pancreatic islet cells and hippocampal neurons, which revealed that several types of neurons make synaptic contacts with the subtypes of endocrine cells (Figure). The co-cultures of primary neurons and islet cells provide a system to investigate mechanisms of signaling between these cells.

EPFL School of Life Sciences - 2014 Annual Report

Team Members Postdoctoral Fellow Edward Phelps

PhD Student Chiara Cianciaruso

Administrative Assistants Doris Sapin Miriella Pasquier

IBI - Institute of Bioengineering

Lab Manager Miriella Pasquier

Co-culture of hippocampal neurons and pancreatic islet cells forming synaptic contacts. Cells are immunostained for insulin (magenta, islet beta cells), glucagon (dark-blue, islet alpha cells), MAP2 (light-blue, neuronal dendrites), and the GABA synthesizing enzyme GAD65 (green), expressed in beta cells and in the soma and presynaptic clusters of GABA-ergic neurons.

Selected Publications Âť Kanaani, J., Ciaciaruso, C., Phelps, E. A., Pasquier, M., Brioudes, E., Billestrup, N. and Baekkeskov S. (2015). Compartmentalization of GABA synthesis by GAD67 differs between pancreatic beta cells and neurons. PLoS One 10(2) : e0117130.

EPFL School of Life Sciences - 2014 Annual Report

Barrandon Lab Yann Barrandon

Full Professor Joint Chair EPFL – Unil – CHUV, Head of Laboratory of Stem Cell Dynamics EPFL & Experimental Surgery, CHUV

http://ldcs.epfl.ch/

Introduction

Yann Barrandon, MD PhD graduated in Dermatology in Paris and obtained his PhD on the long-term cultivation of human hematopoietic stem cells. Prof. Barrandon was a post-doctoral fellow at Stanford Medical School (1982-1983) and Harvard Medical School (1983-1990) where he worked with Pr. Howard Green, a pioneer in Regenerative Medicine of Skin using cultured human epidermal stem cells. He moved to Paris in 1990 as Director of Research at the INSERM and Head of Laboratory at the Ecole Normale Supérieure (Paris-Ulm). Dr. Barrandon is a member of the EMBO, of the EPFL Research Commission, Initiative Director of the Joint Doctoral Program between EPFL and Singapore-A*Star, and a visiting professor, Department of Ophthalmology, Kyoto Prefectural University of Medicine.

Adult (tissue) stem cells are instrumental for renewal, repair and regeneration and hold great potential for disease modeling, drug discovery and regenerative medicine. Skin is privileged because several skin stem cells (epidermal, mesenchymal and melanocyte) can be expanded in culture, manipulated and transplanted. Epidermis, the skin’s outer layer is a stratified epithelium that is constantly renewing. Its basal layer contains adult stem cells and progenitor/transient amplifying cells whose multiplication balances the loss of squames that are continuously sloughed off in the environment. The Barrandon laboratory has three main objectives: 1- to understand the relationship between stem/progenitors cells of stratified epithelia, 2- to understand the impact of the environment on stem cell behavior and 3- to comprehend stem cell engraftment. All projects ultimately aim at improving cell and gene therapy. A major project is to understand how stratified epithelia respond to environmental cues since chronic exposure to environmental hazards can result in metaplasia, a situation in which an epithelium adopts another phenotype and that is linked to carcinogenesis. The laboratory has demonstrated that clonogenic epithelial cells of the ocular surface, the oral cavity, the oesophagus, the vagina and the bladder can increase their lineage capabilities and behave like bona fide multipotent hair follicle stem cells. Most importantly, this capacity is maintained in serial transplantations and is intrinsic because cells that have never been exposed to cell culture behave in a similar fashion. These observations together with the finding that clonogenic thymic epithelial cells can also function as bona fide multipotent hair follicle stem cells (Bonfanti et al., Nature 2010) indicates that the microenvironment can impact the potency of epithelial stem/progenitor cells.

Results Obtained in 2014

Safety is critical when it comes to ex vivo autologous gene therapy but current stem cell technology makes it difficult to thoroughly investigate the properties of human recombinant stem cells before cells are transplanted. Because of the remarkable property of epidermal stem cells to be massively expanded ex vivo, it is theoretically possible to completely reconstruct the epidermis of an adult human from the progeny of a single autologous epidermal stem cell. We have explored the feasibility of a single cell approach for ex vivo gene therapy of skin using recessive dystrophic epidermolysis bullosa (RDEB), a horrendous blistering genodermatosis, as a model system. This approach allows for a full characterization of the recombinant clone(s) both for stem cell capabilities (long term production of the medicinal protein, long term regeneration of a cured human epidermis onto immunodeficient mice) and for safety criteria (determination of proviral insertions, absence of tumorogenicity and dissemination). The combination of a clonal approach with high throughput technologies should permit to thoroughly evaluate the properties of the genetically corrected stem cells before the patient is transplanted and bringing safety to a level that otherwise is difficult to achieve (Droz-Georget Lathion et al., EMBO Mol Med 2015).

Keywords

Stem cell, microenvironment, epithelia, skin, cornea, thymus, cell and gene therapy.

EPFL School of Life Sciences - 2014 Annual Report

Team Members Senior Scientists Stéphanie Claudinot Ariane Rochat Postdoctoral Fellows Michiko Kanemitsu Melissa Maggioni

PhD Students Tiphaine Arlabosse Marine de Lageneste Diane Hemon Pierluigi Manti Georges Muller Marie-Noëlle Perseguers Matteo Pluchinotta Lilia Salimova Andrea Zaffalon

Master’s Students Amélie Borghini Bérénice Charrez Sara de Meyer

Research Assistants Marco Burki Olga de Souza Silva Dorinne Savoy

Administrative Assistant Guex Nathalie

IBI - Institute of Bioengineering

Confocal image of a 12 days old colony of clonogenic epithelial cells isolated from a human thymus and immunostained against KERATIN 5 (red) and KERATIN 8 (green). K8/K5 double positive cells appear yellow.

Selected Publications » Nanba, D., Toki, F., Tate, S., Imai, M., Matsushita, N., Shiraishi, K., Sayama, K., Toki H., Higashiyama, S., Barrandon, Y. (2015). Cell motion predicts human epidermal stemness. J Cell Biol. In press » Droz-Georget Lathion, S., Rochat, A., Knott, G., Recchia, A., Martinet, D., Benmohammed S., Grasset, N, Zaffalon, A., Besuchet Schmutz N., Savioz-Dayer, E., Beckmann, J.S., Rougemont J., Mavilio, F., Barrandon, Y. (2015). A Single Epidermal Stem Cell Strategy for Safe Ex vivo Gene Therapy. EMBO Mol. Med. 7:380-93. » Nakamura T, Hamuro J, Takaishi M, Simmons S, Maruyama K, Zaffalon A, Bentley AJ, Kawasaki S, Tagata-Takaoka M, Fullwood NJ, Itami S, Sano S, Ishii M, Barrandon Y, Kinoshita S (2014). LRIG1 inhibits STAT3-dependent inflammation to maintain cornea homeostasis. J Clin Invest 124:385-397. » Hirata-Tominaga, K., Nakamura, T., Okumura, N., Kawasaki, S., Kay, E.P., Barrandon, Y., Koizumi, N, Kinoshita, S. (2013). Corneal endothelial cell fate is maintained by LGR5 via the regulation of hedgehog and Wnt pathway. Stem Cells. 31:1396-1407. » Nanba, D., Toki, F., Matsushita, N., Matsushita, S., Higashiyama, S. Barrandon, Y. (2013). Actin filament dynamics impacts keratinocyte stem cell maintenance EMBO Mol. Med. 5:640-653. » Barrandon, Y., Grasset, N., Zaffalon, A., Gorostidi, F., Claudinot, S., Droz-Georget, S.L., Nanba, D., Rochat, A. (2012). Capturing epidermal stemness for regenerative medicine. Semin. Cell Dev. Biol. 23:937-944. » 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., Sommer, L. (2012). Sox10 promotes the formation and maintenance of giant congenital naevi and melanoma. Nat Cell Biol. 14:882-90. » Bonfanti, P., Claudinot, S., Amici, A.W., Farley, A., Blackburn, C.C, Barrandon, Y. (2010). Microenvironmental reprogramming of thymic epithelial cells to skin multipotent stem cells. Nature 466: 978-82. (Press release) Commentary in Bilousova and Roop Cell Stem Cell (2010) 7:419-420.

EPFL School of Life Sciences - 2014 Annual Report

Dal Peraro Lab Matteo Dal Peraro

Associate Professor

lbm.epfl.ch

Introduction

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

The Laboratory for Molecular Modeling (LBM) carries out research to understand the physical and chemical properties of complex biological systems, in particular their function emerging from their atomistic structure. To this end, the laboratory uses and develops a broad array of methods for multiscale molecular simulation and modeling, which have nowadays the ability to mimic the conditions found in the cellular environment. By blending theory, computation supported by high-performance computing (HPC) resources and integration with actual experimental data allows for the close description of the composition and evolution of biological systems. The current research program at the LBM is mainly focused in three major axes: • to understand the architecture of large molecular assemblies by integrating a variety of experimental inputs at different resolution; • to accurately study large portions of biological membrane compartments and their interaction with surrounding proteins; and • to capture the effects of cellular crowding on the dynamic determinants of proteins and their molecular interactions.

Keywords

Integrative modeling, molecular simulation, structure-based drug discovery, structural biology, computational biology, biophysics, high-performance computing.

Results Obtained in 2014

Macromolecular assembly - Proteins often assemble in large macromolecular complexes to achieve a specific biological task. Unfortunately, owing to their size and complexity, these structures are difficult to determine at atomistic resolution, preventing thus a complete understanding of their mechanism of action. To approach this problem, the laboratory developed novel ways to predict the structure and function of large biological assemblies. To this end, we established a new approach (that we called POWER: parallel optimization workbench to enhance resolution) that uses heuristic optimization strategies guided by experimental-based restraints to characterize quaternary protein structure accounting for native dynamics. Using this integrative strategy, we were able for instance to reveal the assembly mechanism of aerolysin, a bacterial pore-forming toxin that produces heptameric pores at the target membrane by a concerted swirling motion of its components. Moreover, we determined the basal body structure of Yersinia type III secretion system, and discovered how its flexibility is critical for adapting to thickness variations at the periplasmic space. The native dynamics of individual components emerges, in these studies, as the key determinant to define the architecture, and understand the function of large multi-protein complexes. Therefore, the ability of our approach to integrate protein dynamics with sparse experimental data is a promising step towards the molecular characterization of large pathogenic systems. Towards realistic molecular modeling of subcellular organization - To enhance the general capabilities and accuracy of molecular simulations, the laboratory also worked on a new generation of methods, where an electrostatic-consistent coarse-grained representation of proteins was developed to extend the time- and size-scale accessible to current molecular simulations. Also, novel molecular models of key components of the biological membrane were developed, such for instance as cardiolipins that are fundamental anionic lipids constituting the inner membrane of mitochondria and Gramnegative bacteria. Along with these models, we developed also a framework, currently implemented in the web-server LipidBuilder (at http://lipidbuilder. epfl.ch) that is able to construct bilayers of any given lipid composition in order to mimic as precisely as possible the biological membrane.

EPFL School of Life Sciences - 2014 Annual Report

Team Members Postdoctoral Fellows Luciano Abriata Anna Lindeløv Vestergaard Maria Josefina Marcaida-Lopez

PhD Students Deniz Aydin Martina Audagnotto Christophe Bovigny Alexandra Kalantzi

PhD Students Michele Larocca Thomas Lemmin Enrico Spiga Hassan Pezeshgi Modarres Giorgio Tamo

Administrative Assistant Marie-France Radigois

IBI - Institute of Bioengineering

Near-atomistic models of the prepore and membrane-inserted pore conformations derived from a combination of crystallography, cryo-EM, single-particle analysis, molecular simulation and modeling reveal a swirling mechanism of membrane insertion and pore formation by aerolysin.

Selected Publications » Lemmin, T., Dimitrov, M., Fraering, P.C., Dal Peraro, M. (2014). Perturbations of the straight transmembrane α-helical structure of the amyloid precursor protein affect its processing by γ-secretase. J. Biol. Chem. 289(10): 6763-6774. » Spiga, E., Abriata, L.A., Piazza, F., Dal Peraro, M. (2014). Dissecting the Effects of Concentrated Carbohydrate Solutions on Protein Diffusion, Hydration, and Internal Dynamics. J. Phys. Chem. B 118(20): 5310-5321. » Vestergaard, A.L., Coleman, J.A., Lemmin, T., Mikkelsen, S.A., Molday, L.L., Vilsen, B., Molday, R.S., Dal Peraro, M., Andersen, J.P. (2014). Critical roles of isoleucine-364 and adjacent residues in a hydrophobic gate control of phospholipid transport by the mammalian P4-ATPase ATP8A2. Proc. Natl. Acad. Sci. USA 111(14): E1334-E1343. » Degiacomi M., Dal Peraro M. (2013). Macromolecular Symmetric Assembly Prediction Using Swarm Intelligence Dynamic Modeling. Structure 21(7): 1097-1104. » Degiacomi, M., Iacovache, I. Pernot, L., Chami, M., Kudryashev, M., Stahlberg, H., Van Der Goot, F.G., Dal Peraro, M. (2013). Molecular assembly of the aerolysin pore reveals a swirling membrane-insertion mechanism. Nat. Chem. Biol. 9(10): 623–629. » Kudryashev, M., Stenta M., Schmelz, S., Amstutz, M., Wiesand, U., Castaño-Díez, D., Degiacomi, M.T., Münnich, S., Bleck, S.E.K., Kowal, J., Diepold, A., Heinz, D.W., Dal Peraro, M., Cornelis, G.R., Stahlberg, H. (2013). In situ structural analysis of the Yersinia enterocolitica injectisome. eLife 2: e00792. » E Spiga, D Alemani, MT Degiacomi, M Cascella, MD Peraro, M. (2013). Electrostatic-consistent coarse-grained potentials for molecular simulations of proteins. J. Chem. Theory Comput. 9(8): 3515-3526. » Abriata, L.A., Spiga, E., Dal Peraro, M. (2013). All-atom simulations of crowding effects on ubiquitin dynamics. Phys. Biol. 10(4): 045006. » Lemmin, T., Soto, C.S., Clinthorne, G., DeGrado, W.L., Dal Peraro, M. (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.

EPFL School of Life Sciences - 2014 Annual Report

Deplancke Lab Bart Deplancke

Associate Professor

http://deplanckelab.epfl.ch/

Introduction

Bart Deplancke received his M.Sc. in bio-engineering from Ghent University (Belgium), and his Ph.D. 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. His group develops and uses integrative and population genomics approaches to study the gene regulatory properties of the metazoan genome. He is currently also guest professor at Ghent University and co-founded the BioTech-IT company Genohm SA.

Gene regulatory networks play a vital role in metazoan development and function, and deregulation of these networks is often implicated in disease. The interactions between genes and their respective regulatory transcription factors (TFs) that form the basis of gene regulatory networks have however been poorly characterized. This is because the transcriptional function of most metazoan TFs, which denotes the regulatory elements they bind to, the genes they regulate, the transcriptional consequence of their DNA interactions, and the transcriptional complexes in which they function, remains unknown. Our main focus is to unravel the metazoan gene regulatory code and to examine how variations in this code affect molecular and organismal diversity. Our systems of interest are: • Drosophila melanogaster: the impact of genomic and molecular variation on gut immunity and aging (e.g. Massouras et al., Nat Methods, 2010; PLoS Genetics, 2012; Huang, Massouras et al., Genome Research, 2014) • Mouse: mesenchymal stem cell function and differentiation with a specific focus on understanding the regulatory mechanisms mediating white and brown fat cell differentiation (e.g. Raghav et al. Mol Cell, 2012; Simicevic et al., Nature Methods, 2013, Gubelmann et al., eLife, 2014). • Human: linking genomic to regulatory variation (e.g. Kilpinen et al. Science, 2013). Next to these research interests, we are also actively pursuing the development of new research tools or pipelines that enable a better characterization of gene regulatory networks (e.g. microfluidics and yeast-based screening platforms, Hens et al. Nature Methods, 2011 & Gubelmann et al., Mol Syst Biol, 2013; targeted proteomics of TFs, Simicevic et al., Nature Methods, 2013)

Keywords

Gene regulatory network, integrative genomics, transcription, quantitative genetics, mouse, Drosophila, yeast, genetic engineering, adipogenesis, genomic variation.

Results Obtained in 2014

- A comprehensive understanding of adipogenesis is of high biomedical and societal value, given the current burden of obesity and its associated range of diseases. In a study published in eLife (2014), we presented the results of a large-scale transcription factor (TF) overexpression screen in mouse preadipocytes that led to the identification of 23 novel adipogenic regulators. Going beyond the resource value of this target list, we extensively examined the adipogenic function of our top candidate ZEB1, previously known for its role in epithelial-to-mesenchymal transition and tumor metastasis. Using genome-wide, high-throughput sequencing-based approaches, in vitro and in vivo differentiation assays in both mice and humans, as well as integrative computational analyses, we demonstrate here for the first time ZEB1’s key regulatory importance for adipogenesis, constituting a major conceptual advance in our understanding of the transcriptional mechanisms controlling this important process. - We published in Genome Reserarch (2014) a consortium-driven effort to comprehensively characterize naturally occurring genetic variation in the Drosophila melanogaster Genetic Reference Panel (DGRP) consisting of 205 sequenced inbred lines. Specifically, we employed an integrated genotyping strategy to identify almost 5 million single nucleotide polymorphisms (SNPs) and 1.3 million non-SNPs at high resolution. This level of naturally occurring genetic variation is about 10-fold larger than that found in humans, thus constituting a powerful resource to molecularly dissect quantitative trait loci down to the nucleotide level.

EPFL School of Life Sciences - 2014 Annual Report

Team Members PhD Students Roel Bevers Riccardo Dainese Michael Frochaux Rachana Pradhan

Technician Julie Russeil

Administrative Assistant Marie-France Radigois

IBI - Institute of Bioengineering

Postdoctoral Fellows Alina Isakova Antonio Meireles-Filho Petra Schwalie

Graphical summary of the paper by Gubelmann et al., eLife, 2014.

Selected Publications » Gubelmann, C., Schwalie, P.C., Raghav, S.K., Roder, E., Delessa, T., Kiehlmann, E., Waszak, S.M., Corsinotti, A., Udin, G., Holcombe, W., et al. (2014). Identification of the transcription factor ZEB1 as a central component of the adipogenic gene regulatory network. Elife 3, e03346. » Huang, W., Massouras, A., Inoue, Y., Peiffer, J., Ràmia, M., Tarone, A.M., Turlapati, L., Zichner, T., Zhu, D., Lyman, R.F., et al. (2014). Natural variation in genome architecture among 205 Drosophila melanogaster Genetic Reference Panel lines. Genome Research 24, 1193-1208. » Waszak, S.M., Kilpinen, H., Gschwind, A.R., Orioli, A., Raghav, S.K., Witwicki, R.M., Migliavacca, E., Yurovsky, A., Lappalainen, T., Hernandez, N., et al. (2014). Identification and removal of low-complexity sites in allelespecific analysis of ChIP-seq data. Bioinformatics 30, 165-171. » Kilpinen, H., Waszak, S.M., Gschwind, A.R., Raghav, S.K., Witwicki, R.M., Orioli, A., Migliavacca, E., Wiederkehr, M., Gutierrez-Arcelus, M., Panousis, N.I., et al. (2013). Coordinated Effects of Sequence Variation on DNA Binding, Chromatin Structure, and Transcription. Science 342, 744-747. » Gubelmann, C., Waszak, S.M., Isakova, A., Holcombe, W., Hens, K., Iagovitina, A., Feuz, J.D., Raghav, S.K., Simicevic, J., and Deplancke, B. (2013). A yeast one-hybrid and microfluidics-based pipeline to map mammalian gene regulatory networks. Molecular Systems Biology 9, 682. » Waszak, Sebastian M., and Deplancke, B. (2013). Rounding Up Natural Gene Expression Variation during Development. Developmental Cell 27, 601-603.

EPFL School of Life Sciences - 2014 Annual Report

Hubbell Lab Jeffrey A. Hubbell

Full Professor - Merck-Serono Chair in Drug Delivery

http://lmrp.epfl.ch

Introduction

We design novel materials for applications in medicine such as 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 life sciences. Jeffrey Hubbell was trained as a chemical engineer from Kansas State University (B.S.) and Rice University (Ph.D.) in the United States. Previous to moving to Lausanne, he was on the faculty at the Swiss Federal Institute of Technology Zurich, at the California Institute of Technology, and at the University of Texas in Austin. He is author of more than 250 papers in peer-reviewed journals and inventor on more than 100 patents. He is a member of the National Academy of Engineering, USA. and the National Academy of Inventors, USA.

Regenerative medicine - We study the interaction of protein growth factors, which induce tissue morphogenesis, with proteins of the extracellular matrix, seeking to understand the complex interplay between these two classes of signaling molecules in vivo. Based on this interaction, we design and develop novel biomaterial and growth factor designs, to present these molecules in vivo in a molecular context that resembles their natural biological function. Vaccines and immunotherapeutics - In collaboration with the Laboratory for Lymphatic and Cancer Bioengineering (Prof. M.A. Swartz), we develop approaches to target vaccine antigen and adjuvant formulations to the lymph nodes that drain an injection site. We are particularly interested in situations where one must induce a CD8+ T cell response, for example generating cancer-fighting cytotoxic T lymphocytes for anti-cancer therapeutic vaccination. Tolerogenic vaccination - In addition to effector immune responses, we are also keenly interested in protein engineering approaches to tolerize versus cellular immunity, harnessing the tolerogenic antigen presentation that occurs with antigen from apoptotic cells yet using simple engineered antigen forms that are clinically tractable. We explore ways to deliver antigens to induce these aspects of peripheral tolerance, with a focus on preventing immune responses to protein drugs and on preventing and reversing immune responses in autoimmunity, most notably type-1 diabetes antigens.

Keywords

Immunoengineering, tissue engineering, protein engineering, biomaterials.

Results Obtained in 2014

Regenerative medicine: We have determined that a broad collection of extracellular matrix proteins comprise high affinity binding sites for a broad collection of growth factors. We have also identified certain growth factors that comprise binding sites for matrix proteins that are very high affinity and promiscuous. This has allowed us to develop an engineering concept for cytokines and chemokines, including morphogenetic growth factors, creating molecular variants that display superaffinity for extracellular matrix proteins. We have shown substantial enhancement of efficacy of these candidate drugs in models of chronic skin wounds in diabetics and in bone defects. Vaccines and immunotherapeutics: In collaboration with the laboratory of Prof. M.A. Swartz, we have developed novel nanomaterials as vaccines that comprise conjugated antigen proteins and adjuvant biomolecules, and we have explored the efficacy of these nanomaterials in cancer models in the mouse, for example in lymphoma and melanoma models. We have demonstrated that the nanomaterials can beneficially targeted to the lymph nodes that drain the tumor, which are already primed by having experienced tumor antigens draining to that site. We showed that vaccination of the tumor-draining lymph node was much more effective than vaccinating an uninvolved lymph node. Tolerogenic vaccination: 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. 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. We have spun out a company, located in the EPFL Science Park, to carry this work forward in clinical development.

EPFL School of Life Sciences - 2014 Annual Report

Team Members Postdoctoral Fellows Balet, Eva-Maria Bonner Daniel Borcard Françoise Brubaker Carrie Gai, Shunning Ishihara, Jun Larsson, Mattias Hans Phelps, Edward Allen Sancho, Nuria Oltra Tortelli, Federico Wilson, David Scott

PhD Students Briquez, Priscilla Brünggel, Kym Cianciarus, Chiara Damo, Martina De Titta, Alexandre Grimm, Alizée Julier, Ziad Panagiotou, Vasiliki Vardar, Elif Kivellö, Anna-Sofia (external) Nagpal, Medhavi (external)

Master’s Students Dellacherie, Maxence Jahnsen, Ann-Lena Mottart, Xavier Vincentelli, Helena Specialized Technicians Diaceri, Giacomo Quaglia-Thermes, Xavier

Internships Buck, Emily Calderon, Gisele

Administrative Assistant Carol Bonzon

Other Scientiﬁc Personnel Dr. Wandrey, Christine - Maître d’enseignement et de recherche Prof. Frey, Peter - Adjunct professor Dr. Simeoni, Eleonora – Scientist Gaudry, Jean-Philippe – Bio-engineer

IBI - Institute of Bioengineering

Repair of bone defects in the skull of the rat. On the right, repair is done using growth factors with their wild-type natural form. On the left, repair is enhanced by applying our engineering concept to design the same growth factors, at the same dose, but in a second-generation molecular design.

Selected Publications » Zakrzewski, J.L., van den Brink, M.R. & Hubbell, J.A. (2014) Overcoming immunological barriers in regenerative medicine. Nat Biotechnol 32:786-794. » Martino, M.M., Briquez, P.S., Guc, E., Tortelli, F., Kilarski, W.W., Metzger, S., Rice, J.J., Kuhn, G.A., Muller, R., Swartz, M.A. & Hubbell, J.A. (2014) Growth factors engineered for super-affinity to the extracellular matrix enhance tissue healing. Science 343:885-888. » Jeanbart, L., Ballester, M., de Titta, A., Corthesy, P., Romero, P., Hubbell, J.A. & Swartz, M.A. (2014) Enhancing efficacy of anti-cancer vaccines by targeted delivery to tumor-draining lymph nodes. Cancer Immunology Research 2:436-447. » Martino, M.M., Briquez, P.S., Ranga, A., Lutolf, M.P. & Hubbell, J.A. (2013) Heparin-binding 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. » Kontos, S., Kourtis, I.C., Dane, K.Y. & Hubbell, J.A. (2013) Engineering antigens for in situ erythrocyte binding induces T-cell deletion. Proc Natl Acad Sci U S A 110:E60-68. » de Titta, A., Ballester, M., Julier, Z., Nembrini, C., Jeanbart, L., van der Vlies, A.J., Swartz, M.A. & Hubbell, J.A. (2013) Nanoparticle conjugation of CpG enhances adjuvancy for cellular immunity and memory recall at low dose. Proc Natl Acad Sci U S A 110:19902-19907.

EPFL School of Life Sciences - 2014 Annual Report

Jensen Lab Jeffrey D. Jensen

Tenure-track Assistant Professor

http://jensenlab.epfl.ch

Introduction

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

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 populations, and between species. Lab members work on both applied and theoretical problems in fields ranging from population genomics to medical genetics.

Keywords

Population genetics, adaptation.

Results Obtained in 2014

Over the past year we have thought primarily about how populations adapt to challenging environments. Within this theme, we have developed novel population genetic theory to describe expectations, as well as novel statistical machinery to quantify the distribution of fitness effects under these models and to identify adaptively important mutations in the genome â&#x20AC;&#x201C; generally within a Bayesian framework. Applying these theoretical and statistical approaches, we have primarily focused upon the following empirical data: Ecological - how wild populations of deer mice evolve crypsis in order to adapt to the selective pressure of avian predation on novel substrates. Experimental - how populations of yeast evolve tolerance for high temperature and salinity under controlled laboratory conditions. Clinical - how influenza virus adapts to drug treatment in order to become resistant, and how human cytomegalovirus (HCMV) adapts in the face of the immune response of a newly infected patient. This line of research offers both novel insight in to the mode and tempo of adaptation as an evolutionary process, as well as demonstrates the power of evolutionary analysis to provide insights to related research communities ranging from ecology to virology.

EPFL School of Life Sciences - 2014 Annual Report

Team Members Postdoctoral Fellows Claudia Bank Greg Ewing Anna Ferrer-Admetlla Matthieu Foll Stefan Laurent Lisha Mathew Cornelia Pokalyuk Nicholas Renzette

PhD Students Adamandia Kapopoulou Louise Ormond Hyunjin Shim Alfred Simkin

Staff Kristen Irwin

Administrative Assistant Sophie Barret

IBI - Institute of Bioengineering

Figure from Foll et al. (2014), utilizing our developed statistical software (termed WFABC). In panel A, we plot 10,000 simulated mutational frequency trajectories (where Fs’d indicates the extent to which a mutant frequency decreases through time, and Fs’i the extent to which a mutant frequency increases through time). In the legend, the color-coding indicates the simulated selection coefficient (s). Thus, mutations that are strongly positively selected (shown in red) have a high value of Fs’i and low value of Fs’d (i.e., they almost exclusively increase in frequency), whereas deleterious mutations (shown in green) generally decrease in frequency, and neutral mutations (in yellow) have an equal probability of increasing or decreasing owing to the effects of genetic drift. Thus, comparing an experimentally observed mutational frequency trajectory (shown by the black dot) with the simulated data allows for an estimation of s (an approach known as Approximate Bayesian Computation (ABC)). In panel B the corresponding example is shown as a heat plot, where an estimate of the effective population size (Ne) of the inﬂuenza virus, and the selection coefficient (s) of an identified oseltamivir resistance mutation, are shown. Thus, using this approach, resistance mutations can not only be identified from whole genome data, but their selective effect on the population can also be measured.

Selected Publications » Jensen, J.D., 2014. On the unfounded enthusiasm for soft selective sweeps. Nature Communications 5: 5281 selective sweeps. Nature Communications 5: 5281. » Simkin, A., J. Bailey, B. Theurkauf, F.-B. Gao, and J.D. Jensen, 2014. Inferring the evolutionary history of primate miRNA binding sites: overcoming motif counting biases. Molecular Biology & Evolution 31: 1894-901. » Bank, C., R.T. Hietpas, A. Wong, D.N. Bolon, and J.D. Jensen, 2014. A Bayesian MCMC approach to assess the complete distribution of fitness effects of new mutations: uncovering the potential for adaptive walks in challenging environments. Genetics 196: 841-52. » Foll, M., Y.-P. Poh, N. Renzette, A. Ferrer-Admetlla, C. Bank, H. Shim, A.-S. Malaspinas, G. Ewing, P. Liu, D. Wegmann, D.R. Caffrey, K.B. Zeldovich, D.N. Bolon, J.P. Wang, T.F. Kowalik, C.A. Schiffer, R.W. Finberg, and J.D. Jensen, 2014. Influenza virus drug resistance: a time-sampled population genetics perspective. PLoS Genetics 10(2):e1004185. » Simkin, A., A. Wong, Y.-P. Poh, B. Theurkauf, and J.D. Jensen, 2013. Recurrent and recent selective sweeps in the piRNA pathway. Evolution 67: 1081-90. » Linnen, C.R., Y.-P. Poh, B. Peterson, R. Barrett, J. Larson, J.D. Jensen, and H.E. Hoekstra, 2013. Adaptive evolution of multiple traits through multiple mutations at a single gene. Science 339: 1312-1316.

EPFL School of Life Sciences - 2014 Annual Report

Lutolf Lab Matthias Lutolf

Associate Professor - Director of the Institute of Bioengineering - IBI

http://lscb.epfl.ch/

Introduction

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

By interfacing advanced biomaterials engineering, microtechnology and stem cell biology, the overarching goal of the Lutolf Laboratory is to uncover mechanisms of stem cell fate regulation; knowledge that will contribute to better ways to grow stem cells in culture and use them for various applications. A major recent goal in his lab aims at inducing organogenesis in 3D stem cell culture.

Keywords

Stem cells, self-renewal, differentiation, niche, single cell analysis, hydrogel engineering, microfluidics, stem cell-based organogenesis.

Results Obtained in 2014

The behaviour of cells in tissues is governed by the 3D microenvironment, which involves a dynamic interplay between biochemical and mechanical signals. The complexity of microenvironments and the context-dependent cell responses that arise from these interactions have posed a major challenge to understanding the underlying regulatory mechanisms. To systematically dissect the role of the various factors that can determine cell fate in 3D, we have developed novel experimental paradigms to simultaneously generate thousands of unique microenvironments and probe their effects on (single) cell fate in vitro (e.g. Ranga et al., Nature Communications, 2014). We have applied this unique approach to discover minimal artificial niches for hematopoietic stem cells (Roch et al., in revision), as well as chemically defined 3D microenvironments that promote neuroepithelial differentiation of pluripotent stem cells and their self-organization into neural tube-like morphogenetic structures (Meinhardt et al., Stem Cell Reports, 2014 and Ranga et al., in revision).

EPFL School of Life Sciences - 2014 Annual Report

Team Members Postdoctoral Fellows Simone Allazetta Massimiliano Caiazzo Nikolce Gjorevski Adrian Ranga Aline Roch

PhD Students Nathalie Brandenberg Sonja Giger Mehmet Girgin Mukul Girotra Laura Kolb Gennady Nikitin Lilia Salimova Yoji Tabata Vincent Trachsel

Master’s Students Thibaud Cherbuin Michael Snyder

Administrative Assistant Maria Fernandes Coelho

IBI - Institute of Bioengineering

3D combinatorial screening from a modular materials library: a, Enzymatically mediated cross-linking scheme, where xxxx xxxx represents specific peptide sequence. b, Components of the combinatorial toolbox are assembled from biologically relevant factors in categorized form. Stiffness and MMP sensitivity of the matrix are set within the experimentally measured ranges shown. c, Experimental process consists of combining the components library with reporter cells using robotic mixing and dispensing technology into 1536 well plates. d, Automated microscopy and image processing to determine colony size and GFP intensity. Average cell density per well is set by the initial cell concentration used in the experiment, and exact initial cell density for each well is determined retrospectively by imaging. Examples of a set of images tracking colony growth in a single well over the course of a 5-day experiment, three-dimensional confocal reconstruction and image segmentation are shown.

Selected Publications » » » » » » » »

A Meinhardt, D Eberle, A Tazaki, A Ranga, M Niesche, A Stec, G Schackert, MP Lutolf, EM Tanaka (2014). 3D Reconstitution of the Patterned Neural Tube from Embryonic Stem Cells, Stem cell reports 3 (6), 987-999 Gjorevski N, Ranga A, Lutolf MP, (2014). Bioengineering approaches to guide stem cell-based organogenesis, Development 141 (9), 1794-1804 Ranga A, Gobaa S, Mosiewicz KA, Okawa Y, Negro A, Lutolf MP (2014). Systems biology of cell-matrix interactions: Discovery of cell fate regulators via arrays of 3D microenvironments, Nature Communications, 5, 4324 A Ranga, N Gjorevski, MP Lutolf (2014). Drug discovery through stem cell-based organoid models, Advanced drug delivery reviews 69, 19-28 Mosiewicz KA, Kolb L, van der Vlies AJ, Martino MM, Lienemann PS, Hubbell JA, Ehrbar M, Lutolf MP (2014). In situ cell manipulation through enzymatic hydrogel photopatterning, Nature Materials, 12 (11), 1072-1078 Cosson S, Lutolf MP (2014) Hydrogel microfluidics for the patterning of pluripotent stem cells, Scientific Reports, Mar 25;4:4462 Roccio M, Schmitter D, Knobloch M, Okawa Y, Sage D, Lutolf MP (2013). Predicting stem cell fate changes by differential cell cycle progression patterns, Development, 140(2):459-70 M Knobloch, SMG Braun, L Zurkirchen, C Von Schoultz, N Zamboni, MJ Araúzo-Bravo, WJ Kovacs, Ö Karalay, U Suter, RAC Machado, M Roccio, MP Lutolf, CF Semenkovich, S Jessberger (2013). Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis, Nature 493 (7431), 226-230 » Woodruff K, Fidalgo LM, Gobaa S, Lutolf MP, Maerkl SJ, (2013). Live mammalian cell arrays, Nature Methods, Jun;10(6):550-2 » Allazetta S, Hausherr TC, Lutolf MP (2014). Microfluidic synthesis of cell-type-specific artificial extracellular matrix hydrogels, Biomacromolecules, Apr 8;14(4):1122-31 » Cosson S, Allazetta S, Lutolf MP (2013). Patterning of cell-instructive hydrogels by hydrodynamic flow focusing, Lab on a Chip. 2013 Jun 7;13(11):2099-105

EPFL School of Life Sciences - 2014 Annual Report

Naef Lab Felix Naef

Associate Professor

http://naef-lab.epfl.ch

Introduction

Our lab is interested in computational, quantitative and systems biology. We work on various problems including circadian rhythms, developmental patterning, gene expression networks, and stochastic transcription in single cells. To study these systems we combine theoretical, computational and experimental approaches. Felix Naef studied theoretical physics at the ETHZ and obtained his PhD from the EPFL in 2000. He then received postdoctoral training at the Center for Studies in Physics and Biology at the Rockefeller University (NYC) under the guidance of Prof. Magnasco. His research at the interface of physics and biology focuses on the gene regulation, transcription, circadian rhythms and single cell analysis. He joined EPFL in 2006 where he is currently Associate Professor in the Institute of Bioengineering (IBI).

Diurnal oscillations of gene expression controlled by the circadian clock underlie rhythmic physiology across most living organisms. In this context our lab is highly interested in combining functional genomics (RNA-seq, ChIPseq, DNAse1-seq, mass spectrometry), bioinformatics and mathematical modeling to understand how the circadian clock impinges on many of the regulatory layers underlying rhythmic gene expression. The ultimate goal is to better understand rhythms in physiology, notably in the mouse liver, but also in other tissues. We are also very keen on using microscopy to study cellular rhythms in individual mammalian cells. Notably, we have been intrigued by the interactions of the circadian and cell cycles, since previously work has argued that the clock might control cell division timing. Better understanding of how the two systems mutually interact is currently of great interest, notably with regards to the role of circadian clocks in proliferating tissues, such as the epidermis, immune or stem cells. Another main focus of our group is on transcriptional kinetics in single mammalian cells. Mammalian genes are often transcribed discontinuously as short bursts of RNA synthesis followed by longer silent periods. However, how these “on” and “off” transitions, together with the burst sizes, are controlled in single cells is still poorly characterized. To address this problem, we combine single-cell time-lapse luminescence imaging with stochastic modeling of the time.

Results Obtained in 2014

“Circadian clock-dependent and -independent rhythmic proteomes implement distinct diurnal functions in mouse liver”, Mauvoisin et al., PNAS 2014. We quantified temporal profiles in the murine hepatic proteome under physiological light–dark conditions using quantitative MS. Our analysis identified over 5,000 proteins, of which several hundred showed robust diurnal oscillations with peak phases enriched in the morning and during the night. Combined mathematical modeling of temporal protein and mRNA profiles indicated that proteins accumulate with reduced amplitudes and significant delays, consistent with protein half-life data. Moreover, some rhythmic proteins showed no corresponding rhythmic mRNAs. Such rhythms were highly enriched in secreted proteins accumulating tightly during the night and persisted in clock-deficient animals, suggesting that food-related entrainment signals influence rhythms in circulating plasma factors. “Robust synchronization of coupled circadian and cell cycle oscillators in single mammalian cells”, Bieler et al., MSB 2014. Circadian and cell cycles are two periodic cell-autonomous processes with a period of about one day. Consequently, when these cycles run in parallel in the same cell, their coupling may lead to resonances or even synchronization. Observations of circadian variations in mitotic indices and on the daytime-dependence of cell divisions led to the hypothesis that the circadian cycle might gate cell-cycle progression. We completed a quantitative time-lapse imaging study of circadian cycles in dividing mammalian NIH3T3 cells clearly indicated that both oscillators tick in a tightly synchronized state. Moreover, contrary to our expectations, we unambiguously showed that in NIH3T3 cells the cell cycle progression exerts a unilateral influence on the circadian clock, and not the opposite.

Keywords

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

EPFL School of Life Sciences - 2014 Annual Report

Team Members Postdoctoral Fellows Paola Gilardoni Saeed Omidi Jingkui Wang Kyle Gustafson

PhD Students Johannes Becker Jonathan Bieler Simon Blanchoud Rosamaria Cannavo Damien Nicolas Jonathan Sobel Laura Symul Onur Tidin Jake Yeung

Master’s Students Cédric Gobet Matthieu Quinodoz Nicolas Villa

Administrative Assistant Sophie Barret

IBI - Institute of Bioengineering

Circadian cycles resonate to the cell cycle. Model underlying the synchronization of circadian and cell cycle oscillators in individual mammalian cells. Time runs clockwise as indicated, key circadian event are indicated. Cell division at the different times can either phase advance or phase delay the circadian cycle, as indicated by the red and green arrows. This phase shifting by cell division induces a resonance of the circadian clock, such that the two cycles are synchronized (1:1 mode locking) with division occurring typically just after the night-day transition.

Selected Publications » Bieler, J., Cannavo, R., Gustafson, K., Gobet, C., Gatfield, D., Naef, F,. Robust synchronization of coupled circadian and cell cycle oscillators in single mammalian cells. Mol Syst Biol. 2014 Jul 15. 10:739. doi: 10.15252/ msb.20145218. PubMed PMID: 25028488; PubMed Central PMCID: PMC4299496. » Mauvoisin, D., Wang, J., Jouffe, C., Martin, E., Atger, F., Waridel, P., Quadroni, M., Gachon, F., Naef, F. Circadian clock-dependent and -independent rhythmic proteomes implement distinct diurnal functions in mouse liver. Proc. Natl. Acad. Sci. U S A. 2014 Jan 7;111(1):167-72. doi: 10.1073/pnas.1314066111. Epub 2013 Dec 16. PubMed PMID: 24344304; PubMed Central PMCID: PMC3890886. » Molina, N., Suter, D.M., Cannavo, R., Zoller, B., Gotic, I., Naef, F. Stimulus-induced modulation of transcriptional bursting in a single mammalian gene. Proc. Natl. Acad. Sci. U S A. 2013 Dec 17;110(51):20563-8. doi: 10.1073/pnas.1312310110. Epub. 2013 Dec 2. PubMed PMID: 24297917; PubMed Central PMCID: PMC3870742. » d’Eysmond, T., De Simone, A., Naef, F. Analysis of precision in chemical oscillators: implications for circadian clocks. Phys. Biol. 2013 Oct;10(5):056005. doi: 10.1088/1478-3975/10/5/056005. Epub. 2013 Sep 16. PubMed PMID: 24043227. » Jouffe, C., Cretenet, G., Symul, L., Martin, E., Atger, F., Naef, F., Gachon, F. The circadian clock coordinates ribosome biogenesis. PLoS Biol. 2013;11(1):e1001455. doi: 10.1371/journal.pbio.1001455. Epub 2013 Jan 3. PubMed PMID: 23300384; PubMed Central PMCID: PMC3536797. » Simicevic, J., Schmid, A.W., Gilardoni, P.A., Zoller, B., Raghav, S.K., Krier, I., Gubelmann, C., Lisacek, F., Naef, F., Moniatte, M., Deplancke, B. Absolute quantification of transcription factors during cellular differentiation using multiplexed targeted proteomics. Nat Methods. 2013 Jun;10(6):570-6. doi: 10.1038/nmeth.2441. Epub 2013. Apr 14. PubMed PMID: 23584187.

EPFL School of Life Sciences - 2014 Annual Report

Naveiras Lab Olaia Naveiras

SNSF Professor, IBI (50%), Haematology Service, CHUV (50%)

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

Introduction

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

We are interested in understanding the regulation of the reversible transition between mammalian yellow (adipocyitic) and red bone marrow (hematopoietic). This naturally occurring process can be enhanced to increase safety and efficacy of hematopoietic stem cell (HSC) transplantation, and, possibly, to slow the progression of myelodysplasia or even aplastic anemia into overt leukemia. Currently, all clinical approaches to increase HSC engraftment and to enhance hematopoiesis target the HSC itself. Alternatively, we focus on studying how manipulations of the HSC niche can enhance hematopoiesis and, in particular, how inhibiting adipocytic differentiation within failing marrow accelerates hematopoietic recovery. Specifically, we are developing several strategies to induce metabolic changes in the HSC niche and to regulate the function of mesenchymal stem cells (MSCs), the main precursor to stromal supportive cells within the hematopoietic marrow, and to dissect the differential fates of MSCs within the adipocytic and hematopoietic marrow. The relevance of this research relies on the early mortality associated to HSC transplantation. Reducing the toxicity of the preparative regimen and accelerating the time to engraftment is critical to improving the safety of hematopoietic stem cell transplantation and making this most successful stem cell therapy available to a wider subset of patients.

Keywords

Hematopoietic stem cell (HSC), bone marrow transplantation, adipocyte, preadipocyte, mesenchymal Stem Cell (MSC), HSC niche, regenerative hematopoiesis.

Results Obtained in 2014

Our laboratory was established in January 2014. Since then, we have optimized complex models of hematopoietic stem cell (HSC) transplantation extending to, thanks to our collaborators, single cell transplants and NSG human-into-mouse xenotransplantation. We have established a high-throughput screening platform for mesenchymal stem cell differentiation based on digital holographic microscopy (DHM), adapted for the study of bone marrow adipogenesis, and have developed quantitative methods to assess the red-to-yellow and yellow-to-red bone marrow transitions upon bone marrow transplantation. Aside from method-development, following up on the work initiated by our group at the Laboratory of Stem Cell Bioengineering, we have demonstrated the capacity of specific mitochondrial modulators within the NAD pathway to accelerate the yellow-to-red bone marrow transition upon HSC transplant in mice, opening the possibility of translating these findings to reduce the mortality associated to HSC transplant in patients suffering from leukemia or lymphoma. Future work will concentrate on characterizing the mesenchymal stem cell (MSC) and preadipocyte populations in relationship to the expanding hematopoietic compartment, as well as identifying small molecule inhibitors of the yellow-to-red bone marrow transition that may be used in the context of HSC transplantation and aplastic anemia. A special emphasis will be placed on developing in vivo screening tissue-based bioassays for the creation of microenvironments capable of mediating hematopoietic progenitor expansion.

EPFL School of Life Sciences - 2014 Annual Report

Team Members Postdoctoral Fellows Shanti Rojas-Sutterlin Nicola Vannini

PhD Students Vasco Campos Josefine Tratwal

Bachelor Students Chiheb Boussema Yannick Yersin

Research Assistant Evangelos Panopoulos

Administrative Assistant Laura Bischoff

IBI - Institute of Bioengineering

Master’s Students Cédric Jules-Etienne Jasmina Rubattelol

Mixed yellow (adipocytic) and red (hematopoietic) marrow in the mouse tail vertebra. Bone marrow adipocytes are seen as white, empty ovals surrounded by hematopoietic cells in classic H&E stains (left). Right: adipocyte quantification via the AdipoQ tool developed in the lab.

Selected Publications » Vannini N, Roch A, Naveiras O, Griffa A, Kobel S, Lutolf MP, Identification of in vitro HSC fate regulators by differential lipid raft clustering, Cell Cycle. 2012 Apr 15;11(8):1535-43. » Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ, Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment, Nature. 2009 Jul 9;460(7252):259-63. » Adamo L, Naveiras O, Wenzel PL, McKinney-Freeman S, Mack PJ, Gracia-Sancho J, Suchy-Dicey A, Yoshimoto M, Lensch MW, Yoder MC, García-Cardeña G, Daley GQ, Biomechanical forces promote embryonic haematopoiesis, Nature. 2009 Jun 25;459(7250):1131-5. doi: 10.1038/nature08073. Epub 2009 May 13. » Wang Y, Yates F, Naveiras O, Ernst P, Daley GQ, Embryonic stem cell-derived hematopoietic stem cells. Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19081-6. Epub 2005 Dec 15.

EPFL School of Life Sciences - 2014 Annual Report

Schoonjans Lab Kristina Schoonjans

Adjunct Professor

http://schoonjans-lab.epfl.ch

Introduction

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

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

Keywords

Liver-gut axis, macrophages, bile acids, nutrient sensing, intermediary metabolism, immuno-metabolism, nuclear receptors, TGR5, type 2 diabetes, atherosclerosis.

Results Obtained in 2014

In the past we established the metabolic role of several enterohepatic nuclear receptors and causally linked their functions to immune regulation and cancer. An example is the enterohepatic orphan nuclear receptor, LRH-1, which we identified as a critical regulator of hepatic glucose sensing, steroid hormone production and of bile acid homeostasis. We showed that some of these actions, if perturbed by inappropriate activity of LRH-1, have farreaching effects on multiple intestinal diseases, including IBD and colorectal cancer. More recently, we identified SUMOylation as a prime mode of LRH-1 regulation. We discovered that SUMOylation of LRH-1 promotes its interaction with the co-repressor, PROX1, and selectively inhibits gene programs linked to reverse cholesterol transport. By generating an LRH-1 K289R knockin mouse model, we showed that SUMOylation-defective LRH-1 mice display enhanced cholesterol and bile acid fluxes in the liver and are protected against the development of atherosclerosis, highlighting the physiological and pathophysiological importance of this post-translational modification of LRH-1. Earlier studies in our lab also identified bile acids as endocrine regulators of energy expenditure and glucose homeostasis, through the activation of the GPCR, TGR5. More recently, we have highlighted the role of macrophage TGR5 in the context of inflammation-driven metabolic disorders, such as atherosclerosis. In a follow-up study, we provided evidence that the anti-inflammatory response of TGR5 also directly contributes to the insulin sensitizing effects of bile acids. More specifically, we showed that TGR5 activation reduces chemokine expression in macrophages via mTOR-dependent stimulation of translation of the dominant-negative C/EBPÎ˛-LIP isoform, thereby ameliorating obesity-induced insulin resistance

EPFL School of Life Sciences - 2014 Annual Report

Team Members PhD Students Vera Lemos Pan Xu

Project Student Silas Kieser

Technicians Thibaud Clerc Soline Odouard

Administrative Assistant Soledad Andany

IBI - Institute of Bioengineering

Postdoctoral Fellows Alessia Perino Ning Shen Matthias Stein

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

Selected Publications » Alemi F, Kwon E, Poole DP, Lieu T, Lyo V, Cattaruzza F, Cevikbas F, Steinhoff M, Nassini R, Materazzi S, Guerrero-Alba R, Valdez-Morales E, Cottrell GS, Schoonjans K, Geppetti P, Vanner SJ, Bunnett NW, Corvera CU. The TGR5 receptor mediates bile acid-induced itch and analgesia. J Clin Invest. 2013, 123, 1513-30. » Zhang C, Large MJ, Duggavathi R, DeMayo FJ, Lydon JP, Schoonjans K, Kovanci E, Murphy BD. Liver receptor homolog-1 is essential for pregnancy. Nat Med. 2013, 19, 1061-6. » Oosterveer M.H. and K. Schoonjans. Hepatic glucose sensing and integrative pathways in the liver. Cell Mol. Life Sci. 2014, 71, 1453-67. » Perino A. and K. Schoonjans. Another Shp on the horizon for bile acids. Cell Metab. 2014, 20, 203-5. » Macchiarulo A., A. Gioiello A, C. Thomas, T.W. Pols, R. Nuti, C. Ferrari, N. Giacchè, F. De Franco, M. Pruzanski, J. Auwerx, K. Schoonjans and R. Pellicciari. Probing the binding site of bile acids in TGR5. ACS Med Chem Lett. 2013, 4, 1158-62. » Stein S., M.H. Oosterveer, C. Mataki, P. Xu, V. Lemos, R. Havinga, C. Dittner, D. Ryu, K.J. Menzies, X. Wang, A. Perino, S.M. Houten, F. Melchior and K. Schoonjans. SUMOylation-dependent LRH-1/PROX1 interaction promotes atherosclerosis. Cell Metab. 2014, 20, 603-13. » Ryu D., Y.S. Jo, G. Lo Sasso, S. Stein, H. Zhang, A. Perino, J.U. Lee, M. Zeviani, R. Romand, M.O. Hottiger, K. Schoonjans and J. Auwerx. A SIRT7-dependent acetylation switch of GABPβ1 controls mitochondrial function. Cell Metab. 2014, 20, 856-69. » Perino A., T.W.H. Pols, M. Nomura, R. Pellicciari and K. Schoonjans. TGR5 reduces macrophage migration through mTOR-induced C/EBP� differential translation. J Clin Invest. 2014, 124, 5424-36.

EPFL School of Life Sciences - 2014 Annual Report

Suter Lab David Suter

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

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

Introduction

David Suter obtained his MD/PhD at the University of Geneva on stem cell biology. He then worked on single cell monitoring of transcription in Geneva before joining Harvard University where he developed a new method for single molecule live imaging of transcription factors in mammalian cells. Since 2013, he is a Swiss National Science Foundation Professor and tenure track Assistant Professor at the Bioengineering Institute of the EPFL School of Life Sciences. His research focuses on mechanisms of cell fate choices using single cell and single molecule approaches.

We are interested in understanding how cell fate choices are made during early embryogenesis, and use embryonic stem (ES) cells as a model system. ES cells are derived from the inner cell mass of the embryo at the blastocyst stage. They can be maintained in culture and instructed to differentiate towards virtually any cell type of the body, thereby providing a powerful tool to study developmental processes in vitro. In addition, they are a promising source for future cell therapy applications, which aim at replacing cells lost in pathological conditions such as Parkinson’s disease, myocardial infarction, diabetes, and other major human diseases. Our aim is to decipher the molecular mechanisms underlying cell fate choices made at early developmental stages. To address this question, we are using new single-cell and single-molecule approaches to investigate the dynamics of gene expression during embryonic stem (ES) cell differentiation and their relationship to cell fate choices. We are particularly interested in the following questions: • How does gene expression fluctuate in ES cells, and to what extent do these fluctuations influence cell fate decisions ? • What are the gene regulatory networks active at different stages of differentiation ? • What are the dynamics of DNA-binding proteins in ES cells and differentiated cells ?

Keywords

Embryonic stem cells, gene expression dynamics, single cell analysis, single molecule imaging, cell fate choices, high throughput screening.

Results Obtained in 2014

Over the past year we have been working on the development of molecular and cellular tools to monitor gene expression at different levels. First, we improved and adapted our previously developed approach to monitor transcription at high temporal resolution in single embryonic stem (ES) cells. Briefly, this method is based on gene trap of a short-lived luciferase under the control of various endogenous genes. The oscillations of the luminescence signal can then be deconvolved to obtain time traces of transcriptional oscillations. Second, we developed a CRIPSR-Cas9 knock-in approach to tag endogenous transcription factors with luciferase. We successfully generated a heterozygous knock-in ES cell line allowing to monitor absolute levels of Sox2 in single living cells. We are currently engineering a homozygous Sox2-luciferase knock-in cell line that will be used to correlate Sox2 fluctuations to cell fate choices. Third, we developed a new method to analyze the contribution of protein synthesis and degradation to protein level fluctuations in single living cells. Briefly, we generated over 100 ES cell lines in which different endogenous proteins are tagged with a fluorescent timer, allowing to disentangle changes in protein synthesis from changes in protein degradation. Our ultimate goal is to analyze the contribution of protein synthesis and degradation to changes in protein level both in undifferentiated ES cells and during differentiation. Finally, at the end of 2014 we started a parallel line of research focused on the development of a new functional high throughput screening strategy to discover novel mediators of cell fate choices. We plan to use this new method to discover novel regulators of the first specification events occurring in the embryo proper, using in vitro differentiation of ES cells as a model system.

EPFL School of Life Sciences - 2014 Annual Report

Team Members PhD Students Andrea Alber Elias Friman Aleksandra Mandic Mahé Raccaud Daniel Strebinger Onur Tidin

Technician Cédric Deluz

Administrative Assistant Laura Bischoff

IBI - Institute of Bioengineering

Single frame of a gene trap mouse embryonic stem cell line taken with our luminescence microscope. Monitoring luminescence intensity over time allows to follow the expression of endogenous genes in single living cells, with a time resolution of 5 minutes over several days of recording.

Selected Publications » Zhao ZW*, Roy R*, Gebhardt JC*, Suter DM*, Chapman AR, Xie XS. *Equal contribution (2014). Spatial organization of RNA polymerase II inside a mammalian cell nucleus revealed by reflected light-sheet superresolution microscopy. Proc. Natl.Acad.Sci U S A. 111(2):681-6. » Molina N*, Suter DM*†, Cannavo R, Zoller B, Gotic I, Naef F†. *Equal contribution. †Corresponding authors (2014) Stimulus-induced modulation of transcriptional bursting in a single mammalian gene. Proc. Natl.Acad.Sci U S A. 110(51):20563-8. » Gebhardt JCM* Suter DM*, Roy R, Zhao ZW, Chapman A, Basu S, Maniatis T, Xie XS. *Equal contribution (2013). Probing Transcription Factor DNA Binding at the Single Molecule Level in Live Mammalian Cells. Nature Methods 10(5):421-6.

EPFL School of Life Sciences - 2014 Annual Report

Swartz Lab Melody Swartz

Full Professor

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

Introduction

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

The human body has roughly 1000 lymph nodes (LN) that act as subsidiary immune centers where adaptive immune responses are launched and local tolerance is maintained. Lymphatic vessels are the conduits that communicate local conditions to these LNs by transporting immune cells as well as the cytokines, growth factors, and antigens present in the periphery. Once considered simply a passive ‘sewer drain’, a major focus of our lab is the active roles that lymphatics play in regulating immunity. By uncovering its complex roles in immunity and tolerance, we hope to understand – and ultimately manipulate – the immunomodulatory roles of lymphatic vessels in cancer progression and metastasis.

Keywords

Lymphatics, cancer, immunomodulation, lymphangiogenesis, immunology, in vitro models, microfluidics, intravital imaging, nanoparticles, immunotherapy, antigen presentation.

Results Obtained in 2014

In 2014, we furthered our understanding of how tumor-associated lymphangiogenesis promotes immune tolerance and directly demonstrated that lymphatic endothelial cells (LECs) can scavenge and process exogenous antigen for MHCI presentation, leading to dysfunctional activation of CD8+ T cells (Hirosue et al, 2014). In collaboration with Stephanie Hugues’s lab at the University of Geneva, we found that LEC expression of MHCII could dysfunctionally activate CD4+ T cells (Dubrot et al, 2014). Furthermore, although LECs express endogenous, IFN-g-inducible MHCII, they could also acquire peptide-MHC II complexes from dendritic cells via exosomes. In both of these studies, LECs expressed higher levels of PD-L1 compared to other LN stromal cells, leading to early PD-1 expression by T cells. In collaboration with the Hubbell lab (EPFL), we explored targeting strategies for nanoparticle cancer vaccines. Although tumor-draining (td) LNs are immune suppressed, they were also more antigen-primed and ultimately more sensitive to immune activation compared to non-tdLN, suggesting that specific targeting of tdLN could be interesting for immunotherapy. Our lab continued to develop new tools for exploring lymphatic immunophysiology. Our intravital imaging method allows real-time investigation of tumor cell migration and interactions with the extracellular matrix (Guç et al., 2014 and Kilarski et al., 2013). Stromal cell, including LECs, and immune cell interactions can be observed using this method. We have also developed microfluidic chambers to study both interstitial and transmural flow, the two types of flow that the LECs experience, especially in the initial lymphatics (Pisano et al, in revision). In summary, our research accomplishments in 2014 bring us closer to our overall goals of elucidating the immunological roles of LECs and lymph angiogenesis in cancer and more generally in regulating immunity and tolerance, so that we can develop novel therapeutic strategies to exploit and target lymphatics for immunomodulation.

EPFL School of Life Sciences - 2014 Annual Report

Team Members Postdoctoral Fellows Marie Ballester Maria Broggi Cara Buchanan Catherine Card Sachiko Hirosue Jeanbart Laura Witold Kilarski Oliver Scott Shann Yu

PhD Students Manuel Fankhauser Gabriele Galliverti Esra Güç Sylvie Hauert Marco Pisano Lambert Potin Marcela Rincon Valentina Triacca Ingrid Van Mier Efthymia Vocali

Vistiting Scientists Prof. Sanjay Kumar Dr. Renata Mecyk Kopec

Technicians Patricia Corthésy Henrioud Yassin Ben Saida

Administrative Assistants Ingrid Margot Stéphanie Bouchet

Master’s /Internship Students Christopher Tremblay Thomas Vetterli

IBI - Institute of Bioengineering

Live imaging of the tumor microenvironment using multi-photon microscopy. Shown is the tumor margin of an implanted B16-F10 melanoma (cyan) with total fibrillar collagen detected by second harmonic generation (SHG, green) and the extracellular matrix protein tenascin C (red), detected using intravital immunofluorescence. Scale 100 µm.

Selected Publications » » » » » » » » »

S Hirosue, et al. (2014). Steady-state antigen scavenging, cross-presentation and CD8+ T cell priming: a new role for lymphatic endothelial cells. J. Immunol. 192(11):5002-11. L Jeanbart, M Ballester, A de Titta, P Corthésy, P Romero, JA Hubbell, MA Swartz (2014). Enhancing efficacy of anticancer vaccines by targeted delivery to tumor-draining lymph nodes. Cancer Immunol Res. 2(5):436-47. J Dubrot, et al. (2014). Lymph node stromal cells acquire peptide-MHCII complexes from dendritic cells and induce antigen-specific CD4+ T cell tolerance. J Exp. Med. 221(6):1153-66. C.M. Card, S.S. Yu, M.A. Swartz (2014). Emerging roles of lymphatic endothelium in regulating adaptive immunity. J. Clin. Invest. 124(3):943-52. SN Thomas, E Vokali, AW Lund, JA Hubbell, and MA Swartz (2014). Targeting the tumor-draining lymph node with adjuvanted nanoparticles reshapes the anti-tumor immune response. Biomaterials, 35(2):814-24. A de Titta, et al. (2013). Nanoparticle conjugation of CpG enhances adjuvancy for cellular immunity and memory recall at low dose. Proc Natl Acad Sci USA. 110(49):19902-7 JM Rutkowski, et al. (2013). VEGFR-3 neutralization inhibits ovarian lymphangiogenesis, follicle maturation, and murine pregnancy. Am. J. Pathol. 183(5):1596-607. IC Kourtis, S Hirosue, A deTitta, J Stegmann, JA Hubbell, and MA Swartz (2013). Peripherally administered nanoparticles target monocytic myeloid cells, secondary lymphoid organs and tumors in mice. PLoS One 8(4):e61646. WW Kilarski, E Güç, JCM Teo, SR Oliver, AW Lund, MA Swartz (2013). Intravital immunofluorescence for visualizing the microcirculatory and immune microenvironments in the mouse ear dermis. PLoS One 8(2):e57135.

» JM Munson, RV Bellamkonda, and MA Swartz (2013). Interstitial flow in a 3D microenvironment increases glioma invasion by a CXCR4-dependent mechanism. Cancer Res. 73(5):1536-46.

EPFL School of Life Sciences - 2014 Annual Report

Aminian Lab Kamiar Aminian

Adjunct Professor - School of Engineering (STI)

http://lmam.epfl.ch

Research Interests

LMAM has three major focus: • 1) Design of measuring and analysing systems using wearable technology for biomechanics of movement; Kamiar Aminian received his PhD degree in biomedical engineering in 1989 from EPFL. He is currently Professor of medical instrumentation and the director of the Laboratory of Movement Analysis and Measurement of EPFL. His research interests include methodologies for human movement monitoring and analysis in real world conditions mainly based on wearable technologies and inertial sensors with emphasis on gait, physical activity and sport. He is author or co-author of more than 450 scientific papers published in reviewed journals and presented at international conferences and holds 8 patents related to medical devices.

• 2) Monitoring patients activity behaviour outside the laboratory and in various clinical settings to gather clinically significant data and objective information on mobility impairment and movement disorders; • 3) Designing assistive devices and original rehabilitation approaches using new technologies and based on adapted physical activity, exercises and interventions that involve cognitive and sensorimotor capacities. Four PhD theses have been finalized in 2013 and 2014 in the field of orthopaedic and sport. Based on these projects a new instrumented knee implant for in vivo 3D kinematics and prediction of implant loosening has been designed and soft tissue artefact has been quantified. Daily upper limb mobility in patients with the cervical and shoulder disease was quantified using inertial sensor. In

swimming, coordination, performance and energy expenditure were measured accurately with the use of sensors worn on the swimming suit. LMAM was involved in the large Cohorte 65+ of the city of Lausanne where for the first time the inter-relation between gait speed and foot clearance were analysed on 1400 elderly adults using inertial sensors. Moreover in the framework of EU project (FARSEEING) LMAM designed a new type of smart home for active aging and analysis of the complexity of physical activity (fractal behaviour and entropy). Member of the LMAM obtained three awards including the Prix de la ville de Lausanne.

Keywords

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

Team Members Postdoctoral Fellows Anisoara Inoescu Alan Bourke Nan Wang Arash Arami

PhD Students Arnaud Barré Cyntia Duc Farzin Dadashi Fabien Massé Christopher Moufawad El Achkar Matteo Mancuso Master’s Students Natacha Vida Martins Sylvain Hirth Rebekka Anker Serge Métrailler Techniciens Jean Gramiger Pascal Morel Exchange PhD Students Nora Millor Lai Kuan Tham Administrative Assistants Francine Eglez Danielle Alvarez

Selected Publications » Dadashi, F., Millet, G. P. and Aminian K. (2014) Estimation of Front-Crawl Energy Expenditure UsingWearable Inertial Measurement Units, IEEE Sensors Journal, 14 (4), 1020-1027 » Arami, A., Rechenmann, J.D. and Aminian, K. (2014) Reference-Free Calibration of Magnetic Sensors for Angle Estimation in Smart Knee Prostheses, IEEE Sensors, 14 (6), 1788-1796 » Duc, C., Pichonnaz, C., Bassin, JP., Farron, A., Jolles, B., Aminian, K. (2014) Evaluation of the muscular activity duration in shoulders with rotator cuff tear using inertial sensors and electromyography” accepted in Physiological Measurement, 35, 2389-2400. » Chardonnens, J., Favre, J., B., Cuendet, F., Gremion, G., Aminian, K. (2014) Measurement of the dynamics in ski jumping using a wearable inertial sensor-based system. Journal of Sports Sciences, 32:6, 591-600 » Paraschiv-Ionescu, A., Buchser E., Aminian K. (2013) Unraveling dynamics of human physical activity patterns in chronic pain conditions, Scientific Reports, 3, 2019, DOI: 10.1038/srep02019 » Barré, A., Thiran, JP., Jolles, BM, Theumann, N., Aminian, K. (2013) Soft tissue artifact assessment during treadmill walking in subjects with total knee arthroplasty, IEEE TBME, 60(11), 3131-3149

EPFL School of Life Sciences - 2014 Annual Report

Fantner Lab Georg Ernest Fantner

Tenure-track Assistant Professor - School of Engineering (STI)

http://lbni.epfl.ch

Georg Fantner is a TenureTrack Assistant Professor for bio- and nano-instrumentation 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 microfabrication. 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.

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

nism”, 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.

Keywords

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

Team Members

Postdoctoral Fellows Jonathan D. Adams Soma Biswas Haig-Alexander Eskandarian PhD Students Maja Dukic Nahid Hosseini Adrian Pascal Nievergelt Pascal Damian Odermatt Oliver Peric Joëlle Ven Chen Yang Master’s Student Santiago Andany Administrative Assistant Tamina Sissoko

Selected Publications » » » »

A. Béduer, T. Braschler, O. Peric, G. E. Fantner and S. Mosser et al. (2015) A Compressible Scaffold for Minimally Invasive Delivery of Large Intact Neuronal Networks, Advanced Healthcare Materials, vol. 4, num. 2, p. 301-312 A. P. Nievergelt, J. D. Adams, P. D. Odermatt and G. E. Fantner. (2014)High-frequency multimodal atomic force microscopy. Beilstein Journal of Nanotechnology, vol. 5, p. 2459-2467, 2014. J. D. Adams, A. Nievergelt, B. W. Erickson, C. Yang and M. Dukic et al. (2015) High-speed imaging upgrade for a standard sample scanning atomic force microscope using small cantilevers. Rev.Sci.Instrum., 85(9) 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

IBI - Co-affiliated Research Groups

Research Interests

EPFL School of Life Sciences - 2014 Annual Report

Guiducci Lab Carlotta Guiducci

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

http://clse.epfl.ch

Research Interests

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

In the clinical research and practice, the need to dramatically increase the number of analyzed samples and push towards “companion diagnostics” can only be fulfilled by highly automatized devices integrating both processing and analytical functions that are entirely or partially disposable. More-than-Moore electronics holds the promise to play a fundamental role in providing analytical systems with high-throughput capabilities, high sensitivity and packaged in USB-sized systems. Prof. Guiducci’s research team is committed to: • innovate the therapeutic drug monitoring practice by DNA aptamer-based assays for in vitro drug quantification;

• push the scalability of solid-state nanosensors to enable high-throughput digital DNA quantification; • provide innovative 3D integration solutions for BioMEMS; • contribute to develop clinically compliant approaches for T cell-based therapeutics by label-free microsystems for cell characterization. The research activity is carried on in close collaboration with clinical institutes and with private companies working in the biomedical, electronic and pharmaceutical fields.

Keywords

Micro-nano sensors, bioanalytics, lab-on-a-chip, 3D sensors, drug monitoring, aptamers, DNA quantification, trigate FET nanosensors, electrochemical impedance, circulating biomarkers.

Team Members Postdoctoral Fellows Enrico Accastelli Giulia Cappi Marco Letizia Enrico Tenaglia

PhD Students Elena-Diana Burghelea Anna Ferretti Samuel Kilchenmann Enrica Rollo Master’s Students Andrea De Micheli Edna Luz Sanchez Vera Administrative Assistant Homeira Salimi

Selected Publications » Cappi, G., Spiga, F., Moncada, Y., Ferretti, A., Beyeler, M., Bianchessi, M. Decosterd, L., Buclin, T., Guiducci, C. (2015) Label-free detection of Tobramycin in Serum by Transmission-LSPR. to appear in Analytical Chemsitry. » Spiga, F., Maietta, P., Guiducci, C., (2015). More DNA−aptamers for small drugs: a capture−SELEX coupled with Surface Plasmon Resonance and High Throughput Sequencing. To appear in ACS Combinatorial Science. » Spiga, F.M., Bonyár, A., Ring, B., Onofri, M., Vinelli, A., Sántha, H., Guiducci, C., Zuccheri, G. (2014) Hybridization chain reaction performed on a metal surface as a means of signal amplification in SPR and electrochemical biosensors. Biosensors and Bioelectronics, 54:102-108. » Guiducci, C., Spiga, F.M. (2013). Another transistor-based revolution: On-chip qPCR . Nature Methods, 10 (7): pp. 617-618. » Kilchenmann, S.C., Rollo, E., Bianchi, E., Guiducci, C. (2013). Metal-coated silicon micropillars for freestanding 3D-electrode arrays in microchannels. Sensors and Actuators, B: Chemical. 185 : 713-719. » 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: Chemical, 176: 225-231. » Temiz, Y., Guiducci, C., Leblebici, Y. (2013). Post-CMOS processing and 3-D integration based on dry-film lithography. IEEE Transactions on Components, Packaging and Manufacturing Technology, 3(9) :1458-1466.

EPFL School of Life Sciences - 2014 Annual Report

Hatzimanikatis Lab Vassily Hatzimanikatis

Associate Professor - School of Basic Sciences (SB)

http://lcsb.epfl.ch 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. Vassily Hatzimanikatis received his PhD (1996) and MS (1994) in Chemical Engineering from the California Institute of Technology and his Diploma (1991) in Chemical Engineering from the Uni Patras. Over the years, he has held positions such as Group leader (ETH Zurich); Senior research Scientist (DuPont and Cargill) and Assistant Professor (Northwestern University). Prof. Hatzimanikatis has authored over 70 technical publications and has three patents and patent applications. He has given over 100 invited lectures. He is the associate editor of the journals Biotechnology & Bioengineering , Biotechnology Journal, Integrative Biology and Metabolic Engineering and on the editorial advisory board of four biotechnology journals.

LCSB develops expertise in the formulation of mathematical models of cellular processes, in process systems engineering methods for the integration, and in the analysis of experimental information from different levels. As most of this information in biological systems is partial and it is subject to uncertainty, researchers in LCSB develop methods that can account quantitatively for the uncertainty in the available information and can provide guidance on solving problems in biotechnology and medicine.

LCSB is one of the leading laboratories in the study of energetics and thermodynamics of complex cellular processes. Research in LCSB has also pioneered the development of computational methods for the discovery of novel metabolic pathways for metabolic engineering and synthetic biology. The applications areas of research in LCSB are: metabolic engineering and metabolic diseases, bioenergetics, protein synthesis, lipidomics, and drug discovery for infectious diseases.

Keywords

Metabolism, metabolic engineering, systems biology, computational biology, chemical biology.

Team Members

Postdoctoral Fellows Anirikh Chakrabarti Georgios Fengos Alexandros Kiparissides Georgios Savoglidis Katerina Zisaki PhD Students Stefano Andreozzi Meric Ataman Yves Berset Anush Chiappino Pepe Tiziano Dallavilla Noushin Hadadi Tuure Hameri Daniel Hernadez Gardiol Joana Piento Vieira Julien Racle Milenko Tokic Stepan Tymoshenko Research Associate Ljubisa Miskovic Administrative Assistant Christine Kupper

Selected Publications » » » »

Hadadi, N., Soh, K. C., Seijo, M., Zisaki, A., Guan, X., Wenk, M.R., and Hatzimanikatis V. (2014). A computational framework for integration of lipidomics data into metabolic pathways. Metab Eng. 23:1-8. Racle, J., Picard, F., Girbal, L., Cocaign-Bousquet, M., Hatzimanikatis, V. (2013). A genome-scale integration and analysis of Lactococcus lactis translation data. PLoS Comput Biol. 9(10):e1003240. Tymoshenko, S., Oppenheim, R. D., Soldati-Favre, D., and Hatzimanikatis, V. (2013). Functional genomics of Plasmodium falciparum using metabolic modelling and analysis. Brief Funct Genomics. 12(4):316-327. Fierro-Monti, I., Racle, J., Hernandez, C., Waridel, P., Hatzimanikatis, V., and Quadroni, M. (2013). A novel pulse-chase SILAC strategy measures changes in protein decay and synthesis rates induced by perturbation of proteostasis with an Hsp90 inhibitor. PLoS One. 8(11):e80423. » Chakrabarti, A., Miskovic, L., Soh, K. C., and Hatzimanikatis, V. (2013). Towards kinetic modeling of genome-scale metabolic networks without sacrificing stoichiometric, thermodynamic and physiological constraints. Biotechnol J. 8(9):10431057.

IBI - Co-affiliated Research Groups

Research Interests

EPFL School of Life Sciences - 2014 Annual Report

Ijspeert Lab Auke Ijspeert

Associate Professor - School of Engineering (STI)

http://biorob.epfl.ch/

Research Interests

Auke Ijspeert is an associate professor at the EPFL in the Institute of Bioengineering, and head of the Biorobotics Laboratory. He is also an 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.

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: • to program and design robots that exhibit motor skills with the same efficiency, adaptivity, and robustness as animals, and • to get a better understanding of the functioning of animals using numerical simulation and robots as scientific tools. Together with neurobiologists (Jean-Marie Cabelguen and Sten Grillner), we have developed mathematical models of the neural circuits controlling locomotion in lower vertebrates. We have demonstrated how a primitive neural circuit for swimming like the one found in the lamprey can be extended by phylogenetically more recent limb oscillatory centers to explain the ability of salamanders to switch between swimming and walking. These models have been tested in an innovative salamander-like robot capable of swimming and walking.

We also develop a dynamical systems approach for controlling movements in robots. For instance, we designed the concept of dynamical movement primitives: nonlinear dynamical systems with well-defined attractor properties that can learn demonstrated discrete or rhythmic movements. Our methods are applied to various robots (quadruped, humanoid and reconfigurable modular robots) and more recently to lower limb exoskeletons for patients with locomotor deficiencies.

Keywords

Biorobotics, computational neuroscience, locomotion control, modeling of spinal cord circuits, central pattern generators.

Team Members Postdoctoral Fellows Bonardi Stéphane Colasanto Luca Crespi Alessandro Estier Thomas Melo Kamilo Müllhaupt Philippe Renjewski Daniel

PhD Students Ajallooeian Mostafa Eckert Peter Faraji Salman Horvat Tomislav Mutlu Mehmet Thiandackal Robin Tuleu Alexandre Van der Noot Nicolas Vespignani Massimo Administrative Assistant Fiaux Sylvie

Selected Publications » » » » » » »

A. Ijspeert. Biorobotics: Using robots to emulate and investigate agile animal locomotion, Science, vol. 346, num. 6206, p. 196-203, 2014. D. Floreano, A. Ijspeert and S. Schaal. Robotics and Neuroscience, Current Biology, vol. 24, p. R910-R920, 2014. F. Dzeladini, J. Van Den Kieboom and A. Ijspeert. The contribution of a central pattern generator in a reflex-based neuromuscular model, Frontiers In Human Neuroscience, vol. 8, 2014. M. D. Mcdonnell, K. Boahen, A. Ijspeert and T. J. Sejnowski. Engineering Intelligent Electronic Systems Based on Computational Neuroscience, in Proceedings Of The IEEE, vol. 102, num. 5, p. 646-651, 2014. A. J. Ijspeert, J. Nakanishi, H. Hoffmann, P. Pastor and S. Schaal. Dynamical Movement Primitives: Learning Attractor Models for Motor Behaviors, 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. A. Sproewitz, A. Tuleu, M. Vespignani, M. Ajallooeian and E. Badri et al. Towards Dynamic Trot Gait Locomotion---Design, Control and Experiments with Cheetah-cub, a Compliant Quadruped Robot, in International Journal of Robotics Research, vol. 32, num. 8, p. 932 - 950, 2013.

EPFL School of Life Sciences - 2014 Annual Report

Johnsson Lab Kai Johnsson

Full Professor - School of Basic Science (SB)

http://lip.epfl.ch The primary research interests of the Johnsson group are in the field of chemical biology and its major scientific achievements were in the following three areas:

Kai Johnsson obtained his PhD at ETHZ in Organic Chemistry. After a postdoctoral stay at UC Berkeley he took a position as a tenuretrack assistant professor at EPFL in 1999. Continuing at the EPFL, Prof. Johnsson then became an Associate Professor (2005) and finally a Full Professor (2009). He has received several awards for his ground breaking work in protein engineering and chemical biology.

Protein-based tools for research in biology and medicine One of the main achievements of the lab is the development of a new class of protein tags, i.e. SNAP-tag, CLIP-tag and ACP-tag, which can be labeled with synthetic probes in living cells. These tags have become popular research tools as they enable scientists to approach problems that cannot be resolved with conventional techniques. New fluorescent probes One of the key strengths of the Johnsson group is its expertise in synthetic chemistry. This has allowed the group to design and synthesize various novel fluorescent probes to visualize biochemical activities.

Drug mechanism of action The Johnsson group has a long-standing interest in studying the mechanism of action of clinically used drugs or drug candidates. For example, the group was able to identify the target of the important anti-inflammatory drug sulfasalazine, whose mechanism of action has remained obscure since its introduction in 1942! The Johnsson group furthermore identified an off-target for anti-bacterial sulfa drugs that provides a rational for the CNS side effects of this important class of drugs. This work should also translate into an improved medical use of sulfa drugs.

Keywords

Chemical biology, protein engineering, fluorescent probes.

Team Members

Postdoctoral Fellows Rudolf Griss Julien Hiblot Grazvydas Lukinavicius Luc Reymond Alberto Schena Lin Xue PhD Students Hellen Farrants Nioclas Goeldel Olvier Sallin Silvia Scarabelli Administrative Assistant Claudia Gasparini

Selected Publications » Lukinavicius, G., Reymond, L., D’Este, E., Masharina, A., Gottfert, F., Ta, H., Guther, A., Fournier, M., Rizzo, S., Waldmann, H., Blaukopf, C., Sommer, C., Gerlich, D. W., Arndt, H. D., Hell, S. W., Johnsson, K. (2014). Fluorogenic probes for live-cell imaging of the cytoskeleton. Nature Methods. 11, 731. » Griss, R., Schena, A., Reymond, L., Patiny, L., Werner, D., Tinberg, C. E., Baker, D., Johnsson, K. (2014). Bioluminescent sensor proteins for point-of-care therapeutic drug monitoring. Nature Chem Biol. 10, 598. » Haruki, H., Pedersen, M. G., Gorska, K. I., Pojer, F., Johnsson, K. (2013). Tetrahydrobiopterin biosynthesis as an off-target of sulfa drugs. Science. 340, 987. » Lukinavicius, G., Lavogina, D., Orpinell, M., Umezawa, K., Reymond, L., Garin, N., Gonczy, P., Johnsson, K. (2013). Selective Chemical Crosslinking Reveals a Cep57-Cep63-Cep152 Centrosomal Complex. Curr Biol. 23, 265. » Lukinavicius, G., Umezawa, K., Olivier, N., Honigmann, A., Yang, G., Plass, T., Mueller, V., Reymond, L., Correa, I. R. Jr., Luo, Z. G., Schultz, C., Lemke, E. A., Heppenstall, P., Eggeling, C., Manley, S., Johnsson, K. (2013). A near-infrared fluorophore for live-cell super-resolution microscopy of cellular proteins. Nature Chemistry. 5, 132.

IBI - Co-affiliated Research Groups

Research Interests

EPFL School of Life Sciences - 2014 Annual Report

Jolles-Haeberli Lab Brigitte Jolles-Haeberli

Adjunct Professor - School of Enginerring (STI) - Director of Center of Translational Biomechanics

http://cbt.epfl.ch/

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. Brigette Haeberli-Jolles graduated from EPFL with a MSc Diploma of Professional Engineer in Microtechnology in 1990. In 1995, she obtained her MD. She then received the Diploma in Clinical Epidemiology in 2002 and completed a Clinical Fellowship in Arthritis Surgery at the University of Toronto and obtained the FMH Specialist title in Orthopaedic the same year. In 2008 she was nominated Adjunct Professor (EPFL) where she heads the Interinstitutional Center of Translational Biomechanics (CBT). She was nominated Associate Professor (UNIL) in 2010 and is the director of the Swiss BioMotion Lab.

Our groups 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.

analyses, original solutions are developed such as fetal cell therapy, scaffolds with high mechanical properties or orthopaedic implants used as drug delivery systems.

Team Members

Keywords

PhD Student Adeliya Latypova

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

We also carry out work in tissue engineering of musculoskeletal tissues, implant and joints biomechanics, drug delivery systems and mechanobiology. A combination of biomechanical and biological approaches is used to describe and understand different clinical problems of interest such as bone loss following total joint arthroplasty, arthritis or intervertebral disc degeneration. Based on these

Postdoctoral Fellow Julien Favre

Master’s Students Alessandro Cavinato Pritish Chakravarty Laura Dalang Administrative Assistants Aline Inamahoro Center Groups

• LBO Lab • LMAM Lab for orthopaedic and sport medicine activities • Regenerative Therapy Unit (CHUV) • Swiss BioMotion Lab (CHUV)

Selected Publications » Grzesiak A, Aminian K, Lécureux E, Jobin F, Jolles BM. Total hip replacement with a collarless polished cemented anatomic stem: clinical and gait analysis results at ten years follow-up. Int Orthop. 2014 Apr;38(4):717-24. doi: 10.1007/ s00264-013-2186-9. » Hasenkamp W, Villard J, Delaloye JR, Arami A, Bertsch A, Jolles BM, Aminian K, Renaud P. Smart instrumentation for determination of ligament stiffness and ligament balance in total knee arthroplasty. Med Eng Phys. 2014 Jun 36(6): 721-5. doi: 10.1016/j.medengphy.2013.12.001. PMID: 24405737. » Favre J, Erhart-Hledik JC, Andriacchi TP. Age-related differences in sagittal-plane knee function at heel-strike of walking are increased in osteoarthritic patients. Osteoarthritis Cartilage. 2014 Mar; 22(3):464-71. doi: 10.1016/j. joca.2013.12.014. PMID: 24445065. » 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. vol. 17, num. 8, p. 845-852, 2014. » Pichonnaz C, Bassin JP, Currat D, Martin E, Jolles BM. Bioimpedance for Oedema Evaluation after Total Knee Arthroplasty. Physiother Res Int 2013 Sep;18(3):140-7. doi: 10.1002/pri.1540. » Nicodeme JD, Löcherbach C, Jolles BM. Tibial tunnel placement in posterior cruciate ligament reconstruction: a systematic review. Knee Surg Sports Traumatol Arthros 2014 Jul;22(7):1556-62; DOI 10.1007/s00167-013-2563-3.

EPFL School of Life Sciences - 2014 Annual Report

Lacour Lab Stéphanie P. Lacour

Tenure-track Assistant Professor - Bertarelli Foundation Chair in Neuroprosthetic Technology - Center for Neuroprosthetics - School of Engineering (STI)

http://lsbi.epfl.ch

Stéphanie P. Lacour holds 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). She is the recipient of the 2006 MIT TR35, a University Research Fellowship from the Royal Society (UK), a European Research Council ERC Starting Grant, the 2011 Zonta award and the 2014 World Economic Forum Young Scientist award.

Bioelectronics integrates principles of electrical engineering to biology, medicine and ultimately health. The Laboratory for Soft Bioelectronics Interfaces (LSBI) challenges and seeks to advance our fundamental concepts in man-made electronic interfaces applied to biological systems. Specifically, the focus is on designing and manufacturing electronic devices with mechanical properties close to that of the host biological tissues so that long-term reliability and minimal perturbation are induced in vivo and/or truly wearable systems become possible. Applications include assistive technologies for patients with impaired neurological functions in the form of soft implantable electrodes, and wearable interfaces in skin-like formats for prosthetic tactile skins. We use fabrication methods borrowed from the MEMS industry and adapt them to soft substrates like elastomers.

We develop novel characterization tools adapted to mechanically compliant bioelectronic circuits. Moving soft bioelectronics forward requires innovation in the fields of materials science, fabrication, engineering and biocompatibility, and a multidisciplinary mindset.

Keywords

Microfabrication, soft bioelectronics, implantable electrodes, elastomer, electronic skin.

Team Members Postdoctoral Fellows De Luca Alba Gerratt Aaron Gupta Swati Kulmala Tero Minev Ivan Musick Kate PhD Students Gribi Sandra Guex Amélie Hirsch Arthur Michaud Hadrien Michoud Frédéric Paulou Cédric Romeo Alessia Wu Yi-Li Master’s Students Pas Jolien Young Jolien Administrative Assistants Daidié Christel Weissenberger Carole

Selected Publications » Minev IR*, Musienko P*, Hirsch A, Barraud Q, Wenger N, Moraud EM, Gandar J, Capogrosso M, Milekovic T, Asboth L, Torres RF, Vachicouras N, Liu Q, Pavlova N, Duis S, Larmagnac A, Voros J, Micera S, Z. Suo, Courtine G*, and Lacour SP* (2015). Electronic dura mater for long-term multimodal neural interfaces. Science, 347(6218): 159-63. » Gerratt AP, Sommer N, Lacour SP and Billard A (2014), Stretchable capacitive tactile skin on humanoid robot fingers - first experiments and results, 2014 IEEE-RAS International Conference on Humanoid Robots, Madrid, Spain, paper 202617. » Robinson A, Aziz A, Liu Q, Suo Z, and Lacour SP (2014). Hybrid stretchable circuits on silicone substrate, Journal of Applied Physics, 115(14): 143511. » D. J. Chew DJ, Zhu L, Delivopoulos E, Minev IR, Musick KM, Mosse CA, Craggs M, Donaldson N, Lacour SP, McMahon SB, and Fawcett JW (2013), A microchannel neuroprosthesis for bladder control after spinal cord injury in rat Science Translational Medicine, 5(210), 210ra155. » Vandeparre H, Liu Q, Minev IR, Suo Z, and Lacour SP (2013), Localization of folds and cracks in thin metal films coated on flexible elastomer foams, Advanced Materials, 25(22), 3117-21. » A. Romeo, Q. H. Liu, Z. G. Suo, and S.P. Lacour, “Elastomeric substrates with embedded stiff platforms for stretchable electronics,” Applied Physics Letters, 2013, 102(13), 131904.

IBI - Co-affiliated Research Groups

Research Interests

EPFL School of Life Sciences - 2014 Annual Report

Lasser Lab Theo Lasser

Full Professor - School of Engineering (STI)

lob.epfl.ch

Research Interests

The Laboratoire d’Optique Biomédicale (LOB) pursues research on optical functional imaging for life sciences and medicine.

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

We pioneered Optical Coherence Microscopy (OCM) as a label-free 3D imaging modality. OCM has been successfully applied for high resolution imaging of islets of Langerhans in the pancreas of living mice. The latest achievement has been “diabetes imaging” where we succeeded in imaging transplanted islets (in the anterior eye chamber) during several weeks from the pre-diabetic to the final diabetic state in NOD mice. This animal model and imaging modality is an ideal platform for diabetes research and drug testing.

Our recent research on super-resolved cell imaging, based on SOFI, allows 3D living cell imaging with a spatial resolution < 80 nm. The fast 3D acquisition is an additional feature for functional cell monitoring. More images related to our research can be seen on www. voirestsavoir.ch .

Keywords

Optical microscopy, tomography, super-resolution, diabetes, Alzheimer disease, mitochondria.

Brain Imaging in rodents revealed the extra cellular plaque formation and its progression during several weeks. Recently we extended this OCM imaging towards functional brain imaging trying to “see” the brain response upon electrical stimuli with high spatial and temporal resolution.

Team Members Postdoctoral Fellows Jerome Extermann Taoufiq Harach Amir Nahas Marcin Sylwestrzak Daniel Szlag Tristan Bolmont PhD Students Corinne Berclaz Severine Coquoz Tomas Lukes Paul Marchand David Nguyen Azat Sharipov Miguel Sison Master’s Students Adrien Descloux Moritz Schmidlin Arik Girsault Technical Employee Antonio Lopez Engineer Antonio Lopez Administrative Assistant Noelia Simone

Selected Publications » » » » »

Geissbuehler, Stefan; Sharipov, Azat; Godinat, Aurelien; et al.. (2014) Live-cell multiplane three-dimensional super-resolution optical fluctuation imaging. Nature Communications 5, Article Number: 5830 . Broillet, Stephane; Szlag, Daniel; Bouwens, Arno; et al. (2014)Visible light optical coherence correlation spectroscopy. Optics Express 22(18) : 21944-21957. Bouwens, Arno; Bolmont, Tristan; Szlag, Daniel; et al. (2014) Quantitative cerebral blood flow imaging with extended-focus optical coherence microscopy. Optics Letters 39 (1) : 37-40. Geissbuehler, Matthias; Lasser, Theo. (2013). How to display data by color schemes compatible with red-green color perception deficiencies. Optics Express ,21(8):9862-9874. Bolmont, Tristan; Bouwens, Arno; Pache, Christophe; et al., Label-Free Imaging of Cerebral beta-Amyloidosis with Extended-Focus Optical Coherence Microscopy. (2012)Journal Of Neuroscience, 32 (42) :14548-14556 .

EPFL School of Life Sciences - 2014 Annual Report

Maerkl Lab Sebastian Maerkl

Associate Professor - School of Engineering (STI)

http://lbnc.epfl.ch

Sebastian Maerkl received a B.S. degree in Biology and a B.S. degree with honors in Chemistry from FairleighDickinson University. He then joined the Biophysics and Biochemistry Option at Caltech as a graduate student and contributed to the early development of microfluidic technology. 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 SSVAmbition.

The Maerkl lab conducts research at the interface of engineering and biology and we are active in the areas of systems biology, synthetic biology and molecular diagnostics. We are driven by a desire to learn how to rationally design and engineer biological systems. Unfortunately, despite a vast foundation of fundamental biological knowledge accumulated over the last century, it remains difficult to engineer biological systems, indicating that basic biological research alone is not sufficient to enable biological engineering. We propose that injecting engineering concepts into biology such as reverse engineering, quantitative analysis, and computational/biophysical modeling will enable biological engineering and fundamentally change how the scientific community and the general public applies biological systems in the 21st century.

Progress in biological engineering is also heavily dependent on technological and methodological innovation. To address these needs we are developing novel, state-ofthe-art microfluidic technologies and molecular methods to address current limitations in biological engineering and other fields.

Keywords

Microfluidics, systems biology, synthetic biology, diagnostics

Team Members Postdoctoral Fellow Francesco Piraino

PhD Students Matthew Blackburn Henrike Niederholtmeyer Francesca Volpetti Kristina Woodruff Ekaterina Petrova Master’s Students Zuzana Tatarova Amanda Verpoorte Administrative Assistant Helen Chong

Our specific biological interests lie primarily in reverse engineering gene regulatory networks, transcriptional regulation, transcription factor biophysics, cell-free synthetic biology, protein engineering, and in developing next-generation molecular diagnostic devices.

Selected Publications » Knight B., Kubik S., Ghosh B., Bruzzone M.J., Geertz M., Martin V., Denervaud N., Jacquet P., Ozkan B., Rougemont J., Maerkl S.J., Naef F., and Shore D. (2014). Two distinct promoter architectures centered on dynamic nucleosomes control ribosomal protein gene transcription. Genes & Development. DOI: 10.1101/gad.244434.114 » Acimovic S.S., Ortega M.A., Sanz V., Berthelot J., Garcia-Cordero J.L., Renger J., Maerkl S.J., Kreuzer M., and Quidant R. (2014). LSPR Chip for Parallel, Rapid, and Sensitive Detection of Cancer Markers in Serum. Nano Letters. DOI: 10.1021/ nl500574n. » Nobs J.B. and Maerkl S.J. (2014). Long-term single cell analysis of S. pombe on a microfluidic chemostat. PLoS One. DOI: 10.1371/journal.pone.0093466. » Garcia-Cordero J.L. and Maerkl S.J. (2013). A 1,024-sample serum analyzer chip for cancer diagnostics. Lab on a Chip. DOI: 10.1039/C3LC51153G. » Niederholtmeyer H., Stepanova V. and Maerkl S.J. (2013). Implementation of cell-free genetic networks at steady-state. PNAS. DOI: 10.1073/pnas.1311166110. » Denervaud N., Becker J., Delgado-Gonzalo R., Damay P., Rajkumar A.S., Unser M., Shore D., Naef F. and Maerkl S.J. (2013). A chemostat array enables the spatio-temoral analysis of the yeast proteome. PNAS. DOI:10.1073/ pnas.1308265110. » Rajkumar A., Denervaud N. and Maerkl S.J. (2013). Mapping the fine-structure of a eukaryotic promoter input-output function. Nature Genetics. DOI:10.1038/ng.2729. » Woodruff K., Fidalgo L.M., Gobaa S., Lutolf M.P. and Maerkl S.J. (2013). Live Mammalian Cell Arrays. Nature Methods. DOI:10.1038/nmeth.2473.

IBI - Co-affiliated Research Groups

Research Interests

EPFL School of Life Sciences - 2014 Annual Report

Mermod Lab Nicolas Mermod

Full Professor - IBI- UNIL

http://www.unil.ch/biotech/en/home.html

Research Interests

Nic Mermod did a PhD on 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 of the Swiss National Science Foundation, to become full professor and director of the Institute of Biotechnology. Nic’s laboratory is located at the Center for Biotechnology of UNIL and EPFL. He is also co-founder of Selexis SA, a biotechnology company developing therapeuticproducing cell lines, and he has authored a number of scientific publications and patents.

One of our project aims at identifying epigenetic regulatory sequences and/or DNA recombination pathways that mediate more predictable, higher and/or more stable expression of transgenes in mammalian cells, and to identify more effective gene transfer techniques. This work has led to the development of new methods that were successfully applied to the synthesis of therapeutic proteins, and which may improve the development of new approaches to treat muscular dystrophies by cell therapy. Stable and efficient production of heterologous proteins in mammalian cells and transgenic organisms is limited by technological bottlenecks. For instance, the establishment of stable cell lines requires the production and analysis of numerous clonal cell lines in order to detect the most efficient producer cells. Our work indicates that potent epigenetic insulator elements and microhomology mediated DNA recombination pathways act synergistically to mediate and stabilize very high expression of therapeutic proteins by cultured cells. These discoveries led to the creation of biotechnology companies, such Selexis SA in Switzerland and Selexis Inc. in the U.S., which have become world leaders in the manufacture of cells producing

recombinant therapeutic proteins. These genetic elements and transposable vectors also allow efficient expression of therapeutic genes in animal models of incurable human diseases. Our work has shown an improvement in the expression of therapeutic proteins, and therefore of the therapeutic efficacy in the treatment of animal models for Duchenne muscular dystrophy by gene therapy. Favorable results were also obtained from the use of adult stem cells that may be transplanted in cell therapies after gene transfer. By this work, which has been supported by the European Network of Excellence in Gene Therapy, the Swiss Telethon and the Swiss Foundation for Research on Muscle diseases, we hope to reach safe and effective therapies for these diseases.

Keywords

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

Postdoctoral Fellows Niko Niederländer Stéphanie Renaud Niamh Harraghy Elena Aritonovska Solenne Bire Xuan Luo Lucille Pourcell PhD Students Ruthger van Zwieten Deborah Ley Simone Edelmann Kaja Kostyrko Yaroslav Shcherba Matthias Contie Pavithra Iyer Sandra Bosshardt

Engineers, Informaticians and Bioinformaticians Thomas Junier Etienne Lançon Daniel Peter Technicians Yves Dusserre Jacqueline Masternak Armindo Texeira Ione Gutscher

Selected Publications » » » » » » » » »

Team Members

Ley D, Puttini S, van Zwieten R, Iyer P, and Mermod N. (2014). A PiggyBac-mediated approach for muscle gene transfer or cell therapy. Stem Cell Res. 13:390-403 Administrative Assistant Majocchi S, Aritonovska E and Mermod N. (2014). Epigenetic regulatory elements associate with specific histone modifications to prevent silencing of telomeric genes. Nucl. Acids Res., 42:193-204 Nassim Berberat Le Fourn V, Girod PA, Buceta M, Regamey A, and Mermod N. (2014). CHO cell engineering to prevent polypeptide aggregation and improve therapeutic protein secretion. Metab. Eng., 21:91-102 Bire S, Casteret S, Ley D, Mermod N, Bigot Y, and Rouleux-Bonnin F. (2013). Optimization of PiggyBac gene delivery tool using mRNA and insulators. PloS ONE, 8:e82559 Arope S, Harraghy N, and Mermod N. (2013). Molecular characterization of a human matrix attachment region epigenetic regulator. PLoS ONE, 8:e79262 Pjanic M, Schmid CD, Gaussin A, Ambrosini G, Adamcik J, Pjanic P, Plasari G, Kerschgens J, Dietler G, Bucher P and Mermod N. (2013). Nuclear Factor I genomic binding associates with chromatin boundaries. BMC Genomics, 14:99 Ley D, Harraghy N, Le Fourn V, Bire S, Girod P-A, Regamey A, Rouleux-Bonnin F, Bigot Y and Mermod N. (2013). MAR Elements and Transposons for Improved Transgene Integration and Expression. PLoS ONE, 8:e62784 Puttini S, van Zwieten R, Saugy D, Lekka M, Hogger F, Ley D, Kulik AJ and Mermod N. (2013). MAR-mediated integration of plasmid vectors for in vivo gene transfer and regulation. BMC Molec. Biol., 14:26 van Zwieten RW, Puttini S, Lekka M, Witz G, Gicquel-Zouida E, Richard I, Lobrinus JA, Chevalley F, Brune H, Dietler G, Kulik A, Kuntzer T and Mermod N. (2014). Assessing dystrophies and other muscle diseases at nanometer scale by atomic force microscopy. NanoMedicine, 9:393-406

EPFL School of Life Sciences - 2014 Annual Report

Micera Lab Silvestro Micera

Associate Professor - Bertarelli chair in Translational Neurotechnology - Center for Neuroprosthetics -School of Engineering (STI)

http://tne.epfl.ch

Silvestro Micera is Associate Professor and Head of the Translational Neural Engineering Laboratory and Bertarelli Chair in Translational Neuroengineering at 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.

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 kinds of disabilities (spinal cord injury, stroke, amputation, etc.). In particular, the TNE lab’s aim is to be a technological bridge between basic science and the clinical environment. Therefore, TNE’s novel technologies and approaches are designed and developed, starting from basic scientific knowledge in the fields of neuroscience, neurology and geriatrics. The idea being that the better we understand these fields, the better will be the development of clinical solutions.

a wearable system for functional electrical stimulation to restore grasping in highly disabled subjects. The system is currently in clinical testing in Italy.

Keywords

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

In 2014, we published the first example of a biodirectional arm neuroprosthesis in humans. We showed, for the first time, the possibility to develop a real-time bidirectional control of hand prostheses using intraneural peripheral electrodes. We were also deeply involved in the activities led by Professor Courtine’s team to develop a novel neuroprosthesis to restore locomotion using epidural electrical stimulation (EES). Finally, we developed

Selected Publications » Minev IR, Musienko P, Hirsch A, Barraud Q, Wenger N, Moraud EM, Gandar J, Capogrosso M, Milekovic T, Asboth L, Torres RF, Vachicouras N, Liu Q, Pavlova N, Duis S, Larmagnac A, Vörös J, Micera S, Suo Z, Courtine G, Lacour SP., Biomaterials. Electronic dura mater for long-term multimodal neural interfaces. Science. 2015 Jan 9;347(6218):159-63. doi: 10.1126/science.1260318. » Wenger N, Moraud EM, Raspopovic S, Bonizzato M, DiGiovanna J, Musienko P, Morari M, Micera S, Courtine G., Closed-loop neuromodulation of spinal sensorimotor circuits controls refined locomotion after complete spinal cord injury., Science Translational Medicine. 2014 Sep 24;6(255):255ra133. doi: 10.1126/scitranslmed.3008325. » Nguyen TA, Ranieri M, DiGiovanna J, Peter O, Genovese V, Perez Fornos A, Micera S.,A real-time research platform to study vestibular implants with gyroscopic inputs in vestibular deficient subjects.. IEEE Transaction on Biomedical Circuits and Systems 2014 Aug;8(4):474-84. doi: 10.1109/TBCAS.2013.2290089. » Raspopovic S, Capogrosso M, Petrini FM, Bonizzato M, Rigosa J, Di Pino G, Carpaneto J, Controzzi M, Boretius T, Fernandez E, Granata G, Oddo CM, Citi L, Ciancio AL, Cipriani C, Carrozza MC, Jensen W, Guglielmelli E, Stieglitz T, Rossini PM, Micera S., Restoring natural sensory feedback in real-time bidirectional hand prostheses. , Science Translational Medicine 2014 Feb 5;6(222):222ra19. doi: 10.1126/scitranslmed.3006820. » Capogrosso M, Wenger N, Raspopovic S, Musienko P, Beauparlant J, Bassi Luciani L, Courtine G, Micera S. A computational model for epidural electrical stimulation of spinal sensorimotor circuits. Journal of Neuroscience 2013 Dec 4;33(49):19326-40. doi: 10.1523/JNEUROSCI.1688-13.2013.

Team Members Scientists Jack DiGiovanna Stanisa Raspopovic Jacopo Rigosa

Postdoctoral Fellows Marco Capogrosso Martina Coscia Eduardo Martin-Moraud PhD Students Marco Bonizzato Andrea Crema Edoardo D’Anna Emanuele Formento Beryl Jehenne (visiting) Jenifer Miehlbradt T. Khoa Nguyen Francesco M. Petrini (visiting) Elvira Pirondini Sophie Wurth Master’s Students Yann Amoural Laura Dalong Drissi Daoudi Nicolas Duthilleul Philippe Fabrice Gabrielle Federici Ivan Furfaro Manasi Kane Nawal Noelle Kinani Antoine Philippides Isabelle Pitteloud Flavio Raschella’ Georgia Sousouri Aurelie Staphan Administrative Assistant Anouk Hein

IBI - Co-affiliated Research Groups

Research Interests

EPFL School of Life Sciences - 2014 Annual Report

Millán Lab José del R. Millán

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

http://cnbi.epfl.ch

Research Interests

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 braincomputer interfaces. Dr. Millán is an IEEE SMC Distinguished Lecturer.

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, on the order of hundred milliseconds. Our neuroprostheses are explored in cooperation with clinical partners and disabled volunteers for the main purposes of motor restoration and rehabilitation.

BCI applications extend beyond disabled users, as it has the potential to augment the interaction experience by providing information associated to brain correlates of volitional cognitive processes. We are interested in decoding some of these processes during both covert behavior (no observable action) and while the user is undertaking natural actions such as eye movements to scan a scene or body movements to drive a car.

Team Members

Keywords

PhD Students Andrea Biasiucci Pierluca Borsó Lucian Gheorghe Zahra Khaliliardali Stéphanie Martin Michael Pereira Luca Randazzo Sareh Saeedi Christoph Schneider Huaijian Zhang

Brain-computer interfaces, neuroprosthetics, statistical machine learning, neuroscience, translational medicine, EEG, local field potentials, human-robot interaction.

We have continued to design and test brain-computer interface (BCI) principles for replacing lost motor functions and for enhancing interaction experiences. Users with motor disabilities have demonstrated the effectiveness of our brain-controlled devices, which are based on the voluntary, spontaneous modulation of EEG rhythms.

Postdoctoral Fellows Ricardo Chavarriaga Robert Leeb Aleksander Sobolewski Maria Laura Blefari Iñaki Iturrate Kyuhwa Lee Serafeim Perdikis

Master’s Student Laetitia Perroud Research Engineers Xavier Dubas Hadrien Renold Administrative Assistants Beatriz Descloux Najate Géchoul

Selected Publications » Chavarriaga, R., Sobolewski, A., and Millán, J.d.R. (2014). Errare Machinale Est: The Use of Error-related Potentials in Brain-Machine Interfaces. Front. Neurosci. 8:208. doi:10.3389/fnins.2014.00208. » Perdikis, S., Leeb, R., Williamson, J., Ramsey, A., Tavella, M., Desideri, L., Hoogerwerf, E.-J., Al-Khodairy, A., Murray-Smith, R., and Millán, J.d.R. (2014). Clinical Evaluation of BrainTree, a Motor Imagery Hybrid BCI Speller. J. Neural Eng. 11(3):036003. » Iturrate, I., Chavarriaga, R., Montesano, L., Minguez, J., and Millán, J.d.R. (2014). Latency Correction of Event-Related Potentials between Different Experimental Protocols. J. Neural Eng. 11(3):036005. » Carlson, T.E. and Millán, J.d.R. (2013). Brain-Controlled Wheelchairs: A Robotic Architecture. IEEE Robot. Automat. Mag. 20(1):65–73. » Leeb, R., Perdikis, S., Tonin, L., Biasiucci, A., Tavella, M., Molina, A., Al-Khodairy, A., Carlson, T., and Millán, J.d.R. (2013). Transferring Brain-Computer Interfaces beyond the Laboratory: Successful Application Control for Motor-Disabled Users. Artif. Intell. Med. 59(2):121–132. » Borton, D., Micera, S. Millán, J.d.R., and Courtine, G. (2013). Personalized Neuroprosthetics. Sci. Transl. Med. 5(210):210rv2.

EPFL School of Life Sciences - 2014 Annual Report

Pioletti Lab Dominique Pioletti

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

http://lbo.epfl.ch

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

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

Keywords

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

Team Members Group Leader Alexandre Terrier

Postdoctoral Fellow Philippe Abdel-Sayed PhD Students Ulrike Kettenberger Mohamadreza Nassajian Christoph Engelhardt Adeliya Latypova Tanja Hausherr Valérie Malfroy Camine Naser Nasrollahzadeh Mamaghani Jérôme Hollenstein Master’s Students Jules Bourgnon Nicolas Chatel Patrick Schwizer Sandra Gribi Stefania Rissone Raphael Obrist Anouk Grandegeorge Marco Ammann Annick Baur Arthur Hirsch Lab Assistant Sandra Jaccoud Administrative Assistant Virginie Kokocinski

Selected Publications » » » » »

Kettenberger, U., Ston, J., Thein, E., Procter, P., Pioletti, D.P. (2014). Does locally delivered Zoledronate influence peri-implant bone formation? – Spatio-temporal monitoring of bone remodeling in vivo. Biomaterials. 35:9995-10006. Nassajian Moghadam, M., Kolesov, V., Vogel, A., Klok, H.A., Pioletti, D.P. (2014). Controlled release from a mechanically-stimulated thermosensitive self-heating composite hydrogel. Biomaterials. 35:450-456. Abdel-Sayed, P., Darwiche, S., Kettenberger, U., Pioletti, D.P. (2014). The role of energy dissipation of polymeric scaffolds in the mechanobiological modulation of chondrogenic expression. Biomaterials. 35:1890-1897. Gortchacow, M., Terrier, A., Pioletti, D.P. (2013). A flow sensing model for mesenchymal stromal cells using morphogen dynamics. Biophysical J. 104:2132-2136. Terrier, A., Larrea, X., Malroy-Camine, V., Pioletti, D.P., Farron, A. (2013). Importance of the subscapularis muscle after total shoulder arthroplasty. Clinical Biomechanics. 28:146-150.

IBI - Co-affiliated Research Groups

Research Interests

EPFL School of Life Sciences - 2014 Annual Report

Psaltis Lab Demetri Psaltis

Full professor - Dean of the School of Engineering (STI)

http://lo.epfl.ch

Research Interests

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

The Optics Laboratory focuses on biological imaging and optofluidics. Biological imaging deals with phase conjugation through multimode fibers and biological tissues, imaging through biological media and nonlinear optics for bioparticle characterization. Optofluidics focuses on developing technologies for energy harvesting purposes by leveraging the advantages of microfluidic systems. Biological imaging We utilize imaging techniques to improve detection of the types of cochlear damage. In preliminary studies, two-photon fluorescence microscopy is used to detect the damage on individual hair cells located in the inner ear. We study second harmonic generation (SHG) from nanoparticles for new types of imaging applications. The coherent nature of SHG allows us to capture the complex radiated field information, thus allowing for many novel imaging applications.

We develop and research novel applications of ultrafast ablation for microsurgery. Specifically we are developing a catheter device to remove atheroscerotic plaque and a method to remove bone from the cochlea to allow for advanced imaging of the organ of corti. Optofluidics 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, laser ablation, optical microsurgery.

Team Members Scientists Donald Conkey Laurent Descloux Salma Farahi Miguel Modestino Ye Pu Marcin Zielinski

Postdoctoral Fellow Morteza Hasani Shoreh PhD Students Marilisa Romito Grégoire Laporte Mohammad Hashemi Nicolino Stasio Thomas Lanvin Administrative Assistant Carole Loeffen Berthet

Selected Publications » » » » » » » » »

Grégoire P. J. Laporte, Nicolino Stasio, Colin J. R. Sheppard, and Demetri Psaltis (2014), Resolution enhancement in nonlinear scanning microscopy through post-detection digital computation. Optica. 1 (6): 455-460. Claudia Rodriguez, Miguel A. Modestino, Christopher Moser and Demetri Psaltis (2014), Design and cost considerations for practical solar-hydrogen generators. Energy & Environmental science. 7: 3828. Choi JW, Hosseini Hashemi SM, Erickson D, Psaltis D (2014), A micropillar array for sample concentration via in-plane evaporation. Biomicrofluidics. 8 (4): 044108. Hosseini Hashemi SM, Choi JW, Psaltis D (2014), Solar thermal harvesting for enhanced photocatalytic reactions. Physical Chemistry Chemical Physics. 16 (11): 5137-5141. Yang X, Pu Y, Psaltis D (2014), Imaging blood cells through scattering biological tissue using speckle scanning microscopy. Optics Express. 22 (3): 3405-3413. Laporte GPJ, Conkey DB, Vasdekis A, Piestun R, Psaltis D (2013), Double-helix enhanced axial localization in STED nanoscopy. Optics Express. 21 (25): 30984-30992. Goy A, Psaltis D (2013), Imaging in focusing Kerr media using reverse propagation. Photonics Research. 1 (2): 96-101. 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.

EPFL School of Life Sciences - 2014 Annual Report

Radenovic Lab Aleksandra Radenovic

Tenure-track Assistant Professor - School of Engineering (STI)

http://lben.epfl.ch/

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

LBEN works in the research field that can be termed single molecule biophysics. We develop techniques and methodologies based on optical imaging, biosensing and single molecule manipulation with the aim to monitor the behaviour of individual biological molecules and complexes in vitro and in live cells. Our current research is focused on three major directions: • Developing and using nanopores as a platform for molecular sensing and manipulation. In particular, we focus on solid-state nanopores realized either in glass nanocapillaries, or on suspended 2d-material membranes and standard silicon-nitride membranes.

• Developing super-resolution optical microscopy, based on single molecule localizations (SMLM) in cells with molecular-scale resolution, with an aim to extract quantitative information.

Keywords

Nanopores, 2d materials, nanocapillaries, biosensing, optical tweezers Anti-Brownian Electrokinetic (ABEL) trap, single molecule localization microscopy (SMLM) DNA, proteins, DNA-protein interaction.

• Studying how biomolecules function, especially how proteins and nucleic acids interact, using force-based manipulation single-molecule techniques, in particular optical tweezers, optical wrench system, Anti-Brownian Electrokinetic (ABEL) trap and combination of nanopore/nanocapillaries with OT.

Team Members Postdoctoral Fellows Ke Liu Hendrik Deschout Lorenz Steinbock Flavio Mor

PhD Students Roman Bulushev Jiandong Feng Michael Graf Martina Lihter Metin Kayci Arun Shivanandan Alexander Timin (visiting) Lab Assistant Lely Feletti Administrative Assistant Helen Chong

Selected Publications » R. D. Bulushev, L. J. Steinbock, S. Khlybov J. F. Steinbock and A. Radenovic, Measurement the position-dependent electrophoretic force on DNA in a glass nanocapillary, Nano Letters 2014. » H.-C. Chang and A. Radenovic, Electron spin resonance of nitrogen-vacancy defects embedded in single nanodiamonds in an ABEL trap M. Kayci, Nano Letters 14 (9), pp 5335–5341 2014. » C. Macias-Romero, M.E. P. Didier, V.Zubkovs, L. Delannoy, F. Dutto A. Radenovic, and S.Roke, Probing rotational and translational diffusion of nanodoublers in living cells on microsecond time scales Nano Letters 14 (5), pp 2552–2557 2014. » O. Lopez-Sanchez, V. Koman, E. A. Llado, A. Fontcuberta i Morral, A. Radenovic, and A. Kis, Light Generation and Harvesting in a Van der Waals Heterostructures, ACS Nano, 8 (3), pp 3042–3048 2014. » K. Liu, J. D. Feng, A. Kis and A. Radenovic, Atomically thin molybdenum disulfide nanopores with high sensitivity for DNA translocation, ACS Nano 8 (3), pp 2504–2511 2014. » A.Fanget, F. Traversi, S. Khlybov, P. Granjon, A. Magrez, L. Forró and A. Radenovic, Nanopore integrated nanogaps for DNA detection, Nano Letters 14 (1), pp 244–249 2014. » L. J. Steinbock, R. Bulushev, S. Krishnan and A. Radenovic, DNA translocation through low noise glass nanopores, ACS Nano 7 (12), pp 11255–11262 2013. » F. Dutto, H. Martin, A. M. Fontcuberta and A. Radenovic, Enhancement of Second Harmonic Signal in Nanofabricated Cones, Nano Letters 13 (12), pp 6048–6054 2013 . » F. Traversi, C. Raillon, S. M. Benameur, K. Liu, S. Khlybov, M. Tosun, D. Krasnozhon, A.Kis and A. Radenovic, Detecting the translocation of DNA through a nanopore using graphene nanoribbons, Nature Nanotechnology 8,939–945 2013. » O. López Sánchez, D.S. Lembke, M. Kayci, A. Radenovic and A. Kis, Ultrasensitive photodetectors based on monolayer MoS2, Nature Nanotechnology 8, 497–501 2013. » L.J. Steinbock, J.F. Steinbock and A. Radenovic, Controllable shrinking and shaping of glass nanocapilaries under electron irradiation, Nano Letters, 13 (4), pp 1717–1723 2013.

IBI - Co-affiliated Research Groups

Research Interests

EPFL School of Life Sciences - 2014 Annual Report

Renaud Lab Philippe Renaud

Full Professor - School of Engineering (STI)

http://lmis4.epfl.ch

Research Interests

Philippe Renaud joined EPFL in 1993 as an assistant Professor in Microengineering. He was appointed full Professor in 1997. He is Scientific Director of the EPFL Centre of Microtechnology (CMI). Prior to joining EPFL, Professor Philippe Renaud worked in the Sensors and Actuators group at the Swiss Centre for Electronics and Microtechnology (CSEM) in Neuchâtel, Switzerland. He received a Ph.D. in Physics from the University of Lausanne, Switzerland. He conducted his post-doctoral research at the University of California, Berkeley, USA, and then at the IBM Zürich Research Laboratory in Switzerland.

The research of the Microsystems Laboratory 4 (LMIS4) is related to micro and nanotechnologies in biomedical applications (BioMEMS), with emphasis on cell-chips, nanofluidics and bioelectronics. We use the microfabrication technologies available in the cleanrooms of the EPFL Center of MicroNanoTechnology (CMI) for the realization of our devices. We developed new methods in flow cytometry and cell sorting based on the dielectric properties of cells. We also study micro-bioreactors for on-chip co-culture of cells in drug screening and toxicology applications in such areas as breast cancer and Alzheimer’s disease. In parallel we work on a variety of other biomedical applications such as capillary driven blood plasma separation, bioelectronic implants for neural recordings and stimulation, biosensors for environmental monitoring, 3D cell printing and biomechanical sensors for eye pressure or articular implants.

Research on basic nanofluidic phenomena is used to increase our understanding of molecular transport and electrical conductance in nanochannels. Our group has been involved in the valorisation of our research by means of the creation of several start-up companies.

Keywords

Nanotechnology, microfabrication, BioMEMS, cell chip nanofluidics, flow-cytometry, dielectric cell sorting, micro-bioreactor, drug screening, toxicology, implant, neural recording , biosensor, molecular transport.

Team Members Postdoctoral Fellows & Engineers Amélie Beduer Arnaud Bertsch Thomas Braschler Harald van Lintel Robert Meissner Niccolo Piacentini

PhD Students David Bonzon Jonathan Cottet Carolin Drieschner David Forchelet Guillaume Petitpierre Yufei Ren Ludovic Serex Mojtaba Taghipoor Stefano Varricchio Master’s Students Stéphanie Becker Niklas van Neyghem Gaelle Thurre Administrative Assistant Sylvie Clavel

Selected Publications » » » » »

A. Béduer, T. Braschler, O. Peric, G. E. Fantner and S. Mosser et al. A Compressible Scaffold for Minimally Invasive Delivery of Large Intact Neuronal Networks, Advanced Healthcare Materials,.4, 2, 301, 2015. J. J. Vandersarl, A. Mercanzini and P. Renaud. Integration of 2D and 3D Thin Film Glassy Carbon Electrode Arrays for Electrochemical Dopamine Sensing in Flexible Neuroelectronic Implants, Advanced Functional Materials,25,1, p. 78, 2015. M. Shaker, L. Colella, F. Caselli, P. Bisegna and P. Renaud. An impedance-based flow microcytometer for single cell morphology discrimination, Lab on a Chip,14,14, 2548, 2014. A. Kunze, S. Lengacher, E. Dirren, P. Aebischer and P. J. Magistretti et al. Astrocyte–neuron co-culture on microchips based on the model of SOD mutation to mimic ALS, in Integrative Biology, 5, 7, 964, 2013. B. Eker, R. Meissner, A. Bertsch, K. Mehta and P. Renaud. Label-Free Recognition of Drug Resistance via Impedimetric Screening of Breast Cancer Cells, PLoS ONE, 8, 3, e5742, 2013.

EPFL School of Life Sciences - 2014 Annual Report

Roke Lab Sylvie Roke

Associate Professor - Julia Jacobi Chair in Photomedicine - School of Engineering (STI)

http://lbp.epfl.ch/

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

Water is the liquid of life. Its quantum, molecular, and microscopic properties are essential in understanding the complexity of life. The active role that water plays in biology can be understood better by developing and using label-free and non-invasive optical methods that report on multiple length scales, from quantum effects to millisecond/micrometer time and length scales. Examples include:

Topics: • The unexplained charging of hydrophobic/ aqueous interfaces, • The formation and stabilization of amphiphilic aqueous interfaces • The formation and molecular properties of the electric double layer and the role that charge plays in biology.

Sum frequency scattering: Probes molecular composition, orientation, interactions and dynamics on nanoscopic 3D interfaces (e.g. nanodroplets, lipid vesicles).

• Theoretical models that can link our optical readouts to interfacial electrostatic potentials and chirality.

Second harmonic scattering: Probes correlations between water molecules in aqueous systems.

• The role water plays in cellular dynamics, such as the electrical, metabolic and mechanical activity of neurons.

Multiphoton / second harmonic microscopy: based on our scattering technology a high throughput microscope that allows for a 3-4 orders of magnitude improvement in acquisition time was constructed, which can be used for probing cell dynamics, label-free.

Keywords

Team Members

Postdoctoral Fellows Carlos Macias-Romero Gabriele Tocci Chungwen Liang PhD Students Yixing Chen Marie Didier Yvonne Hu Filip Kovacik Cornelis Lütgebaucks Orly Tarun Nikolay Smolentsev Evangelia Zdrali Vitalijs Zubkovs Administrative Assistant Rebecca Veselinov

Water, aqueous interfaces, nonlinear optics / light scattering / imaging, biological imaging, nanodroplets & particles, membranes.

Selected Publications » C. Macias-Romero, M. E. P. Didier, P. Jourdain, P. Marquet, P. Magistretti, O. B. Tarun, V. Zubkovs, A. Radenovic, and S. Roke. (2014). High throughput second harmonic imaging for label-free biological applications. Opt. Express. 22 (25), 31102-31112 » C. Macias-Romero, M. E. P. Didier, L. Delannoy, F. Dutto, A. Radenovic, S. Roke. Probing rotational and translational diffusion of nanodoublers in living cells on microsecond time scales. (2014). Nano Lett. 14, 2552–2557 » R. Scheu, B. M. Rankin, Y. Chen, K. C Jena, D. Ben-Amotz, S. Roke. Charge Asymmetry at Aqueous Hydrophobic Interfaces and Hydration-Shells. (2014). Angew. Chem. Int. Ed.. 53, 9560-9563 » R. Scheu, Y. Chen, H. B. de Aguiar, B. M. Rankin, D. Ben-Amotz, S. Roke. Specific ion effects in surfactant hydration and nanodroplet stabilization. (2014). J. Am. Chem. Soc.. 136, 2040 – 2047 » J-S. Samson, R. Scheu, N. Smolentsev, S. W. Rick, S. Roke. Sum Frequency Spectroscopy of the Hydrophobic Nanodroplet/Water Interface: Absence of Hydroxyl Ion and Dangling OH Bond Signatures. (2014). Chem. Phys. Lett. Frontiers. 615, 124-130 » R. Scheu, Y. Chen, M. Subinya, S. Roke. Stern layer formation induced by hydrophobic interactions, a molecular level study. (2013). J. Am. Chem. Soc..135, 19330 – 19335

IBI - Co-affiliated Research Groups

Research Interests

EPFL School of Life Sciences - 2014 Annual Report

Stellacci Lab Francesco Stellacci

Full Professor - Constellium Chair - School of Engineering (STI) - Director of Integrative Food and Nutrition Center

http://sunmil.epfl.ch

Research Interests

Francesco Stellacci graduated in Materials Engineering at the Politecnico di Milano in 1998 with a thesis on photochromic polymers with Prof. Giuseppe Zerbi and Mariacarla Gallazzi. In 1999 he moved to the Chemistry Department of the University of Arizona for as a post-doc in the group of Joe Perry in close collaboration with the group of Seth Marder. In 2002 he moved to the Department of Materials Science and Engineering at the Massachusetts Institute of Technology as an assistant professor. He was then promoted to associate without (2006) and with tenure (2009). In 2010 he moved to the Institute of Materials at EPFL as a full Professor. He holds the Constellium Chair. Francesco was one of the recipients of the Technology Review TR35 “35 Innovator under 35” award in 2005, and the Popular Science Magazine “Brilliant 10” award in 2007. He has been a Packard Fellow starting 2005.

The Supramolecular Nano-Materials and Interfaces Laboratory (SuNMIL) research focuses on interfacing supramolecular chemistry to nanoscale materials and surface engineering. One of the overarching goals of the group stems from a simple observation. A bird’s eye view of any folded protein shows a complex surface composed of hydrophobic and hydrophilic patches closely packed. To date, little is known on the fundamental properties that such packing determines. SuNMIL aims at finding these properties. They can be basic physical chemistry ones (i.e. interfacial energy, PNAS ‘08, Nature Materials ‘09) as well as biological interactions (interactions with cell membranes, Nature Materials ‘08, Nature Communications ‘14).

The Laboratory spans many fields, from synthesis and characterization to property measurements, with a multidisciplinary approach and many active collaborations. All forms of diversity are welcomed and fostered.

Keywords

Nanoparticles, nanoclusters, supramolecules, mixed selfassembled monolayers, biological interactions.

Team Members Postdoctoral Fellows Guldin Stefan Quy Ong

Le Ouay Benjamin Timothée Nicolas

Jones Samuel Thomas

PhD Students Allegri Sergio

Athanasopoulou Evangelia Nefeli

Bekdemir Ahmet Ertem Bekdemir Elif Güven Zekiye Pelin Jacob Silva Paulo Henrique Kocabiyik Özgün Luo Zhi Müller Marie Nianias Nikolaos Ricci Maria goto Zhao Shun

Administrative Assistant Chiara Donini

Selected Publications » R. C. Van Lehn, M. Ricci, P. H. J. Silva, P. Andreozzi and J. Reguera et al. Lipid tail protrusions mediate the insertion of nanoparticles into model cell membranes, in Nature Communications, vol. 5, 2014. » Y.-S. Yang, R. Carney, y P., F. Stellacci and D. J. Irvine, Enhancing Radiotherapy by Lipid Nanocapsule-Mediated Delivery of Amphiphilic Gold Nanoparticles to Intracellular Membranes, Acs Nano, vol. 8, num. 9, p. 8992-9002, 2014. » R. Huang, R. R. Carney, K. Ikuma, F. Stellacci and B. L. T. Lau, Effects of Surface Compositional and Structural Heterogeneity on Nanoparticle-Protein Interactions: Different Protein Configurations, Acs Nano, vol. 8, num. 6, p. 5402-5412, 2014. » S. Sabella, R. P. Carney, V. Brunetti, M. A. Malvindi, N. Al-Juffali, G. Vecchio, S. M. Janes, O. M. Bakr, R. Cingolani, F. Stellacci and P. P. Pompa, A general mechanism for intracellular toxicity of metal-containing nanoparticles, Nanoscale, vol. 6, num. 12, p. 7052-7061, 2014. » V. Lehn, C. Reid, P. U. Atukorale, R. P. Carney, Y.-S. Yang, F. Stellacci, D. J. Irvine and A. Alexander-Katz, Effect of Particle Diameter and Surface Composition on the Spontaneous Fusion of Monolayer-Protected Gold Nanoparticles with Lipid Bilayers, Nano Letters, vol. 13, num. 9, p. 4060-4067, 2013. » V. L. S. Lapointe, A. T. Fernandes, N. C. Bell, F. Stellacci and M. M. Stevens, Nanoscale Topography and Chemistry Affect Embryonic Stem Cell Self-Renewal and Early Differentiation, Advanced Healthcare Materials, vol. 2, num. 12, p. 16441650, 2013.

EPFL School of Life Sciences - 2014 Annual Report

Stergiopulos Lab Nikos Stergiopulos

Full Professor - School of Engineering (STI)

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 150 publications and holds more than 15 patents in medical technology. He co-founded EndoArt, world leader in telemetric implants for the treatment of congenital heart disease and morbid obesity, Antlia SA, developer of implantable drug delivery pumps and Rheon Medical, developer of the implantable shunt for the surgical treatment of glaucoma.

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 also study the interaction between the heart and arterial system and the resulting wave propagation phenomena, with the goal of understanding hypertension and aging as well to improve 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, erectile dysfunction, implantable devices.

Team Members

Postdoctoral Fellows Rodrigo Araujo Fraga da Silva Bram Trachet PhD Students Thiresia Gialourou Orestis Vardoulis Adan Villamarin Lydia Aslanidou Research & Technical Staff Michel Bachmann Stéphane Bigler Fabiana Fraga Sylvain Roy Administrative Assistants Tamina Sissoko Sylvia Widmer

Selected Publications » Villamarin A, Stergiopulos N, Bigler S, Mermoud A, Moulin A, Roy S. (2014) In vivo testing of a novel adjustable glaucoma drainage device. Investigative ophthalmology & visual science, 55:7520-4. » Papaioannou TG, Protogerou AD, Stergiopulos N, Vardoulis O, Stefanadis C, Safar M, Blacher J. (2014) Total arterial compliance estimated by a novel method and all-cause mortality in the elderly: the PROTEGER study. Age, 36:9661. » Fraga-Silva RA, Costa-Fraga FP, Faye Y, Sturny M, Santos RA, da Silva RF and Stergiopulos N. (2014) An increased arginase activity is associated with corpus cavernosum impairment induced by hypercholesterolemia. The journal of sexual medicine, 11:1173-81. » Villamarin A, Roy S, Bigler S, Stergiopulos N. (2014) A new adjustable glaucoma drainage device. Investigative ophthalmology & visual science, 55:1848-52. » Papaioannou TG, Vardoulis O, Stergiopulos N. (2014) Validation of algorithms for the estimation of pulse transit time: where do we stand today? Annals of biomedical engineering, 42:1143-4.

IBI - Co-affiliated Research Groups

Research Interests

EPFL School of Life Sciences - 2014 Annual Report

Van de Ville Lab Dimitri Van de Ville

Tenure-track Assistant Professor - SNSF Professor - School of Engineering (STI)

http://miplab.epfl.ch

Research Interests

Dimitri Van De Ville holds an SNSF Professorship with Tenure-Track at the School of Engineering at the EPFL. He has a joint affiliation with the Department of Radiology and Medical Informatics at the University of Geneva. He received his M.S. and Ph.D. in Computer Sciences from Ghent University, Belgium. He has been the Chair of the Biomedical Imaging & Signal Processing (BISP) Technical Committee of the IEEE Signal Processing Society. In 2012, he received the Pfizer Research Award in the category ‘Neurosciences and Diseases of the Nervous System’ for the work on fractal organization of the rapid switching between scalp topographies in spontaneous EEG, which was published in the Proceedings of the National Academy of Sciences. In 2014, he was the recipient of a NARSAD Independent Investigator Award.

MIPLab’s mission is to advance our understanding of human brain function in health and disorder using non-invasive imaging techniques. To that aim, we pursue the development and integration of innovative data-processing tools at various stages of the acquisition, analysis, and interpretation pipeline of neuroimaging data. The first highlight is on modelling of functional brain networks at the systems level; i.e., based on whole-brain functional magnetic resonance imaging (fMRI). Using graph theory, multiscale techniques, and pattern recognition we are able to identify and characterise brain networks in a meaningful way during cognitive tasks, as well as alterations by neurological conditions, which opens the potential for new imaging-based biomarkers that might for instance complement neuropsychological testing in prodromal stage of Alzheimer’s Disease. The second highlight is on temporal dynamics of these networks during spontaneous activity. We have pioneered subspace discovery methods for dynamic functional connectivity, which reveal meaningful interactions between large-scale distributed networks in terms of ongoing fluctuations. These techniques bring us closer to capturing the global brain state, which is essential for future development of invasive and non-invasive neuroprosthetics, such as neurofeedback based on real-

time fMRI. Finally, we can also relate the slow dynamics of fMRI back to fast millisecond-scale EEG signals.

Keywords

Signal processing, neuroimaging, pattern recognition, network modeling, neurofeedback, fMRI, EEG, cognitive & clinical applications.

Team Members Postdoctoral Fellows Isik Karahanoglu Yury Koush Djalel Meskaldji Elena Migacheva Maria Giulia Preti Gwladys Rey Frank Scharnowski PhD Students Zafer Dogan Kirsten Emmert Jeffrey Kasten Rotem Kopel Nora Leonardi Naghmeh Ghazaleh David Nguyen Master’s Students Alessandro Cavinato Marta Comino Jeremy Hofmeister Chiara Musimeci Giorgio Policella Davide Zanchi Administrative Assistant Ruth Fiaux

Selected Publications » » » » »

J. A. Kasten, T. Vetterli, F. Lazeyras, D. Van De Ville, “3D-printed Shepp-Logan phantom as a real-world benchmark for MRI,” Magnetic Resonance in Medicine, in press. N. Leonardi, W. Shirer, M. Greicius, D. Van De Ville, “Disentangling dynamic networks: separated and joint expressions of functional connectivity patterns in time,” Human Brain Mapping, vol. 35, pp. 5984-5995, 2014. J. Richiardi, S. Achard, H. Bunke, D. Van De Ville,“Machine learning with brain graphs,” IEEE Signal Processing Magazine, vol. 30, pp. 58-70, 2013. I. Karahanoglu, C. Caballero Gaudes, F. Lazeyras, D. Van De Ville, “Total activation: fMRI deconvolution through spatio-temporal regularization”, NeuroImage, vol. 73, pp.121-134, 2013. N. Leonardi, J. Richiardi, M. Gschwind, S. Simoni, J.-M. Annoni, M. Schluep, P. Vuilleumier, D. Van De Ville, “Principal components of functional connectivity: a new approach to study dynamic brain connectivity during rest,” NeuroImage, vol. 83, pp. 937-950, 2013.

IBI - Co-affiliated Research Groups

EPFL School of Life Sciences - 2014 Annual Report