Clinical Genomic Analysis Workshop 2015

Abstract: Under healthy conditions, the human body contains an estimated ten times higher number of bacteria than the estimated number of human cells. Emerging evidence indicates that the interaction between the body and its microbiome is highly dynamic and can lead to many outcomes other than infectious diseases. Characterization of the molecular and cellular mechanisms at play in these interactions is providing a new understanding of microbial commensalism and pathogenicity.

Staphylococcus aureus (S. aureus) is carried chronically by over a quarter of healthy individuals without any ill effect. S. aureus is also a very common pathogen with a calculated health burden of $6 - 9 billion per year in the USA alone. This duality of outcomes makes S. aureus a pathobiont. We are using the interaction between S. aureus and the human immune system as a clinically relevant model to discover new regulatory mechanisms of immunity. Using a system immunobiology approach of S. aureus commensalism and infections, we are identifying those factors that determine the different outcome of encounters between this microbe and human beings, and the mechanisms that govern them.

In this talk, I will discuss our recent work leading to the identification of a TLR2-PI3K-Akt-dependent, IL-10-mediated response to glycopolymers embedded in the peptidoglycan layer of the cell wall of S. aureus (Nature Medicine 2009; 15: 6412; J Infect Dis 2011; 204: 253; Infect Immun 2015; 83: 1587). Our preliminary data indicate that, depending on the site of interaction and the primary antigen-presenting cell, S. aureus can exploit this response to favor commensalism or pathogenicity. In addition, I will present recent data on the identification and characterization of predominantly anti-inflammatory TLR2 ligands and the transcriptional programs of disease tolerance they trigger. This knowledge may translate into novel anti-inflammatory strategies to prevent and treat staphylococcal infections.

Bio: Dr. Joaquín (Quim) Madrenas is Full Professor, Tier I Canada Research Chair in Human Immunology, and Chairman of the Department of Microbiology and Immunology at McGill University, as well as Founding Director of the Microbiome and Disease Tolerance Centre (MDTC) at McGill and Executive Director of the CIHR Human Immunology Network (CHIN).

Dr. Madrenas received an M.D. degree at the University of Barcelona, specialized in Nephrology and Transplantation at the University Autonoma of Barcelona, obtained a M.Sc. degree in Experimental Medicine under Dr. John B. Dossetor, and a Ph.D. degree in Immunology under Dr. Phillip Halloran at the University of Alberta. He was a visiting associate with Dr. Ronald Germain at the NIH (Bethesda, MD, USA), before returning to Canada. He was the founding Director of the FOCIS Centre for Clinical Immunology and Immunotherapeutics in London, ON, the first FOCIS Centre of Excellence in Canada.

Dr. Madrenas' seminal contributions to Immunology and Medicine are illustrated in his more than 140 book chapters and publications in high profile journals including Science, Nature Medicine, Immunity, Journal of Experimental Medicine, Lancet, and Proceedings of the National Academy of Science USA. Among his discoveries are the different signalling patterns through the T cell antigen receptor, the mechanisms of CTLA-4 signalling, and identification of mechanisms of pathobiosis by Staphylococcus aureus. For his research, he has received numerous awards including a Canada Foundation for Innovation Researcher Award, a Premier's Research Excellence Award, a Canada Research Chair, an Ontario Distinguished Researcher Award, The John B. Dossetor Mission Award in Research from The Kidney Foundation of Canada, the UWO Dean's Award of Excellence in Research and UWO Faculty Scholar Award. In 2011, Dr. Madrenas was inducted as a Fellow to the Canadian Academy of Health Sciences.

Professor Madrenas is also an active teacher of Immunology, having received the Schulich Leader Excellence Award in Undergraduate Medical Education, four UWO Hippocratic Council Basic Science Teaching Awards, and being included in the Who's Who in Medical Sciences Education. He also serves as associate editor of several high profile journals, and has extensive experience as a reviewer for national and international agencies and institutional boards. Professor Madrenas is actively engaged in public education and community outreach in Science and History as illustrated by his recent engagement as a TEDx Montreal speaker.

Research in the Madrenas lab is funded by the Canadian Institutes of Health Research (CIHR).

Abstract: Rapid advances in metagenomics and genome sequencing have led to the accumulation of vast amounts of empirical ecological data. With the increase in ecological data production, the need for robust automated functional community analysis approaches rises. The genomic-based construction of a communal metabolic network allows the investigation of the functional division between its participants, showing the metabolic hierarchy within the sampled environment. More specifically, such hierarchy allows the identification of key reaction allowing the environment-specific metagenome to make use of the available resources allowing, for example N- and S assembly as well as the utilization of complex carbohydrates. Taxonomic classification of such reactions further allows delineating the corresponding functional significance of species-groups and their specific contribution to the meta-level metabolism. Here, I will discuss top down and bottom up approaches for using metabolic network approaches for studying functional division within bacterial communities.

Bio: Dr Shiri Freilich is a research staff member at the Newe Yaar Research Center, Agriculture Research Organization (ARO). Prior to joining ARO, she has been a postdoctoral research fellow in the School of Computer Science, Tel Aviv University. Shiri received her Ph.D. in Computational Biology from The University Of Cambridge, UK, in 2007.

Bio: Yehuda Ringel, MD is a Professor of Medicine from the University of North Carolina (UNC) School of Medicine at Chapel Hill and Chief, Division of Gastroenterology at Beilinson Hospital, Rabin Medical Center (RMC). Petach Tikva, Israel.

Dr. Ringel earned his medical degree cum laude at The Technion – The Israel Institute of Technology and completed his medical residency and fellowship in Internal Medicine and Gastroenterology at Tel-Aviv Medical Center in Israel. Additional training includes a Master in Internal Medicine at Tel-Aviv University and a postdoctoral fellowship at UNC-Chapel Hill, Division of Gastroenterology and Hepatology.

Dr. Ringel has been the Director of the UNC Clinic for Functional GI Disorders and the Associate Director of the UNC Center for Functional GI & Motility Disorders. His clinical work focuses on a patient-centered, integrative, multi-disciplinary approach for the evaluation and treatment of patients with functional and motility gastrointestinal disorders. His clinic has become recognized as a national tertiary referral site for patients with complicated and difficult to treat upper GI disorders (e.g., nausea, vomiting, gastroparesis, and functional dyspepsia), lower GI disorders (chronic constipation, diarrhea and IBS) and generalized motility disorders (e.g., functional abdominal pain, bloating and chronic intestinal pseudo-obstruction).

Dr. Ringel has been involved in clinical and translational research for over 15 years. He is an expert in clinical research and has been involved in the design, evaluation and conduct of clinical trials investigating new drugs, dietary and food supplements, medical devises and new approaches for diagnosis and treatment of patients with GI disorders. Dr. Ringel was awarded two grants from the National Institute of Health (NIDDK) to examine the role of intestinal microbiota and intestinal inflammation and immune function in the pathogenesis of functional GI disorders and he is a recipient of several prestigious awards including from the American College of Gastroenterology (ACG), the American Gastroenterology Association (AGA) and the Functional Brain-Gut Research Group (FBG).

Dr. Ringel is a member of the American College of Gastroenterology (ACG) Research Committee, the ACG Educators Task Force and the American Neurogastroenterology and Motility Society (ANMS) Education Committee. He also serves as councilor for the Neurogastroenterology & Motility section of the American Gastroenterology Association (AGA) Institute. He is a Section Editor for the Journal of Clinical Gastroenterology and serves on the Editorial Board of several scientific journals. Dr. Ringel has published multiple original articles, reviews, editorials and book chapters. His clinical and research work have been recognized nationally and internationally and he is frequently invited to present his work and share his experience at national and international professional and scientific meetings.

Abstract: Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD) currently affecting over 2 million patients globally, mostly young adults. These conditions are very often debilitating and may markedly affect the patient's quality of life. Despite important advances in research, the pathogenesis of IBD is still obscure and the condition remains incurable. Patients are rarely diagnosed early, making IBD virtually impossible to be studied throughout its entire course of development. About 20% of UC patients undergo surgery in which the large bowel is removed and a reservoir ("pouch") is created from the unaffected small bowel. Over time, a CD-like inflammation of the pouch ("pouchitis") may develop in ~60% of these patients. It is highly probable that a combination of genetic susceptibility, environmental factors, and an aberrant mucosal immune response underlying the elusive pathogenesis of CD plays a definitive role in pouchitis.

We had hypothesized that the investigation of the development of pouchitis will enable better understanding of the inflammatory pathways involved in CD pathogenesis. In our research project "Pouchitis: a key to understanding Crohn's disease" we had identified multiple genetic, molecular, microbial, serologic and environmental factors associated with pouchitis and CD. These findings together with parallel, mechanistic studies on selected IBD-relevant molecular, genetic and microbial targets identified are performed in order to decipher the function of these molecules and pathways.

Bio: Iris Dotan is Head of the Inflammatory Bowel Disease Center at Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; a tertiary referral center for inflammatory bowel disease patients. Professor Dotan received her medical degree from the Sackler Faculty of Medicine, Tel Aviv University, Israel. Her postdoctoral fellowship was at the Immunobiology Center, Mount Sinai Medical Center, NYC, NY, USA, where she focused on intestinal epithelial cell biology. She is a specialist in internal medicine and in gastroenterology and liver diseases.

The overarching theme at the IBD Center headed by Professor Dotan is to provide cutting edge care for patients and families. Her clinical and research interests focus on patient stratification as a basis for improved patient care, prevention of complications and future cure of IBD. She has expertise in the use of biologicals and novel therapies for inflammatory bowel disease, and the follow-up of ulcerative colitis patients before and after restorative proctocolectomy pouch surgery, in a comprehensive, multidisciplinary pouch clinic. Professor Dotan additionally conducts translational research in mucosal immunology, focusing on the interactions of mucosal lymphocytes with their environment, specifically epithelial cell-derived mediators and chemokines. She first described the new anti-glycan antibodies and their relevance to Crohn's disease a decade ago, and investigates the role of glycans in intestinal immune responses.

Abstract: Cancer cells constantly undergo genomic changes (i.e. mutations), which allow them to escape from the body's defense mechanisms and from targeted drugs, and enables them to continue to divide and spread. Despite the availability of selected second and third line targeted therapies, cancer evolution is expected to prevail and to ultimately result in resistance and treatment failure. The goal of Novitero is to enable future effective precision cancer treatment, aiming at combating cancer by previewing its mutational activities and by overcoming its resistance to therapies. We employ our computational technologies to predict the mutational fingerprints implicated in drug resistance to various therapeutic targets, and we design new drugs that bypass these mutations. Our war strategy on cancer consists on being few steps ahead of cancer by predicting and smartly bypassing the potential future mutations that the cancer may adopt to resist therapies.

Bio: Dr. Itzchak Angel, CEO is an accomplished executive in the pharmaceutical industry, with over 30 years of experience in guiding strategic drug- and business-development in both large and emerging companies, and having brought several drugs to market. Dr. Angel has been instrumental in the creation of the Israeli Pharmalogica Consortium and served as its President and Chairman for several years. He has formerly been VP R&D at Proteologics Ltd and at D-Pharm Biopharmaceuticals (Rehovot, Israel) where he several compounds into advanced clinical development. For numerous years, he was Head of Pharmacology at Sanofi (formerly Synthelabo, Paris, France) where he participated in the research and development of marketed drugs such as Xatral, Ambien and Mizollen. He is also as an international consultant for both emerging and world-renown pharmaceutical companies for more than a decade. Dr. Angel is co-inventor and co-author of over 100 patents and publications.

Abstract: Compugen is a drug discovery company with a unique, broadly applicable, predictive discovery infrastructure, which is applied to drug target discovery. In this talk, I will present Compugen's approach to the discovery of novel immune checkpoint target for cancer immunotherapy and their validation and development path.

Bio:

Bio: Robert H. Brook holds the Distinguished Chair in Health Care Services at the RAND Corporation, where he previously served for 19 years as vice president and director of RAND Health. He is also a professor at the Pardee RAND Graduate School and professor of Medicine and Health Services at UCLA, where he directs the Robert Wood Johnson Clinical Scholars Program. He led the Health and Quality Group on the $80M Health Insurance Experiment and was co-principal investigator on the Health Services Utilization Study. He was the co-principal investigator on the only national study that has investigated, at a clinical level, how Medicare's prospective payment system affected the quality and outcome of acute hospital care. He was also the co-principal investigator on a joint activity of 12 academic medical centers, the American Medical Association, and RAND, the purpose of which was to develop appropriateness criteria and parameters for the use of procedures.

Brook is a member of the Institute of Medicine, the American Society for Clinical Investigation, and the American Association of Physicians. In 2005, Brook won the Institute of Medicine's Gustav O. Lienhard Award, cited "as the individual who, more than any other, developed the science of measuring the quality of medical care and focused U.S. policymakers' attention on quality-of-care issues and their implications for the nation's health." He has been awarded the HRET Trust Award, the David E. Rogers Award of the Association of American Medical Colleges, the Baxter Foundation Prize, the Rosenthal Foundation Award of the American College of Physicians, the Distinguished Health Services Researcher Award of the Association of Health Services Research, and the Robert J. Glaser Award of the Society of General Internal Medicine.

Brook received his M.D. and Sc.D. from Johns Hopkins University

Bio: Dr. Raanan Berger is Director of the Institute of Oncology at the Sheba Medical Center, which is Israel's national hospital and the largest medical center in the Middle East. He is also secretary of the Israeli Society of Clinical Oncology and Radiotherapy. His MD and PhD degrees are from Tel Aviv University and he was a postdoctoral fellow at the Dana Farber Cancer Institute at Harvard Medical School under the supervision of Prof. Phil Kantoff. Seven years ago, he established the Riva Koschitzky Oncology Clinical Research Center, at Sheba, which is the largest center for all-phase oncology clinical trials in Israel, currently conducting over 140 advanced clinical trials backed by the biggest pharmaceutical conglomerates and top scientists in the world.

Abstract: Due to rapid advances in DNA sequencing technologies, both in time as well as cost, genomic medicine is poised to play a significant role in personalized healthcare in the immediate future. Indeed, genomic information is being collected at great pace, depth and breadth. Unprecedented access to such information calls for sophisticated algorithms to make sense of the massive genomic data along with deriving possible actionable solutions from heterogeneous data sources. In this talk, I will present some algorithms we have developed in this context and also discuss our experience with designing a tool for guiding cancer treatment and understanding disease.

Bio: Filippo is a research scientist at the Computational Biology Center at IBM T.J. Watson Research Center (NY - USA). His research involves computational methods for analyzing various types of biological data. Filippo joined IBM Research in 2011 as a post-doctoral researcher, after completing his PhD at University of Palermo (Italy) on Computer Science, and he was converted to research scientist in 2014.

Abstract: No robust set of "metrics" for human immunological health currently exists. Yet immunological insufficiency or dysregulation underlie many known medical conditions and have been implicated in many more. Thus, considering its central role in disease, it is particularly disturbing that we do not understand how an individual's immune system state affects their disease susceptibility or outcome. This is particularly concerning in the elderly, who are thought to be a high risk group with respect to infectious disease and whose immune responsiveness is known to decline. Yet, we lack a systematic picture of immune aging and diagnostics for those at risk. Through longitudinal high resolution profiling of young and older adults we identify distinct stable immune states in older adults, including a profile associated with chronic inflammation and exhaustion. We evaluate the clinical implications of immune states in cardiovascular disease and sepsis which suggest that baseline immune state effects disease outcome.

Bio: Shai Shen-Orr is an Assistant Prof. at the Faculty of Medicine at the Technion – Israeli Institute of Technology. . Since 2012 he heads the Systems Immunology & Precision Medicine laboratory at the Technion's Faculty of Medicine. His research is at the interface of immunology and healthcare and his lab both generates Big Data as well as mines it from publically available biomedical resources.

He received a BSc from the Technion in Information Systems (1999), an M.Sc. in Bioinformatics at the Weizmann Institute of Science (2002), a Ph.D. from Harvard University in Biochemistry (2007). His completed his postdoctoral training at Stanford University 2011.

Abstract: The ability to sequence cancer genomes is revolutionizing our understanding of cancer. We can now characterize the cancer genome with a base-level resolution and detect mutational processes and understand the tumor evolution. A key challenge in cancer genomics is to distinguish between the few driver events -- ones that increased the fitness of the cells when they occurred -- and the many thousands of passenger events that had little or no effect on the cells. I will describe tools that we have developed to address these challenges. In addition, I will describe our analysis of large cohorts of tumors which reveal novel cancer genes and shed light on the number of tumors that need to be studied to complete the cancer gene catalog.

Bio: Dr. Getz is an internationally acclaimed leader in cancer genome analysis and is pioneering widely used cancer genome analysis tools. Dr. Getz joined the MGH staff in 2013 and directs the Bioinformatics Program at the MGH Cancer Center and Department of Pathology. Getz is also the inaugural incumbent of the Paul C. Zamecnik Chair of Oncology at the MGH Cancer Center. In addition to his role at the Massachusetts General Hospital, Getz directs the Cancer Genome Computational Analysis group at the Broad Institute. He has published numerous papers in prominent journals that describe new genes and pathways involved in different tumor types. Getz received his B.S. degree in Physics and Mathematics from Hebrew University and an M.Sc. in Physics from Tel-Aviv University. He later earned a Ph.D. in Physics from the Weizmann Institute of Science in Israel. He completed his postdoctoral training at the Broad Institute of MIT and Harvard with Todd Golub, where he focused on developing computational tools and analyzing expression of miRNAs across cancer.