Annual report - IBI 2015-16 by EPFL School of Life Sciences

IBI

Institute of Bioengineering

Mattias Lutolf - Director

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

.epfl.ch

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

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

auwerx-lab.epfl.ch

Introduction

Results Obtained

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

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

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

IBI - Institute of Bioengineering

Team Members Academic Guest

Keir Menzies ( July to November 2015) Post Doctoral Associates

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

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

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

Selected Publications » Moullan, N., Mouchiroud, L., Wang, X., Ryu, D., Williams,E.G., Mottis, A., Jovaisaite, V., Frochaux, M.V., Quiros, P.M., Deplancke, B., Houtkooper, R.H. and Auwerx, J. (2015). Tetracyclines disturb mitochondrial function across eukaryotic models: a call for caution in biomedical research. Cell Reports 10:1681-1691. » Gariani, K., Menzies, K.J., Ryu, D., Wegner, C.J., Wang, X., Ropelle,E.R.,. Moullan, N., Zhang, H., Perino, A., Lemos, V., Kim,B., Park, Y.K., Piersigilli, A.,, Pham, T.X., Yang, Y., Ku, C.S., Koo, S.I., Fomitchova, A.,

Cantó, C., Schoonjans, K., Sauve, A.A., Lee, J.Y. and Auwerx, J. (2016) Eliciting the mitochondrial unfolded protein response via NAD+ repletion reverses fatty liver disease. Hepatology 63: 1190-1204. » Merkwirth, C., Jovaisaite, V., Durieux, J., Matilainen, O., Jordan, S.D., Quiros, P.M., Steffen, K.K., Williams, E.G., Mouchiroud, L., Uhlein, S.N., Murillo, V., Wolff, S.C., Shaw, R.J., Auwerx, J.* and Dillin, A.* (2016) Two conserved histone demethylases regulate mitochondrial stress-induced longevity. Cell 165: 1209-1223. (*co-last and co-corresponding authors) » Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., D’Amico, D., Ropelle, E.R., Lutolf, M.P., Aebersold, R., Schoonjans, K., Menzies, K.J.* and Auwerx, J.* (2016) NAD+ repletion improves mitochondrial and stem cell function and enhances lifespan in mice. (*co-last and co-corresponding authors). Science 352: 1436-1443. (*co-last and co-corresponding authors) » Williams, E.G., Wu, Y., Dubuis, S., Blattmann, P., Argmann, C.A.,. Houten, S.M., Amariuta, T., Wolski, W., Zamboni, N., Aebersold, R.* and, Auwerx, J.* (2016) Systems proteomics of liver mitochondria function. Science 352 doi: 10.1126/science.aad0189. (*co-last and co-corresponding authors)

» Ryu, D., Mouchiroud, L., Andreux, P.A., Katsyuba, E., Moullan, N., Nicolet-dit-Felix, A.A., Williams, E.G., Jha, P., Lo Sasso, G., Huzard, D., Aebischer, P., Sandi, C., Rinsch, C.*,and Auwerx, J.* (2016) Urolithin A induces mitophagy and prolongs lifespan in C.elegans and increases muscle function in rodents. Nature Medicine 22: 879-888. (*co-last and co-corresponding authors) » Ryu, D., Zhang, H., Ropelle, E.R., Sorrentino, V., Mázala, D.A.G., Mouchiroud, L., Marshall, P.L., Campbell, M.D., Ali, A.S., Knowels, G.M., Bellemin, S., Iyer, S.R., Wang, X., Gariani, K., Sauve, A.A., Cantó, C.,. Conley, K.E., Walter, L., Lovering, R.M., Chin, E.R., Jasmin, B.J., Marcinek, D.J., Menzies, K.J.* and J. Auwerx* (2016) NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation. Sci. Transl. Med. 361ra139; doi: 10.1126/scitranslmed.aaf5504 (*co-last and co-corresponding authors)

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

Leo Diserens Lab Techinicians

Sabrina Bichet Norman Moullan Administrative Assistant

Valérie Stengel

Baekkeskov Lab Steinunn Baekkeskov - Visiting Professor

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

baekkeskov-group.epfl.ch

Introduction

Results Obtained

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

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

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

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

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

IBI - Institute of Bioengineering

Team Members Post Doctoral

Edward Phelps PhD Students

Chiara Cianciaruso Techinicians

Miriella Pasquier Administrative Assistant

Miriella Pasquier

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

Selected Publications » Phelps, E. A., Cianciaruso, C., Santo-Domingo, J., Pasquier, M., Galliverti, G., Piemonti, L., Berishvili, E., Burri, O., Wiederkehr, A., Hubbell, J. A. and Baekkeskov, S. (2017) Advances is pancreatic islet monolayer

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

Barrandon Lab Yann Barrandon - Professor

ldcs.epfl.ch

Introduction

Results Obtained

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

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

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

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

IBI - Institute of Bioengineering

Team Members Senior Scientists

Rochat Ariane Claudinot Stéphanie Post Doctoral Scientists

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

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

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

Research Assistants

Burki Marco De Souza Silva Olga Savoy Dorinne Administrative Assistant

Guex Nathalie

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

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

Introduction

Results Obtained

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

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

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

lbm..epfl.ch

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

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

IBI - Institute of Bioengineering

Team Members Post Doctoral

Luciano Andres Abriata Maria Josefina Marcaida Lopez Nuria Cirauqui PhD Students

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

Julia Prébandier

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

Selected Publications » Audagnotto, M., Lemmin, T., Barducci, A. and Dal Peraro, M. (2016) Effect of the synaptic plasma membrane on the stability of the amyloid precursor protein homodimers. The Journal of Physical Chemistry Letters 7(18): 3572-3578. » Abriata, L.A., Spiga, E. and Dal Peraro. M. (2016) Molecular effects of concentrated solutes on protein hydration, dynamics, and electrostatics. Biophysical Journal 111(4):743-755. » Iacovache, I., De Carlo, S., Cirauqui, N., Dal Peraro, M., Van Der Goot, F.G. and Zuber, B. (2016) Cryo-EM structure of aerolysin variants reveals a novel protein fold and the pore-formation process. Nature Communications 7: 12062.

» Song, A.S., Poor, T.A., Abriata, L.A., Jardetzky, T.S., Dal Peraro, M. and Lamb, R.A. (2016) Immobilization of the N-terminal helix stabilizes prefusion paramyxovirus fusion proteins. Proceedings of the National Academy of Sciences 113(27): E3844-E3851. » Bovigny, C., Tamò, G., Lemmin, T., Maïno, N. and Dal Peraro, M. (2015) LipidBuilder: A framework to build realistic models for biological membranes. Journal of Chemical Information and Modeling 55(12): 2491-2499. » Tamò, G., Abriata, L.A. and Dal Peraro, M. (2015) The importance of dynamics in integrative modeling of supramolecular assemblies. Current Opinion in Structural Biology 31: 28-34. » Palermo, G., Cavalli, A., Klein, M.L., Alfonso-Prieto, M., Dal Peraro, M. and De Vivo, M. (2015) Catalytic metal ions and enzymatic processing of DNA and RNA. Accounts of Chemical Research 48(2): 220-228

Deplancke Lab Bart Deplancke - Associate Professor

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

deplanckelabl..epfl.ch

Introduction

Results Obtained

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

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

We have three major research pillars:

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

1. 2. 3.

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

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

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

IBI - Institute of Bioengineering

Team Members Post Doctoral

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

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

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

Julie Russeil Virginie Braman Administrative Assistant

Magali Masson

Selected Publications » Deplancke, B., Alpern, D., and Gardeux, V. (2016). The genetics of transcription factor DNA binding variation. Cell 166:538-554. » Isakova, A., Berset, Y., Hatzimanikatis, V. and Deplancke, B. (2016) Quantification of cooperativity in heterodimer-DNA binding improves the accuracy of binding specificity models. Journal of Biological Chemistry 291:10293-10306. » Mezan, S., Feuz, J.D., Deplancke, B. and Kadener, S. (2016). PDF signaling Is an integral part of the Drosophila circadian molecular oscillator. Cell Reports 17: 708–719. » Waszak, S.M., Delaneau, O., Gschwind, A.R., Kilpinen, H., Raghav, S.K., Witwicki, R. M., Orioli, A., Wiederkehr, M., Panousis, N.I., Yurovsky, A., et al. (2015) Population variation and genetic control of modular

chromatin architecture in humans. Cell 162:1039-1050. » Bou Sleiman, M.S., Osman, D., Massouras, A., Hoffmann, A.A., Lemaitre, B. and Deplancke, B. (2015) Genetic, molecular and physiological basis of variation in Drosophila gut immunocompetence. Nature Comm. 6:7829. » Schertel, C., Albarca, M., Rockel-Bauer, C., Kelley, N.W., Bischof, J., Hens, K., van Nimwegen, E., Basler, K. and Deplancke, B. (2015). A large-scale, in vivo transcription factor screen defines bivalent chromatin as a key property of regulatory factors mediating Drosophila wing development. Genome Research 25:514-523. » Simicevic, J., Moniatte, M., Hamelin, R., Ahrné, E. and Deplancke, B. (2015). A mammalian transcription factor-specific peptide repository for targeted proteomics. Proteomics 15: 752-756

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

Introduction

Results Obtained

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

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

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

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

Keywords Immunoengineering, tissue engineering, protein engineering, biomaterials.

lmrp.epfl.ch

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

IBI - Institute of Bioengineering

Team Members Post Doctoral

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

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

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

Bonzon Carol Margot Ingrid

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

Frey Peter

Selected Publications » Julier Z., de Titta, A., Grimm, A.J., Simeoni, E., Swartz, M.A. and Hubbell, J.A. (2016) Fibronectin EDA and CpG synergize to enhance antigen-specific Th1 and cytotoxic responses. Vaccine 34:2453-9 » Damo, M., Wilson, D.S., Simeoni, E. and Hubbell, J.A. (2016) TLR-3 stimulation improves anti-tumor immunity elicited by dendritic cell exosome-based vaccines in a murine model of melanoma. Sci Rep 5:17622. » » » » »

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

Jensen Lab Jeffrey D. Jensen - Assistant Professor

jensenlab.epfl.ch

Introduction

Results Obtained

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

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

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

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

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

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

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

Keywords Genetics, Evolution

IBI - Institute of Bioengineering

Team Members Post Doctoral

Stefan Laurent Sebastian Matuszewski Susanne Pfeifer Severine Vuilleumier PhD Students

Mado Kapopoulou Louise Ormond Hyunjin Shim Technicians

Kristen Irwin Administrative Assistant

Geneviève Rossier

From Bank, atuszewski, et al. (P , 20 ) the empirical fitness landscape, by mutational distance to the parental type (X-axis). Each line represents a mutational substitution in the P 0 gene of yeast. n the -axis is growth rate, a proxy for fitness. ellow lines represent the paths to the optimal fitness peak. Green lines represent the fitness trajectories when combining individually beneficial mutations. Purple lines represent fitness trajectories when combining individually deleterious mutations. Thus, this demonstrates a global pattern of negative epistasis, except for strong positively epistatic interactions leading to the fitness peak.

Selected Publications » Renzette, N., T.F. Kowalik, and J.D. Jensen, 2016. The relative roles of background selection and genetic hitchhiking in shaping human cytomegalovirus diversity. Molecular Ecology 25(1): 403-13. » Ewing, G. and J.D. Jensen, 2016. The consequences of not accounting for background selection in demographic inference. Molecular Ecology 25(1): 135-141.

» Bank, C., N. Renzette, P. Liu, S. Matuszewski, H. Shim, M. Foll, D.N. Bolon, T.F. Kowalik, R.W. Finberg, J.P. Wang, and J.D. Jensen, 2016. An experimental evaluation of drug-induced mutational meltdown as an antiviral treatment strategy. Evolution 70: 2470-84. » Pfeifer, S.P., and J.D. Jensen, 2016. The impact of linked selection in chimpanzees: a comparative study. Genome Biology & Evolution 8: 3202-8. » Bank, C. *, S. Matuszewski*, R.T. Hietpas, and J.D. Jensen, 2016. On the (un)predictability of a large intragenic fitness landscape. PNAS 113(49): 14085-90. » Foll, M., Poh, Y.P., Renzette, N., Ferrer, A., Shim, H., Malaspinas, A., Ewing, G., Bank, C., Liu, P., Wegmann, D., Caffrey, D., Zeldovich, K., Bolon, D., Wang, J., Kowalik, T., Schiffer, C., Finberg, R., and Jensen, J.D.

(2014). Influenza virus drug resistance: a time-sample population genetics perspective. PLoS Genetics 10: e1004185. » Bank, C., Hietpas, R., Wong, A., Bolon, D., and Jensen, J.D. (2014). A Bayesian MCMC approach to assess the complete distribution of fitness effects of new mutations: uncovering the potential for adaptive walks in

challenging environments. Genetics 196: 841-52. » Jensen, J.D. (2014) On the unfounded enthusiasm for soft selective sweeps. Nature Communications 5: 5281. » Montano, V., Didelot, X., Foll, M., Linz, B., Moodley, Y., and Jensen, J.D. (2015). Worldwide population structure, long-term demography, and local adaptation of Helicobacter pylori. Genetics 200: 947-63. » Renzette, N., Pfeifer, S., Matuszewski, S., Kowalik, T., and Jensen, J.D. (2017). On the analysis of intra-host and inter-host viral populations: human cytomegalovirus as a case study of pitfalls and expectations. Journal of Virology 91(5): e01976-16.

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

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

lscb.epfl.ch

Introduction

Results Obtained

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

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

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

IBI - Institute of Bioengineering

Team Members Post Doctoral

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

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

Thibaud Cherbuin Evangelos Panopoulos Master Students

Luis Ayala Intestinal stem cell colonies and organoids formed in PEG-based hydrogels. a) Bright-field image of day colonies in P G RGD. b) mmuno uorescent image of day colonies in P G RGD, showing expressing of gr5- GFP. c) Bright-field image of organoids formed in P G RGD matrices. d) mmuno uorescent image of an organoid formed in P G RGD , showing mucin-2-expressing goblet cells. cale bar, 50 μm.

Administrative Assistant

Maria João Fernandes Coelho

Selected Publications » Gjorevski, N., Sachs, N., Manfrin, A., Giger, S., Bragina, M.E., Ordóñez-Morán, P., Clevers, H. and Lutolf, M.P.* (2016) Designer matrices for intestinal stem cell and organoid culture. Nature 539: 560-564. » Vannini, N., Girotra, M., Naveiras, O., Nikitin, G., Campos, V. and Lutolf, M.P.* (2016) Specification of haematopoietic stem cell fate via modulation of mitochondrial activity. Nature Comm. 7: 13125. » » » » »

Caiazzo, M., Okawa, Y., Ranga, A., Piersigilli, A., Tabata, Y. and Lutolf, M.P.* (2016) Defined three-dimensional microenvironments boost induction of pluripotency. Nature Materials 15: 344–352. Brandenberg, N.and Lutolf, M.P.* (2016) In situ patterning of microfluidic networks in 3D cell-laden hydrogels. Advanced Materials 28(34): 7450. Ranga, A., Girgin, M., Meinhardt, A., Eberle, D., Caiazzo, M., Tanaka, E.M. and Lutolf, M.P.* (2016) Neural tube morphogenesis in synthetic 3D microenvironments. Proc. Natl. Acad. Sci. 113 (44): E6831–E6839. Allazetta, S., Kolb, L., Zerbib, S., Bardy, J. and Lutolf, M.P.* (2015) Cell‐instructive microgels with tailor‐made physicochemical properties. Small 11 (42): 5647-5656. Roch, A., Trachsel, V. and Lutolf, M.P.* (2015) Single‐cell analysis reveals cell division‐independent emergence of megakaryocytes from phenotypic hematopoietic stem cells. Stem Cells 33 (10): 3152-3157

Naef Lab Felix Naef - Associate Professor

naef-lab.epfl.ch

Introduction

Felix Naef studied theoretical physics at the ETH 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 oined EPFL in 2006 where he is currently Associate Professor in the Institute of Bioengineering (IBI).

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

Results Obtained

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

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

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

IBI - Institute of Bioengineering

Team Members Post Doctoral

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

The promoter cycle as a generic stochastic gene expression model. A) The model describes gene activation, transcription, translation, and degradation of mRNA and proteins. The promoter follows an irreversible cycle of one transcriptionally active state and multiple (N) sequential inactive states. B) imulation of protein numbers, mR numbers, and gene activity with inactive state. ) ith states. odified from oller et al., B 20 5.

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

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

Administrative Assistant

Selected Publications

Sophie Barret

» Atger, F., Gobet, C., Marquis, J., Martin, E., Wang, J., Weger, B., Lefebvre, G., Descombes, P., *Naef, F. and *Gachon, F. (2015) Circadian and feeding rhythms differentially affect rhythmic mRNA transcription and translation in mouse liver. Proc Natl Acad Sci USA 112(47): E6579-88. *co-corresponding » Zoller, B., Nicolas, D., Molina, N. and Naef, F. (2015) Structure of silent transcription intervals and noise characteristics of mammalian genes. Mol Syst Biol 11(7): 823.

» Blanchoud, S., Nicolas, D., Zoller, B., Tidin, O. and Naef, F. (2015) CAST: An automated segmentation and tracking tool for the analysis of transcriptional kinetics from single-cell time-lapse recordings. Methods 85: 3-11. » Blanchoud, S., Busso, C., Naef, F. and Gönczy, P. (2015) Quantitative analysis and modeling probe polarity establishment in C. elegans embryos. Biophys J 108(4): 799-809. » Gotic, I., Omidi, S., Fleury-Olela, F., Molina, N., Naef, F. and Schibler U. (2016) Temperature regulates splicing efficiency of the cold-inducible RNA-binding protein gene Cirbp. Genes Dev. 30(17): 2005-2017. » Bischofberger, M., Iacovache, I., Boss, D., Naef, F., van der Goot, F.G. and Molina, N. (2016) Revealing assembly of a pore-forming complex using single-cell kinetic analysis and modeling. Biophys J 110(7): 15741581.

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

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

Introduction

Results Obtained

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

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

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

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

naveiras-lab.epfl.ch

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

IBI - Institute of Bioengineering

Team Members Ludwig Project Leader

Nicola Vannini

Post Doctoral Fellow

Shanti Rojas-Sutterlin PhD Students

Vasco Campos Josefine Tratwal Medical Students

Frédérica Schyrr

Master Students

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

Aurélien Oggier Tereza Koliqi

Research Assistant

Yannick Yersin

Administrative Assistant

Laura Bischoff

Selected Publications » Vannini, N. *, Girotra, M.*, Naveiras, O., Nikitin, G, Campos, V., Giger, S., Roch, A., Auwerx, J. and Lutolf , M.P. (2016) Metabolic specification of hematopoietic stem cell fate. Nature Communications 7:13125. » Diaz, M.F., Li, N., Lee, H.J., Adamo, L., Evans, S.M., Willey, H.E., Arora, N., Torisawa, Y.S., Vickers, D.A., Morris, S.A., Naveiras, O., Murthy, S.K., Ingber, D.E., Daley, G.Q., García-Cardeña, G. and Wenzel, P.L.

(2015) Biomechanical forces promote blood development through prostaglandin E2 and the cAMP-PKA signaling axis. J. Exp. Med. 212: 665–680. » McKinney-Freeman, S., Cahan, P., Li, H., Lacadie, S.A., Huang, H.T., Curran, M., Loewer, S., Naveiras, O., Kathrein, K.L., Konantz, M., Langdon, E.M., Lengerke, C., Zon, L.I., Collins, J.J. and Daley, G.Q. (2012)

The transcriptional landscape of hematopoietic stem cell ontogeny. Cell Stem Cell 11: 701–714. » Vannini, N., Roch, A., Naveiras, O., Griffa, A., Kobel, S. and Lutolf, M.P. (2012) Identification of in vitro HSC fate regulators by differential lipid raft clustering. Cell Cycle 11(8):1535-1543. » Naveiras, O., Nardi, V., Wenzel, P.L., Hauschka, P., Fahey, F. and Daley, G.Q. (2009) Bone marrow adipocytes as negative regulators of the hematopoietic microenvironment. Nature 460: 259-263. » Adamo, L.*, Naveiras, O.*, Wenzel, P.L., McKinney-Freeman, S., Mack, P.J., Gracia-Sancho, J., Suchy-Dicey, A., Yoshimoto, M., Lensch, M.W., Yoder, M.C., García-Cardeña, G. and Daley, G.Q. (2009) Biomechanical forces promote embryonic haematopoiesis. Nature 459(7250): 1131-1135.

Schoonjans Lab Kristina Schoonjans - Associate Professor

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

schoonjans-lab.epfl.ch

Introduction

Results Obtained

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

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

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

IBI - Institute of Bioengineering

Team Members Post Doctoral Associates

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

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

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

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

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

Soledad Andany

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

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

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

Introduction

Results Obtained

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

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

We are particularly interested in the following questions: 1. 2. 3. 4.

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 is the role of mitotic bookmarking of transcription factors in the maintenance and differentiation of ES cells ? What confers mitotic chromosome binding properties to transcription factors ?

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

suter-lab.epfl.ch

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

IBI - Institute of Bioengineering

Team Members PhD Students

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

Cédric Deluz Administrative Assistant

Laura Bischoff

Fluorescent time-lapse imaging of Pet- ox2 during cell division in ing its colocalization with mitotic chromosomes.

, highlight-

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

BIOS Lab Hatice Altug - Associate Professor

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

bios.epfl.ch

Introduction

Results Obtained

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

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

Keywords Optical Nano-Biosensors, Nanofabrication.

Lab-on-a-chip

Systems,

Microfluidics,

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

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Andreas Tittl Filiz Yesilköy Kosmas Tsakmakidis Maria Soler Aznar PhD Students

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

Rosana Blanchard

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

Selected Publications » » » »

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

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

Introduction

Results Obtained

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

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

Five main topics are concerned: 1. Kamiar Aminian received his PhD degree in biomedical engineering in 1989 from EPFL. He is currently Professor of medical instrumentation and the director of the Laboratory of Movement Analysis and Measurement of EPFL. His research interests include methodologies for human movement monitoring and analysis in real world conditions mainly based on wearable technologies and inertial sensors with emphasis on gait, physical activity and sport. He is author or co-author of more than 500 scientific papers published in reviewed journals and presented at international conferences and holds 11 patents related to medical devices.

lmam.epfl.ch

2. 3. 4. 5.

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

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

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

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Wei Zhang Hooman Dejnabadi Senior Researcher

Anisoara Inonescu PhD Students

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

Pascal Morel Administrative Assistants

Francine Eglese

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

Selected Publications » Paraschiv-Ionescu, A., Perruchoud, C., Rutschmann, B., Buchser, E. andAminian, K.(2016) Quantifying dimensions of physical behavior in chronic pain conditions. Journal of NeuroEngineering and Rehabilitation 13(1):85. » Moufawad el Achkar, C., Lenoble-Hoskovec, C., Paraschiv-Ionescu, A., Major, K., Büla, K. and Aminian, K. (2016) Instrumented shoes for activity classification in the elderly. Gait and Posture 44: 12-17.

» Fasel, B., Favre, J., Chardonnens, J., Gremion G. and Aminian, K. (2015) An inertial sensor-based system for spatio-temporal analysis in classic cross-country skiing diagonal technique. Journal of Biomechanics 48(12): 3199-3205. » Dadashi, F., Millet, G. and Aminian, K. (2015) Front-crawl stroke descriptors variability assessment for skill characterisation, Journal of Sports Sciences 34: 1405-1412. » Arami, A., Vida Martins, N. and Aminian, K. (2015) Locally linear neuro-fuzzy estimate of the prosthetic knee angle and its validation in a robotic simulator. IEEE Sensors Journal 15:6271-6278. » Massé, F., Gonzenbach, R.R., Arami, A., Paraschiv-Ionescu, A., Luft, A.R. and Aminian, K. (2015) Improving activity recognition using a wearable barometric pressure sensor in mobility-impaired stroke patients. Journal of NeuroEngineering and Rehabilitation 12: 72-86. » Barré, A., Jolles, B.M., Theumann, N. and Aminian, K. (2015) Soft tissue artifact distribution on lower limbs during treadmill gait: Influence of skin markers’ location on cluster design. Journal of Biomechanics 48: 1965-1971.

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

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

lnbi.epfl.ch

Introduction

Results Obtained

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

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

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

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Haig-Alexander Eskandarian Nikola Pascher PhD Students

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

Santiago Andany Administrative Assistants

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

Selected Publications » Adams, J. D., Erickson, B. W., Grossenbacher, J., Brugger, J., Nievergelt, A. and Fantner, G. E. (2015) Harnessing the damping properties of materials for high-speed atomic force microscopy. Nat. Nanotechnol. 11: 147–151. » Dukic, M., Adams, J. D. and Fantner, G. E. (2015) Piezoresistive AFM cantilevers surpassing standard optical beam deflection in low noise topography imaging. Sci. Rep. 5: 16393. » Nievergelt, A. P., Erickson, B. W., Hosseini, N., Adams, J. D. and Fantner, G. E. (2015) Studying biological membranes with extended range high-speed atomic force microscopy. Sci. Rep. 5: 11987. » Nowell, C. S., Odermatt, P. D., Azzolin, L., Hohnel, S., Wagner, E. F., Fantner, G. E., Lutolf, M. P., Barrandon, Y., Piccolo, S. and Radtke, F. (2015) Chronic inflammation imposes aberrant cell fate in regenerating

epithelia through mechanotransduction. Nat. Cell Biol. 18: 168–180. » Odermatt, P. D., Shivanandan, A., Deschout, H., Jankele, R., Nievergelt, A. P., Feletti, L., Davidson, M. W., Radenovic, A. and Fantner, G. E. (2015) High-Resolution Correlative Microscopy: Bridging the Gap between Single Molecule Localization Microscopy and Atomic Force Microscopy. Nano Lett. 15: 4896–4904. » Dukic, M., Winhold, M., Schwalb, C. H., Adams, J. D., Stavrov, V., Huth, M. and Fantner, G.E. (2016) Direct-write nanoscale printing of nanogranular tunnelling strain sensors for sub-micrometre cantilevers. Nat. Commun. 7: 12487. » Hosseini, N., Nievergelt, A. P., Adams, J. D., Stavrov, V. T. and Fantner, G. E. (2016) A monolithic MEMS position sensor for closed-loop high-speed atomic force microscopy. Nanotechnology 27: 135705.

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

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

Introduction

Results Obtained

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

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

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

lne.epfl.ch

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Laura Ferlauto PhD Students

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

Manuela da Silva

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

Selected Publications » Antognazza, M.R., Di Paolo, M., Ghezzi, D., Mete M., Di Marco, S., Maya-Vetencourt, J. F., Maccarone, R., Desii, A., Di Fonzo, F., Bramini, M., Russo, A., Donelli, I., Cilli, M., Freddi, G., Pertile, G., Lanzani, G.,

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

Guiducci Lab Carlotta Guiducci - Tenure-Track Assistant Professor

clse.epfl.ch

Introduction

Results Obtained

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

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

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

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

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

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

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

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Marco Letizia Pietro Maoddi Enrico Tenaglia Miyuki Tbata PhD Students

Diana Burghelea Samuel Kilchenmann Enrica Rolo Kevin Keim Administrative Assistants

Monica Navarro Suarez

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

Selected Publications » Kilchenmann, S.C., Rollo, E., Maoddi, P. and Guiducci, C. (2016) Metal-coated SU-8 structures for high-density 3D microelectrode arrays. JMEMS 25 (3 )

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

Hatzimanikatis Lab Vassily Hatzimanikatis - Associate Professor

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

lcsb.epfl.ch

Introduction

Results Obtained

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

• • • •

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

Keywords Mathematical modeling, Metabolic Engineering, Synthetic Biology

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

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

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

Selected Publications » Hadadi, N., Hafner, J., Shajkofci, A., Zisaki, A. and Hatzimanikatis, V. (2016). ATLAS of Biochemistry: A Repository of All Possible Biochemical Reactions for Synthetic Biology and Metabolic Engineering Studies. ACS Synthetic Biology. 5(10): 1155-1166 » Savoglidis, G. dos Santos, A.X.D., Riezman, I., Angelino, P., Riezman, H. and Hatzimanikatis, V. (2016). A method for analysis and design of metabolism using metabolomics data and kinetic models: Application on lipidomics using a novel kinetic model of sphingolipid metabolism. Metabolic Engineering. 37:46-62. » Isakova, A., Berset, Y., Hatzimanikatis, V. and Deplancke, B. (2016). Quantification of Cooperativity in Heterodimer-DNA Binding Improves the Accuracy of Binding Specificity Models. Journal of Biological Chemistry. 291(19):10293- 10306

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

Ljubisa Miskovic

Administrative Assistants

Kupper Christine

» Dallavilla, T., Abrami, L., Sandoz, P.A., Savoglidis, G., Hatzimanikatis, V. and van der Goot, F.G. (2016) Model-Driven Understanding of Palmitoylation Dynamics: Regulated Acylation of the Endoplasmic Reticulum Chaperone Calnexin. PLOS Computational Biology. 12(2):e1004774. » Andreozzi, S., Miskovic, L. and Hatzimanikatis., V. (2916). iSCHRUNK - In Silico Approach to Characterization and Reduction of Uncertainty in the Kinetic Models of Genome-scale Metabolic Networks. Metabolic Engineering. 33:158-168. » Hadadi, N., and Hatzimanikatis, V. (2015). Design of computational retrobiosynthesis tools for the design of de novo synthetic pathways. Current Opinion in Chemical Biology. 28:99-104. » Ataman, M., and Hatzimanikatis, V. (2015). Heading in the right direction: thermodynamics-based network analysis and pathway engineering. Current Opinion in Biotechnology. 36:176-182. » Tymoshenko, S., Oppenheim, R. D., Agren, R., Nielsen, J., Soldati-Favre, D., Hatzimanikatis, V. (2015) Metabolic Needs and Capabilities of Toxoplasma gondii through Combined Computational and Experimental Analysis. PLOS Computational Biology. 11(5): e1004261.

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

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

biorob.epfl.ch

Introduction

Results Obtained

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

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

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

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

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

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

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

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

Technicians

François Longchamp Administrative Assistants

Sylvie Fiaux

Selected Publications » Karakasiliotis, K., Thandiackal, R., Melo, K., Horvat, T., Mahabadi, N.K., Tsitkov, S., Cabelguen, J.M. and Ijspeert, A.J. (2016) From cineradiography to biorobots: an approach for designing robots to emulate and study animal locomotion. Journal of The Royal Society Interface 13(119): pii20151089. » Ijspeert, A.J., Bicanski, A., Knuesel, J., Cabelguen, J.M. (2016) Motor pattern generation. In From Neuron to Cognition (M. Arbib Editor), MIT Press. » Vitiello, N., Ijspeert, A.J. and Schaal, S. (2016) Bioinspired motor control for articulated robots. IEEE Robotics & Automation Magazine 23 (1): 20-21. » Ryczko, D., Knüsel, J., Crespi, A., Lamarque, S., Mathou, A., Ijspeert, A.J. and Cabelguen, J.M. (2015) Flexibility of the axial central pattern generator network for locomotion in the salamander. Journal of » » » »

Neurophysiology 113(6):1921-1940. Gams, A., Van den Kieboom, J., Dzeladini, F., Ude, A. and Ijspeert, A.J. (2015) Real-time full body motion imitation on the COMAN humanoid robot. Robotica, 33(05): 1049-1061. Pouya, S., Khodabakhsh, M., Spröwitz, A. and Ijspeert, A. (2015) Spinal joint compliance and actuation in a simulated bounding quadruped robot. Autonomous Robots: 1-16. Righetti, L., Nylén, A., Rosander, K. and Ijspeert, A.J. (2015) Kinematic and gait similarities between crawling human infants and other quadruped mammals. Frontiers in Neurology 6. Ijspeert, A.J. and Cabelguen, J.M. (2015). Control of aquatic and terrestrial gaits in Salamander. Encyclopedia of Computational Neuroscience, Springer: 812-820.

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

Introduction

Results Obtained

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

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

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

lip.epfl.ch

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

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

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

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

Rengifo Gonzalez Monica Administrative Assistants

Claudia Gasparini

Selected Publications » Xue, L., Prifti, E. and Johnsson, K.(2016) A general strategy for the semisynthesis of ratiometric fluorescent sensor proteins with increased dynamic range. J Am Chem Soc 138 (16): 5258-5261. » Lukinavicius, G., Reymond, L., Umezawa, K., Sallin, O., D’Este, E., Gottfert, F., Ta, H., Hell, S. W., Urano, Y. and Johnsson, K. (2016) Fluorogenic probes for multicolor imaging in living cells. J Am Chem Soc 138 (30): 9365-9368. » Haruki, H., Hovius, R., Pedersen, M.G. and Johnsson, K. (2016) Tetrahydrobiopterin biosynthesis as a potential target of the kynurenine pathway metabolite Xanthurenic acid. J Biol Chem 291 (2): 652-657. » Xue, L., Karpenko, I.A., Hiblot, J. and Johnsson, K. (2015) Imaging and manipulating proteins in live cells through covalent labeling. Nature Chemical Biology 11 (12): 917–923.

» Lukinavičius, G., Blaukopf, C., Pershagen, E., Schena, A., Reymond, L., Derivery, E., Gonzalez-Gaitan, M., D’Este, E., Hell, S.W., Gerlich, D.W. and Johnsson, K. (2015) SiR–Hoechst is a far-red DNA stain for livecell nanoscopy. Nature Communications 6: 8497. » Lee, R.F.S., Escrig, S., Croisier, M., Clerc-Rosset, S., Knott, G.W., Meibom, A., Davey, C.A., Johnsson, K. and Dyson, P.J. (2015) NanoSIMS analysis of an isotopically labelled organometallic ruthenium(II) drug to probe its distribution and state in vitro. Chemical Communications 51: 16486-16489. » Schena, A., Griss, R., and Johnsson, K. (2015) Modulating protein activity using tethered ligands with mutually exclusive binding sites. Nature Communications 6: 7830

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

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

lsbi.epfl.ch

Introduction

Results Obtained

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

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

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

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

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

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

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

Philippe Campiche Frédéric Giraud Christina Tringides Administrative Assistants

Christel Daidié

Selected Publications » de Luca, A.C., Fonta, C.M., Rafful, W., di Summa, P.* and Lacour, S.P.* (2017) Encapsulation of adipose-derived stem cells in degradable gels supports in vivo nerve regeneration through long silicone conduits. J. Tissue Eng. & Regen. Med. (in revision).

» Nguyen-Dang, T., de Luca, A.C., Yan, W., Qu, Y., Page, A., Lacour, S.P. and Sorin, F. (2017) Controlled sub-micrometer hierarchical textures engineered in polymeric fibers and micro-channels via thermal drawing. Advanced Functional Materials (2017), available on-line.

» Lacour, S.P., Courtine, G. and Guck, J. (2016) Materials and technology for soft implantable neuroprostheses. Nature Reviews Materials 1: 16063. » Lantoine, J., Grevesse, T., Villers, A., Delhaye, G., Mestdagh, C., Versaevel, M., Mohammed, D., Bruyère, C., Alaimo, L., Lacour, S.P., Ris, L. and Gabriele, S. (2016) Matrix stiffness modulates formation and activity of neuronal networks of controlled architectures. Biomaterials 89:14-24. » Hirsch, A.*, Michaud, H.O.*, Gerratt, A.P., de Mulatier, S. and Lacour, S.P. (2016) Intrinsically stretchable biphasic (solid-liquid) thin metal films. Advanced Materials 28(22): 4506. » Wenger, N. et al. (2016) Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury. Nature Medicine 22(2): 138-14.

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

lob.epfl.ch

Introduction

Theo Lasser is heading the Laboratoire d Opti ue Biom dicale (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 oining EPFL he pursued an industry career at Carl Zeiss as R&D manager for ophthalmic instruments and in his last assignment as director of Carl Zeiss Research, Jena.

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

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

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

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

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

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

D b F superresolution e a cell Vimentin structure R < 90 nm

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

Antonio Lopez Administrative Assistants

Noelia Simone

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

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

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

lnbc.epfl.ch

Introduction

Results Obtained

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

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

Keywords Microfluidics, synthetic biology, systems biology, molecular diagnostics

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Nadanai Laohakunakorn Francesco Piraino PhD Students

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

Helen Chong-Horrigan

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

Selected Publications » Piraino, F., Volpetti, F., Watson C. and Maerkl, S.J. (2016) A digital-analog platform for patient-centric multiplexed biomarker diagnostics of ultra-low volume samples. ACS Nano. 10: 1699-1710.

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

Mermod Lab Nicolas Mermod - Full Professor - IBI - UNIL

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

Introduction

Results Obtained

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

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

Keywords

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

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

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

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

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

Pavithra Iyer Sandra Bosshard informatician

Daniel Peter Technicians

Yves Dusserre Jacqueline Masternak Armindo Texeira Ione Gutscher Administrative Assistants

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

Selected Publications » Droz, X., Harraghy, N., Lançon, E., Le Fourn, V., Calabrese, D., Colombet, T., Liechti, P., Rida, A., Girod, P.A. and Mermod, N. (2017) Automated microfluidic sorting of mammalian cells for those that efficiently

express and secrete a protein of interest. In revision. » Kostyrko, K., Neuenschwander, S., Junier, T., Regamey, A., Iseli, C., Schmid-Siegert, E., Bosshard, S., Majocchi, S., LeFourn, V., Girod, P.A., Xenarios, I. and Mermod, N. (2017) MAR-mediated transgene integration

into permissive chromatin and increased expression involve an SD-MMEJ-like DNA repair pathway. Biotechnol. Bioeng. 114: 384-396. » Mee, E.T., Preston, M.D., CS533 study participants, Minor, P.D. and Schepelmann, S. (2016) Development of a candidate reference material for adventitious virus detection in vaccine and biologicals manufacturing by deep sequencing. Vaccine 34: 2035-2043. » Kostyrko, K. and Mermod, N. (2016) Assays for DNA double-strand break repair by microhomology-based end-joining repair mechanisms. Nucl. Acids Res. 44(6): e56. » Van Zwieten, R.W., Majocchi, S., Puttini, S., Messina, G., Tedesco, F.S., Cossu, G. and Mermod, N. (2015) MAR-mediated dystrophin expression in mesoangioblasts for Duchenne muscular dystrophy cell therapy. Molec. Biol. 4:134.

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

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

Introduction

Results Obtained

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

Bionic limbs In the recent past, our â&#x20AC;&#x153;bionicâ&#x20AC;? prosthesis was tested for a month, during which the intraneural TIME electrodes were implanted. In 2016 we investigated the possibility to restore the ability to judge textural features. We sought to achieve this goal via an integrated approach to mimic natural coding using a neuromorphic, real-time, mechano-neuro-transduction process (MNT). The MNT process was tested in four intact subjects by delivering electrical stimulation to their sensory peripheral nerve fibers during microstimulation via tungsten needle microelectrodes and with one amputee using TIME electrodes. The participants achieved excellent performance in terms of texture discrimination confirming that this feature can be artificially restored. We also investigated the long-term usability of our approach with two patients. The first one was implanted in November 2015, for six months. The second one was implanted from June 2016 also for six months. The sensations elicited from electric current injected in 4 TIME electrodes implanted in the median and ulnar nerves, have been recorded weekly up to 80 days after the implant, in terms of type, location, extension and intensity of the sensation elicited over the missing (phantom) hand.

Keywords Neuroprosthetics, Bionics, Hand prosthesis, Modelling and control

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

IBI - Co-affiliated Research Groups

Team Members Scientists & Postdoctoral Fellows

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

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

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

Selected Publications » Alia, C., Spalletti, C., Lai, S., Panarese, A., Micera, S. and Caleo, M. (2016) Reducing GABA(A)-mediated inhibition improves forelimb motor function after focal cortical stroke in mice. Sci Rep 6: 37823. » Capogrosso, M., Milekovic, T., Borton, D., Wagner, F., Moraud, E.M., Mignardot, J.B., Buse, N., Gandar, J., Barraud, Q., Xing, D., Rey, E., Duis, S., Jianzhong, Y., Ko, W.K., Li, Q., Detemple, P., Denison, T., Micera, S., Bezard, E., Bloch, J. and Courtine, G. (2016) A brain-spine interface alleviating gait deficits after spinal cord injury in primates. Nature 539(7628): 284-288. » Oddo, C.M., Raspopovic, S., Artoni, F., Mazzoni, A., Spigler, G., Petrini, F., Giambattistelli, F., Vecchio, F., Miraglia, F., Zollo, L., Di Pino, G., Camboni, D., Carrozza, M.C., Guglielmelli, E., Rossini, P.M., Faraguna, U. and Micera, S. (2016) Intraneural stimulation elicits discrimination of textural features by artificial fingertip in intact and amputee humans. Elife 5:e09148.. » Moraud, E.M., Capogrosso, M., Formento, E., Wenger, N., DiGiovanna, J. and Courtine, G. and Micera, S. (2016) Mechanisms underlying the neuromodulation of spinal circuits for correcting gait and balance deficits after spinal cord injury. Neuron 89(4): 814-828.

Guy Aymeric Orset Bastien Pham Hoang Mac Administrative Assistants

Anouk Hein

» Wenger, N, Moraud, E.M., Gandar, J., Musienko, P., Capogrosso, M., Baud, L, Le Goff, C.G., Barraud, Q., Pavlova, N., Dominici, N., Minev, I.R., Asboth, L., Hirsch, A., Duis, S., Kreider, J., Mortera, A., Haverbeck, O., Kraus, S., Schmitz, F., DiGiovanna, J., van den Brand, R., Bloch, J., Detemple, P., Lacour, S.P., Bézard, E., Micera, S. and Courtine, G. (2016) Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury. Nat Med 22(2): 138-145. » DiGiovanna, J., Dominici, N., Friedli, L., Rigosa, J., Duis, S., Kreider, J., Beauparlant, J., van den Brand, R., Schieppati, M., Micera, S. and Courtine, G. (2016) Engagement of the rat hindlimb motor cortex across natural locomotor behaviors. J Neurosci 36(40): 10440-10455.

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

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

cnbi.epfl.ch

Introduction

Results Obtained

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

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

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

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

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IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

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

B won the ybathlon B race. ur pilot, uma Poujouly, in the podium with the gold medal. Dr. uca onin is behind. See http://www.cybathlon.ethz.ch/en/ for more details.

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

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

Géraud L’Eplattenier Arnaud Desvachez Master’s Students

Selected Publications » Martin S., Brunner P., Iturrate I., Millán J.d.R. and G. Schalk et al. (2016) Word pair classification during imagined speech using direct brain recordings. Scientific Reports, 6:25803. » » » »

Perdikis S., Leeb R. and Millán J.d.R. (2016) Context-aware adaptive spelling in motor imagery BCI. Journal of Neural Engineering, 13(3): 036018. Saeedi S., Chavarriaga R., Leeb R. and Millán J.d.R. (2016) Adaptive assistance for brain-computer interfaces by online prediction of command reliability. IEEE Computational Intelligence Magazine, 11:32-39. Lee K., Liu D., Perroud L., Chavarriaga R. and J. d. R. Millán. (2016) A brain-controlled exoskeleton with cascaded event-related desynchronization classifiers. Robotics and Autonomous Systems, To appear. Saeedi S., Chavarriaga R., and Millán J.d.R. (2017) Long-term stable control of motor-imagery BCI by a locked-in user through adaptive assistance. IEEE Transactions on Neural Systems and Rehabilitation Engineering, To appear

Arnaud Desvachez Naik Londoño Administrative Assistants

Christel Daidié

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

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

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lboi.epfl.ch

Introduction

Results Obtained

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

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

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

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

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

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

S. Jaccoud R. Obrist

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

V. Kokocinski

Selected Publications » Nassajian Moghadam, M., and Pioletti D.P. (2016) Biodegradable HEMA-based hydrogels with enhanced mechanical properties. J Biomed Mat Res B, 104: 1161-1169. » Schmocker, A., Khoushabi, A., Frauchiger, D.A., Schizas, C., Gantenbein, B., Moser, C., Bourban, P.E. and Pioletti D.P. (2016) A photopolymerized composite hydrogel and surgical implanting tool for a nucleus pulposus replacement. Biomaterials 88: 110-119.

» Nasrollahzadeh, N. and Pioletti D.P. (2016) Experimental method to characterize the strain dependent permeability of tissue engineering scaffolds. J Biomechanics 49: 3749-3752. » Latypova, A., Arami, A., Becce, F., Jolles-Haeberli, B., Aminian, K., Pioletti, D.P. and Terrier, A. (2016) A patient-specific model of total knee arthroplasty to estimate patellar strain: a case study. Clin Biomech 32:

212-219. » Malfroy Camine, V.M., Rüdiger, H., Pioletti, D.P. and Terrier A. (2016) Full-field measurement of micromotion around a cementless femoral stem using micro-CT imaging and radiopaque markers. J Biomechanics 49: 4002-4008. » Nassajian Moghadam, M. and Pioletti, D.P. (2015) Improving hydrogels’ toughness by increasing the dissipative properties of their network. J Mech Behav Biomed Mat 41: 161-167. » Kettenberger, U., Latypova, A., Terrier, A. and Pioletti, D.P. (2015) Time course of bone screw fixation following a local delivery of zoledronate in a rat femoral model – a micro-finite element analysis. J Mech Behav Biomed Mat 45: 22-31.

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Psaltis Lab Demetri Psaltis - Full Professor - Optics Laboratory

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

http://lo.epfl.ch

Introduction

Results Obtained

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

In the research area of Optofluidics, studies about the plantâ&#x20AC;&#x2122;s functionalities present a great interest as they involve mechanisms combining optics, fluidics and biochemistry. On the bioimaging side, optical fibers have shown impressive possibilities for endoscopic imaging. Pixelation-free images of fluorescent samples have been demonstrated through multicore fibers (MCFs) using speckle scanning microscopy with no calibration step. Bending does not affect the image quality as long as it does not happen during one single scan. In addition, the twophoton fluorescence microscopy has been implemented for endoscopic imaging of biological samples. Using wavefront shaping techniques, the laser beam is focused and scanned at the distal end of the fiber exciting the samples, and the fluorescence signal is collected back through the MCF. These results, open the path for advanced endoscopic imaging through optical fibers. Moreover, optical tomographic imaging has been studied in order to improve the current limitations due to artifacts and noise that other known techniques suffer from. A novel computational method for the estimation of the refractive index distribution of a 3D object from the measurements of the transmitted light-field has been presented showing promising results.

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

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

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IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

Ye Pu Alexandre Goy Fauzia Albertin Nicolino Stasio PhD Students

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

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

Silke Jan

Selected Publications » Demetri Psaltis, Andreas E. Vasdekis, Jae-Woo Choi. Optofluidics of plants. APL Photonics. 1, 020901 (2016) » Nicolino Stasio, Christophe Moser and Demetri Psaltis. Calibration-free imaging through a multicore fiber using speckle scanning microscopy. Optics Letters, Vol 41, Issue 13, 3078-3081 (2016) » Donald Conkey, Nicolino Stasio, Marilisa Romito, Edgar E. Morales-Delgado, Christophe Moser and Demetri Psaltis. Lensless two-photon imaging through a multicore fiber with coherence-gated digital phase conjugation. Journal of Biomedical Optics, 21, 045002 (2016)

» Ulugbek S. Kamilov, Ioannis N. Papadopoulos, Morteza H. Shoreh, Alexandre Goy, Cedric Vonesch, Michael Unser and Demetri Psaltis. Optical tomographic image reconstruction based on beam propagation and sparse regularization. IEEE Transactions on Computational Imaging, Vol 2, No. 1, 59-70 (2016)

» Thomas Lanvin, Donald B. Conkey, Aurelien Frobert, Jeremy Valentin, Jean-Jacques Goy, Stéphane Cook, Marie-Noelle Giraud, and Demetri Psaltis. Subsurface ablation of atherosclerotic plaque using ultrafast laser pulses. Biomed. Opt. Express 6(7), 2552-2561 (2015) » Ulugbek S. Kamilov, Ioannis N. Papadopoulos, Morteza H. Shoreh, Alexandre Goy, Cedric Vonesch, Michael Unser and Demetri Psaltis. Learning Approach to Optical Tomography. Optica Volume 2, Issue 6, pp. 517-522 (2015) » Olivier Simandoux, Nicolino Stasio, Jerome Gateau, Jean-Pierre Huignard, Christophe Moser, Demetri Psaltis, Emmanuel Bossy. Optical-resolution photoacoustic imaging through thick tissue with a thin capillary as a dual optical-in acoustic-out waveguide. Applied Physics Letters 106, 094102 (2015)

109

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

Aleksandra Radenovic received her master s degree in physics from the University of Zagreb in 1999 before joining Professor Giovanni Dietler s Laboratory of Physics of Living Matter in 2000 at niversity 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 oining 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.

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lben.epfl.ch

Introduction

Results Obtained

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

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

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

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

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

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

Lely Feletti

Administrative Assistants

Helen Chong

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

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

Introduction

Results Obtained

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

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

Research Topics:

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

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lbp.epfl.ch

• • • • • •

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

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

Techniques: • • • •

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

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

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

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

Yixing Chen Jan Dedic Marie Didier Filip Kovacik Cornelis Lütgebaucks Igor Nahalka Orly Tarun Nikolay Smolentsev Siyuan Wang Evangelia Zdrali Artistic impression of the long-range interactions between ions and water as probed with fs elastic second harmonic scattering and surface tension measurements. From cience dvances, vol. 2, num. , p. e 50 e 50 .

Administrative Assistants

Rebecca Veselinov

Selected Publications » Lütgebaucks, C., Gonella, G. and Roke, S. (2016) Optical label-free and model-freeprobe of the surface potential of nanoscale and microscopic objects in aqueous solution. Physical Review B 94 (19). » De Beer, A.G.F. and Roke, S. (2016) What interactions can distort the orientational distribution of interfacial water molecules as probed by second harmonic and sum frequency generation? Journal of Chemical Physics, 145 (4): 044705. » Gonella, G., Luetgebaucks, C., De Beer, A.G.F. and Roke, S. (2016) Second harmonic and sum-frequency generation from aqueous interfaces is modulated by interference. Journal of Physical Chemistry C 120 (17): 9165-9173. » Chen, Y., Okur, H. I., Gomopoulos, N., Macias-Romero, C., Cremer, P.S., Petersen, P.B., Tocci, G., Wilkins, D.M., Liang, C., Ceriotti, M., Roke, S. (2016).

» Electrolytes induce long-range orientational order and free energy changes in the H-bond network of bulk water. Science Advances 2 (4): e1501891. » Macias-Romero, C., Zubkovs, V., Wang, S. and Roke, S. (2016) Wide-field medium-repetition-rate multiphoton microscopy reduces photodamage of living cells. Biomedical Optics Express 7 (4): 1458. » Smolentsev, N., Lütgebaucks, C., Okur, H. I., De Beer, A. G. F. and Roke, S. (2016) Intermolecular headgroup interaction and hydration as driving forces for lipid transmembrane asymmetry. Journal of the American Chemical Society, 138 (12) 4053-4060. » Chen, Y., Jena, K.C., Lütgebaucks, C., Okur, H.I. and Roke, S. (2015) Three dimensional nano ‘Langmuir trough’ for lipid studies. Nano Lett.15: 5558−5563.

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

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

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sunmil.epfl.ch

Introduction

Results Obtained

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

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

Keywords Nanomaterials, supramolecular, advanced materials, interfaces, nanoscale

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

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

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

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

Quy Khac Ong

Administrative Assistants

Chiara Donini

Selected Publications » Atukorale, P. U., Yang, Y.S., Bekdemir, A., Carney, R. P., Silva, P. J., Watson, N., Stellacci, F. and Irvine, D. J. (2015) Influence of the glycocalyx and plasma membrane composition on amphiphilic gold nanoparticles association with erythrocytes. Nanoscale 7: 11420. » Le Ouay, B. and Stellacci, F. (2015) Antibacterial activity of silver nanoparticles: A surface science insight. Nano Today 10(3): 339. » Salvati, E., Stellacci, F. and Krol, S. (2015) Nanosensors for early cancer detection and for therapeutic drug monitoring. Nanomedicine 10(23):3495. » » » »

Sanchez-Ferrer, A., Carney, R. P., Stellacci, F., Mezzenga, R. and Isa, L. (2015) Isolation and characterization of monodisperse core shell nanoparticles fractions. Langmuir 31(41):11179. Ricci, M., Segura, J. J., Erickson, B. W., Fantner, G., Stellacci, F. and Voitchovsky, K. (2015), Growth and dissolution of calcite in the presence of adsorbed stearic acid. Langmuir 31(27):7563. Bekdemir, A. and Stellacci, F. A. (2016) Centrifugation-based physicochemical characterization method for the interaction between proteins and nanoparticles. Nature Communications 7:1321. Pelliccia, M., Andreozzi, P., Paulose, J., D’Alicarnasso, M., Cagno, V., Donalisio, M., Civra, A., Broeckel, R. M., Haese, N., Silva, P.J., Majormaki, V., Strebow, D.N., Lembo, D., Stellacci, F., Vitelli, V. and Krol, S. (2016) A Additives for vaccine storage to improve thermal stability of adenoviruses from hours to months. Nature Communications 7:1350.

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

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

116

lhtc.epfl.ch

Introduction

Results Obtained

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

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

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

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

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

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

Lydia Aslanidou Maiia Bragina Michael Sturny Stamatia Pagoulatou Research & technical staff eft D representation based on P images of a dissecting aneurysm, with tunica media in (transparent) white, intramural hematoma in (transparent) orange, blood filled lumen in red. op P -guided histology showing (i) endothelization of the false channel parallel to an unchanged aortic lumen ( D , endothelium in blue, left stain) and (ii) apparent dilatation as the hemorrhage resulting from the tear in the tunica media is enclosed within the distended adventitia (combined SR and Miller, media in brown, adventitia in red, right stain). Bottom: 2D PCXTM image with .5 micron resolution shows how a false channel is formed within the dissecting aneurysm (left); photograph of the gross anatomy (right).

Michel Bachmann Stéphane Bigler Fabiana Fraga Sébastien Pittet Sylvain Roy

Administrative Assistants

Sylvia Widmer

Selected Publications » Trachet, B., Piersigilli, A., Fraga-Silva, R.A., Aslanidou, L., Sordet-Dessimoz, J., Astolfo, A., Stampanoni, M.F., Segers, P. and Stergiopulos, N. (2016) Ascending aortic aneurysm in angiotensin II-infused mice: formation, progression, and the role of focal dissections. Arterioscler Thromb Vasc Biol 36(4): 673-681. » Aslanidou, L., Trachet, B., Reymond, P., Fraga-Silva, R.A., Segers, P. and Stergiopulos, N. (2016) A 1D model of the arterial circulation in mice. ALTEX 33(1): 13-28. » Trachet, B., Fraga-Silva, R.A., Londono, F.J., Swillens, A., Stergiopulos, N. and Segers, P. (2015) Performance comparison of ultrasound-based methods to assess aortic diameter and stiffness in normal and aneurysmal

mice. PLoS One 10(5): e0129007. » Trachet, B., Fraga-Silva, R.A., Jacquet, P., Segers, P. and Stergiopulos, N. (2015) Dissecting abdominal aortic aneurysm in Angiotensin II-infused mice: the importance of imaging. Curr Pharm Des 21(28): 4049-4060.

» Fraga-Silva, R.A., Montecucco. F., Costa-Fraga. F.P., Nencioni, A., Caffa, I., Bragina, M.E., Mach, F., Raizada, M.K., Santos, R.A., da Silva, R.F. and Stergiopulos, N. (2015) Diminazene enhances stability of atherosclerotic plaques in ApoE-deficient mice. Vascul Pharmacol 74: 103-113. » Trachet, B., Fraga-Silva, R.A., A. Piersigilli, A., Tedgui, A., Sordet-Dessimoz, J., Astolfo, A., Van der Donckt, C., Modregger, P., Stampanoni, M.F., Segers, P. and Stergiopulos, N. (2015) Dissecting abdominal aortic aneurysm in Ang II-infused mice: suprarenal branch ruptures and apparent luminal dilatation. Cardiovasc Res 105(2): 213-222. » Fraga-Silva, R. A., Costa-Fraga, F.P., Montecucco, F., Sturny, M., Faye, Y., Mach, F., Pelli, G., Shenoy, V., da Silva, R.F., Raizada, M.K., Santos, R.A. and Stergiopulos, N. (2015) Diminazene protects corpus cavernosum against hypercholesterolemia-induced injury. J Sex Med 12(2): 289-302

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

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

118

miplab.epfl.ch

Introduction

Results Obtained

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

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

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

IBI - Co-affiliated Research Groups

Team Members Postdoctoral Fellows

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

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

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

Master’s Students

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

Omar Al-Kadi Michal Bola Younes Farouj Engineer

Nicolas Gninenko Interns

Akshay Kumar Stefano Moia Administrative Assistant

Selected Publications » Emmert, K. et al. (2016) Meta-Analysis of Real-Time fMRI Neurofeedback Studies using Individual Participant Data: How Is Brain Regulation Mediated? » NeuroImage. 124:806-812. » » » » »

Manuela Da Silva

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

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Editor: Laurence Mauro Many thanks to Friedrich Beermann, Lucia Baldi, Dietrich Reinhard, Sacha Sidjanski, Harald Hirling and Roland Chabloz at the Repro for their help and support!

12th edition 2015/2016 Produced and edited by the EPFL School of Life Sciences Printed at the EPFL “Atelier de Reprographie”

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