ICAHN INSTITUTE FOR GENOMICS AND MULTISCALE BIOLOGY DEPARTMENT OF GENETICS AND GENOMIC SCIENCES ANNUAL REPORT
We’ve recruited stellar people all of whom came to Mount Sinai because they believe in our vision that embracing the full complexity of biology and mastering the digital universe of information will be essential to eventually curing or preventing disease… We are proud to be considered a “hot place to be” in the world of genomics, big data, and medicine. ERIC E. SCHADT, PHD
Letter from the Chair
Basic Research Grants Schizophrenia Hepatitis C Cardiovascular
13 New Capabilities and Initiatives Next Gen Genomics Research Facility Customized Gene Screening Panels New Supercomputer Funded by NIH Harris Center for Precision Wellness 17 Translational Research Drug Repurposing Consumer Engagement IBD and the Microbiome 23 Patient Care Clinical Services 27 Diagnostic Testing 31 Recruiting Profiles 37 In the News 43 Recognizing Our Partners
Letter from the Chair In 2014, our Icahn Institute for Genomics and Multiscale Biology rapidly scaled up to achieve key milestones of success, and our Department of Genetics and Genomic Sciences continued its leadership role in the biomedical community. Together, the Mount Sinai genomics team made significant advances in basic and translational research, clinical and diagnostic services, and education. On the research side, our national rankings in NIH grant funding continue to soar, as we are now the #8 ranked genetics department in the nation, up from #15 in 2013 and #29 in 2012. Despite a difficult grant funding environment, our genetics researchers have been quite successful in winning federal grants to support their groundbreaking efforts. I’m particularly proud to say that we are now the number 1 ranked genetics institution in the New York metro area, ahead of Columbia, Cornell and others, when only 3 years ago we lagged in 6th spot locally. Our genetics clinic and clinical lab represents the critical point at which the science meets the patient. In 2014 our team continued the remarkable expansion of the past few years, with genetic testing volume and revenues up 52%. Our lab launched new diagnostic tests such as an expanded carrier screening panel for Ashkenazi Jews, enhanced SMA, and a cancer hotspot panel in collaboration with our Pathology Dept. We’ve had to expand to support this extraordinary growth, and so we launched a High Throughput, Next Generation Sequencing facility in Branford, Connecticut , supported by a $9.5m loan from the Connecticut Department of Economic Development. We were honored that Connecticut Governor Malloy launched our facility at an event in October. The Icahn Institute was launched in 2011 to build upon the formidable strengths of the genetics department in translational research and clinical care. It was created around the idea that advancing the era of precision medicine requires completely new approaches: with cutting-edge technologies, novel partnerships between the public and private sector, and world class computational and analytical resources. We’ve recruited stellar people from medical centers, academic institutions, major corporations , and even Silicon Valley start-ups - all of whom came to Mount Sinai because they believe in our vision that embracing the full complexity of biology and mastering the digital universe of information will be essential to eventually curing or preventing disease. In 2014, we grew our incredible team with 75 new hires, and reached 100 faculty members total. We are proud to be considered a “hot place to be” in the world of genomics, big data, and medicine. In 2015, we will massively scale up our genomic sequencing capabilities for both research and clinical operations, in order to continue our progress in delivering precision medicine. We will embrace the use of mobile technology to advance medical research by enabling participation from volunteers on an unprecedented scale, such as with our partnership with Apple. In the pages that follow, I am pleased to share a sampling of our many promising programs , such as our efforts in cardiovascular disease, schizophrenia, hepatitis C, and inflammatory bowel disease. You will also meet some of the people who make the genomics group at Mount Sinai such a remarkable team. Together, these stories illustrate the incredible potential we hold to dramatically improve patient care and overall human well-being. Thank you for your continued support and encouragement.
Eric E. Schadt, PhD Jean C. and James W. Crystal Professor of Genomics Chairman and Professor, Department of Genetics and Genomic Sciences Director, Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai
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Basic research is the foundation in advancing our understanding of the genetic underpinnings of human health and disease states. Federal grant funding from the National Institutes for Health (NIH) is a crucial source of support for our researchers and, given the highly competitive nature of such funding, it provides a barometer of our relative standing within the academic community. The NIH budget has experienced a 20% decline in inflation-adjusted dollars since 2003, resulting in an even steeper drop of 34% in R01-equivalent research grants, the type that support most independent labs. Given these trends in a very difficult funding environment, our NIH grant awards in 2014 are remarkable. We received total awards from federal sources of more than $17.8m, making us the fastest growing department for federal grant funding at Mount Sinai. Our success in receiving NIH grant awards was reflected in our ranking relative to other academic genetics departments, where we are now #8 in the nation. Breaking into the top ten is a remarkable milestone. In the past 2 years, we have leapfrogged by 21 spots in the national rankings, moving from the 29th ranked genetics department nationwide in 2012, and rising up from #15 in 2013. This dramatic increase demonstrates the impressive strength of both our established and recently hired faculty, and the scientific collaborations that thrive within our genetics researcher team and across the entire Mount Sinai community. Within the highly competitive New York City area, we’re pleased that we are ranked #1 in 2014 in NIH grant funding, up from a #6 ranking in 2011.
NATIONAL RANKINGS / FROM THE BLUE RIDGE INSTITUTE FOR MEDICAL RESEARCH 1
BAYLOR COLLEGE OF MEDICINE WASHINGTON UNIVERSITY STANFORD UNIVERSITY UNIVERSITY OF WASHINGTON UNIV OF NORTH CAROLINA CHAPEL HILL HARVARD MEDICAL SCHOOL DUKE UNIVERSITY
4 5 6 6
8 7 8
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI UNIVERSITY OF CHICAGO YALE UNIVERSITY COLUMBIA UNIVERSITY HEALTH SCIENCES WEILL MEDICAL COLL OF CORNELL UNIV EMORY UNIVERSITY JOHNS HOPKINS UNIVERSITY UNIVERSITY OF PENNSYLVANIA
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29 9 10 11
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Birth Defects: Moebius Syndrome and Related Facial Weakness Disorders
Integrative multivariate association and genomic analyses
NIH (Univ of Chicago)
The relationship between host diet, the gut microbiota, and host transcription
The Center for Research on Influenza Pathogenisis (CRIP)
Harm van Bakel, Adolfo Garcia-Sastre
Transforming Genomics with 5 PB Big Omics Data Engine Cray CS300-AC Supercomputer
Transcriptome Atlases of the Craniofacial Sutures
Ethylin Jabs, Greg Holmes
Mount Sinai's Knowledge Management Center for Illuminating the Druggable Genome
Joel Dudley, Avi Ma'ayan
Genomic approaches to cardiometabolic risk and treatment in HIV
Linking disease-associated variants to transcriptional regulation using ENCODE
NIH NHGRI (transfer)
Whole Genome Sequencing to Discover Familial Myeloma Risk Genes
NIH (Weill Cornell)
Roles of Transcription Factors in Kidney Development
Ethylin Jabs, Inga Peter, Eric Schadt
Network Based Predictive Drug Discovery for Alzheimer's Disease
Joel Dudley, Sam Gandy
Probing networks underlying sleep and stress with multiscale data
Joe Sarpa (Andrew Kasarskis)
Analysis Of Influenza Virus Polymerase Interactions With The Host Transcriptome
Zuylema Peralta (Harm van Bakel)
Diabetes research and Training center
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Pamela Sklar, MD, PhD - Chief of the Division Psychiatric Genomics
Although the complexity is sobering, these types of studies should provide a firm base from which we can chart a course toward the ultimate goal of subtyping patients and offering a more personalized treatment path.
Pamela Sklar, MD, PhD
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Schizophrenia Millions of Americans suffer from schizophrenia, a potentially severe and disabling mental illness accompanied by hallucinations, delusions and cognitive problems. Mount Sinai investigators within the Division of Psychiatric Genomics, the Department of Psychiatry, and the Psychosis Research Program are conducting ongoing studies to identify the genetic origins and biological mechanisms behind schizophrenia and spectrum disorders. This year our team led two studies in the prestigious journal Nature. Drs. Shaun Purcell, Menachem Fromer, and Pamela Sklar reported the largest application of DNA sequencing to schizophrenia to date and found that many rare DNA changes contribute to the risk of developing schizophrenia and that some new mutations found in patients overlap those found in autism and intellectual disability, and importantly, that specific aspects of the synapse are the targets. “The sheer volume of data generated in these projects is remarkable and suggests new ways of thinking about the role of rare mutations in schizophrenia,” said Shaun Purcell, head of the Center for Statistical Genomics at Mount Sinai. Pamela Sklar, Chief of the Division of Psychiatric Genomics, stated, “Although the complexity of the genetics is sobering, these types of studies should provide a firm base from which we can chart a course toward the ultimate goal of subtyping patients and offering a more personalized treatment path than the one-size-fits-all approach currently used.” Mount Sinai researchers have been in the forefront in building the large datasets that will be needed to make this a reality. Our Icahn Institute investigators have received several multimillion dollar awards this year to enhance the activities of the CommonMind Consortium, a public-private group of industry and academic leaders, whose goal is to generate and analyze large scale data from human subjects with neuropsychiatric disorders and to make this data and the analytical results broadly available to the public as a free resource. The Icahn Institute Genomics Core is the main site of data generation including a new three-year project to study epigenetic signatures in schizophrenia led by Dr. Pamela Sklar and Friedman Brain Institute faculty member Dr. Schahram Akbarian that is part of the large NIMH PsychENCODE initiative. Dr. Sklar presented at the 2014 EMTECH MIT Media Lab Conference on Emerging Technologies that Matter where she described how we are moving from a phase of discovery of genetic risk factors to understanding how they produce abnormal biology. She pointed out that right now, it is like having a jigsaw puzzle without the picture on the box for reference and described how Mount Sinai investigators are working to redefine schizophrenia at the molecular level, updating old ideas to models of diseases with new genomic information, which can more fully account for the observed complexity. While challenging because our understanding of the human genome and function is incomplete, analyzing the diverse set of genomic information will allow us to build more precise network models of disease that can help us discover key mechanisms of diseases and specific genes that might be targeted for therapeutics.
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Hepatitis C The Hepatitis C Virus (HCV) is widespread, affecting over 3 percent of the world’s population and more than 3 million people in the United States alone. The vast majority of people who get HCV will suffer chronic infection, which can lead to liver inflammation, cirrhosis, and liver cancer. Effective new treatments have been launched recently, but their high prices have caused public outcry and limited widespread use. There is no commercially available vaccine for hepatitis C. In November 2014, a team of Mount Sinai scientists led by Drs. Brian Brown and Matthew Evans revealed important new information about HCV, including its response to targeted therapeutics and new insight about its role in cancer development. The work, published in Nature Communications, focused on microRNA genes — a recently discovered type of regulatory gene —and used whole-genome sequencing of the virus to challenge conventional wisdom about how the virus responds to emerging therapies. The findings may contribute to more effective development of hepatitis C drugs in the future and to more personalized treatment for patients. This new study examined HCV response to an experimental treatment that targets and blocks the supply of a microRNA that the virus needs for infection of human cells. Contrary to expectations, the researchers found that depleting the supply of this microRNA could trigger drug resistance with the emergence of HCV strains able to infect cells with negligible levels of the microRNA. This information could be used for more effective dosing of drugs targeting this gene, as well as for pre-treatment analysis to determine which patients may respond best to this class of drugs. Also, the scientists uncovered knowledge that may help answer the longstanding question of how HCV leads to cancer. The study demonstrated that HCV hijacks the microRNA gene, diminishing its normal activity in liver cells. Since this microRNA is known to be a potent tumor repressor, it is possible that HCV robs cells of their natural defenses against uncontrolled growth and contributes to cancer development in patients infected with HCV.
“There is a critical need for more weapons in our arsenal to fight HCVparticularly for affordable, effective treatment as we try to stay a step ahead of this virus and prevent it from developing the kind of drug resistance we’re seeing in the bacterial realm.” – Matthew Evans, PhD, Assistant Professor of Microbiology at the Icahn School of Medicine at Mount Sinai
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â€œWe have known for years that hepatitis C is linked to cancer, but the biological mechanism behind that was never known. Realizing that HCV is leeching an important anti-cancer gene from its human host may be the puzzle piece needed to explain the relationship.â€? Brian Brown, PhD, Associate Professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai
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Cardiovascular As cardiovascular diseases (CVDs) now account for near 1/3 of all deaths worldwide, new strategies to battle this threatening pandemic are desperately needed. The vast majority of CVD deaths are caused by heart attacks and strokes, both of which are typically the consequences of the formation of atherosclerotic plaques in the wall of arterial vessels. These plaques narrow the vessels interfering with the blood flow leading to insufficient delivery of oxygen to vital organs such as the heart and brain. Atherosclerosis can also lead to the formation of blood clots that risk traveling to the brain where they can cause a stroke. Professor Johan Björkegren at Mount Sinai, a cardiovascular geneticist recruited from the Karolinska Institute in Sweden, has taken a new approach to understanding atherosclerosis, heart attack and stroke. Instead of trying to find single genes, proteins or other isolated CVD risk factors, Dr. Björkegren has gathered a unique cohort of nearly all relevant tissues involved in CVD. The samples from each individual patient are being analyzed with a systems biology perspective, looking at DNA, RNA, and other related molecules and how their interaction leads to CVD. “By understanding the network biology of disease you can divide the patients according to their molecular disease profiles and tailor the therapy accordingly, as we drive towards precision medicine for CVD” say Dr. Björkegren. He has launched a new clinical study, the PREDICT study, with Cardiologist Dr. Jason Kovacic to translate findings from systems biology analysis into clinical practice with CVD patients. Together with Dr. Kovacic at the Division of Cardiology and Drs. Dudley and Schadt at the Icahn Institute, Dr Björkegren recently authored a review article in the Journal of American Association for Cardiology describing the state-of-the-art systems genetics approach to CVD that he pursues in his lab. Another area of Dr. Björkegren’s research is the study of how genetics can help improve early CVD prevention. As most risk factors for heart disease and stroke are present early in life, early prevention is of greatest importance. Almost one-third of adults and children in the United States are obese, with the highest rates affecting the Hispanic and African-American communications in New York City and elsewhere. Preventing obesity is particularly important as it can cause early type-2 diabetes in young people, which in turn drastically increases the risk for premature heart disease and stroke. Mount Sinai Heart at Icahn School of Medicine was recently awarded a $3.8 million grant by the American Heart Association (AHA) to promote cardiovascular health among high-risk New York City children, and their parents, living in Harlem and the Bronx. The research team’s mission is to reduce each child’s future risk of obesity, type 2 diabetes, heart attack and stroke. Mount Sinai along with other institutions will support the AHA’s goal to improve the cardiovascular health of all Americans by 20 percent. The organization also seeks to reduce deaths from cardiovascular diseases and stroke by 20 percent by 2020.
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“We hope to better understand how the intersection of a child’s behavior, environment and genetics lead to heart disease, which will help to refine our future prevention strategies”
“Mount Sinai Heart’s multidisciplinary research team is thrilled to be awarded this critical $4 million grant by the AHA to pursue our pioneering family-centric approach to the prevention of heart disease in New York City’s highest-risk communities.” –Dr. Fuster, who leads the AHA grant and is the Director of Mount Sinai Heart, Physician-in-chief of the Mount Sinai Hospital and Chief of the Division of Cardiology at the Icahn School of Medicine at Mount Sinai
Johan Bjorkegren, MD, PhD Professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai
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New Capabilities and Initiatives
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Next Gen Genomics Research Facility The significant growth in our genetic testing lab over the last 3 years necessitated physical expansion, so we were delighted to announce the launch of our state-of-the art genomics research facility in Branford, Connecticut in October 2014. Connecticut Governor Malloy attended the launch and celebrated the support of the CT Economic Development Agency with a $9.5 million loan. Under the leadership of Todd Arnold, Managing Director, the highly automated facility will focus on large volume sequencing projects for both research and clinical applications. We are building a highly efficient system for high throughput targeted sequencing of many diverse samples that is centered around state-of-the art Ion Proton DNA sequencers and an associated automated sample preparation workflow. Across a range of major projects, we plan to sequence hundreds of thousands of samples over the next two-to-three years. As we scale up to this large volume, we expect to rapidly translate our research findings in major disease areas such as cancer, rare inherited disorders, and characterization of risk across a broad spectrum of common human diseases into effective clinical diagnostics.
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The future growth of our genetic testing efforts depends upon our R&D initiatives, particularly those that involve deploying novel or cutting edge genomic techniques into patient care for the first time. Dr. Robert Sebra, Director of Technology Development, is leading a number of efforts to trial such approaches, including a a collaboration with Thermo Fisher to develop a single targeted panel that covers 25,000 amplicons across 700 genes and 4,000 hotspots affiliated with inherited genetic diseases, cancer, cardiovascular, obesity, and other disorders identified from a retrospective analysis done by Dr. Rong Chen. In addition to comprehensive panels designed to profile many gene exons and hotspots, we also developed long-read methods to sequence full genes including BRCA1, BRCA2 and p53 to survey not only SNVs but larger structural variants afforded by read lengths achieved using single-molecule sequencing that we have optimized to provide reads as large as 70,000bp. The implications of using longer read technologies to assemble human and microbial genomes have been submitted in various publications with Dr. Ali Bashir and others to resolve otherwise impossible structural variation and resolve better reference genomes for NA12878 and an additional Ashkenazi Jewish trio through the National Institute of Standards and Technology (NIST) Genome in a Bottle Consortium. Our development work also includes long-read HLA Class I and II sequencing to 8-digit resolution, pharmacogenomics (PGx), cancer hotspot sequencing, and a full-length RNA isoform sequencing methodology for better detection of gene fusions and novel isoforms. Moreover, as we pioneer new panels for screening bulk samples, in 2014 we also began a new paradigm to target and characterize DNA and RNA in single cells toward a better understanding of sub clonal heterogeneity. To achieve this we are working with a technology that utilizes optoelectronic tweezers to help select, sort, and even sub clone up to 1,000 cells in parallel, prior to high throughput amplification and sequencing. In 2015, we hope to merge these new technologies and targeted sequencing methods with Clinical Genomics to offer new niche diagnostic assays.
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Customized Gene Screening Panels
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New Supercomputer Funded by NIH A $2 million grant from the National Institutes of Health to build a new supercomputer, dubbed the “Big Omics Data Engine,” or BODE, was awarded to Patricia Kovatch, the Associate Dean of Scientific Computing at the Icahn School of Medicine at Mount Sinai. This new specialized Cray supercomputer will enable sophisticated analytics with its 2,484 Intel Haswell compute power and 5 petabytes of Data Direct Networks storage. The new BODE supercomputer will enhance the “Minerva” supercomputer and storage infrastructure already existing at Mount Sinai. This brings the total amount of computing and data resources to over 200 teraflops with 12,000 cores and 60 terabytes of RAM, 10 petabytes of storage and 160 terabytes of flash. There are over 700 users in 11 departments and almost 200 external users of these resources. BODE will provide a dedicated system for genomics-related research for Mount Sinai researchers and their collaborators at 61 external partner institutions in areas as diverse as autism, cancer, and influenza. One major benefactor of the new BODE supercomputer is Pamela Sklar, M.D., whose group is integrating a broad range of genomic, imaging, and clinical data to advance research on schizophrenia by building advanced, multidimensional neurological models.
Harris Center for Precision Wellness Joshua Harris, Senior Managing Director and Founder of Apollo Global Management, and his wife Marjorie, made a $5 million gift to establish the Harris Center for Precision Wellness. The new center, part of the Icahn Institute, will develop new approaches to health monitoring and wellness management by integrating emerging technologies in digital health, data science, and genomics that enable people’s health to be treated in precise, highly individualized ways. The Harris Center, a first-of-its-kind center at a major academic medical center, will provide a focus for a network of precision wellness research programs and clinical initiatives across the Mount Sinai Health System. The Harris Center is directed by Joel Dudley, PhD,a highly regarded genomics and bioinformatics expert at the Icahn Institute, and by Gregory Stock, PhD, an accomplished life-science entrepreneur and technologyinnovation expert. The team is evaluating wearable devices to see how reliably they can measure activity, stress, sleep, cognitive functioning, mood, and environmental exposures. The team is also using sequencing technology to bring DNA, microbiome, and immune system profiles into predictive models of wellness. The goal is to apply state-of-the-science analytics and machine learning to this trove of individualized information to seek actionable, data-driven insights into key aspects of wellness, and to help lead the way to a nextgen healthcare that is scalable and far superior to anything now available.
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Drug Repurposing What if the next life-saving drug was already on the pharmacy shelf? Drug repurposing is the concept of using an existing drug for a new clinical purpose, such as treating a disease beyond its original intended use. Because drug repurposing usually begins with an approved compound, it can drastically reduce the cost and time required to bring a new drug to market. The concept of drug repurposing is not just wishful thinking; there have been several drug repurposing success stories in recent history. Thalidomide, an anti-nausea drug once maligned for its ability to cause birth defects when taken by pregnant women, has a new role as a valuable therapy for treating patients affected by the fatal bone marrow cancer multiple myeloma. A more familiar example of drug repurposing is sildenafil (brand name Viagra) originally developed for treating hypertension, was repurposed as one of the first blockbuster drugs for treating erectile dysfunction. Other examples of successful drug repurposing exist, and all share one thing in common—they were all discovered through serendipity. Thalidomide’s horrific sideeffect of disrupting fetal limb development and causing birth defects led researchers to believe that it would inhibit angiogenesis--the process responsible for formation of new blood vessels--and could thus inhibit the progression of blood-born cancers. Sildenafil’s secondary effects on erectile dysfunction only became apparent when given to human patients in clinical trials for its ultimately failed bid to emerge as a new treatment for hypertension. We are using big data analysis and genomics to move drug repurposing from serendipity to big science. Drug repurposing is an exercise in “connecting the dots” between drugs and other diseases they may be able to treat. Data can help us discover new connections between drugs and disease. For example, similar to the case of thalidomide, the side effect of a drug can offer clues on how a drug could treat another disease. There are projects underway at the Icahn Institute that use sophisticated algorithms to analyze the Electronic Medical Records (EMRs) of millions of patients to discover connections between drugs and disease that may give new insights into drug repurposing. Additionally, there are opportunities to use genome sequencing technologies to accelerate drug repurposing. Scientist Dr. Joel Dudley published one of the first papers showing how computer algorithms can use genomic “fingerprints” of drug activity for drug repurposing. A genomic “fingerprint” of a drug represents how the action of a particular drug might increase or decrease the activity of various genes across the genome. In previous work, Dr. Dudley matched genomic fingerprints of drugs with genomic fingerprints of disease to identify opportunities to repurpose psychiatric medications to treat cancer and autoimmune disease. Dr. Dudley is now working with Dr. Eric Schadt and others at the Icahn Institute to enhance his computational drug repurposing algorithms by integrating advanced network biology methods. He is also leveraging the massive computing power offered by Minerva, one of our supercomputers to search through more data and find new connections faster. Dudley and his colleagues are also exploring drug repurposing opportunities for drug combinations. For example, one drug could be repurposed to minimize or eliminate the side effect of another, or given in combination with another drug (e.g., a chemotherapy) to increase its therapeutic effects.
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Having world-leading expertise in big data, genomics, and clinical research under one roof is helping the Icahn Institute emerge as one of the premier institutes for drug repurposing research. In fact, major pharmaceutical companies recognize our leadership in this area and have begun to forge partnerships with us in hopes of reviving many of their “failed” compounds sitting on shelves. Drug repurposing, accelerated by our big data and genomics capabilities, may offer our fastest path and greatest hope for bringing new therapies to the clinic to help patients in need.
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Consumer Engagement Historically, participating in clinical research was a labor-intensive, and paperwork intensive process that ultimately restricted the number of people who could be involved in research. Fewer people participating in research studies meant fewer major advances, because our ability to discern patterns and separate signal from noise increases tremendously as a larger swath of our population can participate. Today, we are harnessing modern technology to make the advantages of research available to more people than ever before and at the same time make the research itself much stronger than it could ever have been in the past. Mobile Health Apps: People- powered research on a massive scale The rise of mobile devices, in the hands of billions of people worldwide, offers incredible opportunities for scaling medical research and enhancing patient care in new ways. We created a mobile health application (MHA), in partnership with Apple, to conduct a medical research study with individuals suffering from Asthma. Led by Dr. Yvonne Chan, Director of Digital Health and Personalized Medicine, our Mount Sinai Asthma App was designed to facilitate asthma patient education and self-monitoring, promote positive behavioral changes, and reinforce adherence to treatment plans. By monitoring the usage of our app and patients’ health outcomes, our research study will assess the efficacy of self-reported asthma control, quality of life, and health care utilization. Ultimately, our learnings will drive improvements to our Asthma App and additional mobile health apps we plan to develop in the near future. Apple’s new ResearchKit software, upon which our Asthma App is based, offers an exciting opportunity for health and fitness research studies to be conducted on a massive, unprecedented scale due to the popularity of Apple iPhones amongst consumers. We are delighted to be amongst a select group of institutions to pioneer the use of Apple’s ResearchKit for medical research.
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In our Resilience Project, we’re inviting people 30+ years of age to donate their DNA to help us find individuals with rare genetic mutations that textbook medical knowledge indicates should have caused catastrophic illness in childhood, but didn’t. Somehow these individuals are “resilient” – they have been protected via yet to be discovered genetic or environmental factors. Led by Jason Bobe, Director of the Sharing Lab at the Icahn Institute, our study of “resilient” individuals will help us understand how they avoided illness, and could pave the way to develop new treatments or even prevent certain diseases. The combination of new technology enabling low-cost genetic sequencing and an open approach to clinical study provides the opportunity to search for people who carry these genetic mutations, yet are somehow protected from these diseases.
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The Resilience Project: Crowd-sourcing for the Cure Nearly all medical research focuses today on studying people after they get sick. There is a major opportunity to study healthy people to learn how to protect ourselves, and how to recover from illness or prevent illness altogether.
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IBD and the Microbiome Inflammatory Bowel Disease (IBD), which encompasses Crohnâ€™s disease and ulcerative colitis, is characterized by an abnormal activation of our immune system in response to otherwise normal bacteria in our intestine. While the goal of therapy is to treat the inflammation in this disease, we have begun to unravel the important role that the bacteria play. With the advent of new technology, including culture-independent assays, we are now able to study the role of the human microbiome and how it contributes to human disease. The study of bacteria and its influence on human physiology suggests that we may one day have interventions designed to prevent or treat disease that involve the purposeful manipulation of the community of microbes that live in and on our bodies. This manipulation may involve the removal of harmful bacteria, the addition of beneficial ones, or the administration of drugs developed from a molecular understanding of human/bacteria interactions. One such therapy is already on the rise and to date has proved incredibly effective. This microbial cocktailbased treatment, termed fecal microbiota transplantation (FMT), has revolutionized the treatment of an infectious colitis, caused by the bacterium Clostridium difficile, with cure rates of over 90%. The basic principle of FMT is to replace an unhealthy microbiota with the microbiota of a healthy donor. The success of FMT in treating CDI has spurred interest in FMT as a potential treatment strategy of other diseases associated with the microbiota, notably IBD. We at Mount Sinai have pioneered a FMT program to treat colitis caused by Clostridium difficile, and have begun a collaboration with international scholars to investigate the utility of FMT in IBD. Combining our clinical expertise in IBD under the leadership of Drs. Sands, Colombel and Grinspan with our state-of-the-art basic science capabilities (laboratories of Drs. Cho, Faith and Clemente), we at Mount Sinai are in a unique position to not only study the intricate relationship between the human microbiome and IBD but also explore the use of microbial manipulation as a therapeutic target. In addition to our work on FMT, we are taking advantage of one of the largest IBD populations in the country to search for microbiome features that correlate with disease status and progression as well as other host markers of health and disease like the host transcriptome. With our expertise in genetics, we have identified the largest collection of IBD associated genes available and we are probing the role of these disease-associated genes with a variety of cutting edge molecular tools.
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Dr. George Diaz, Division Chief of Medical Genetics, with Dr. Kimihiko Oishi, Assistant Professor, Department of Genetics
Clinical Services Division of Medical Genetics 2014 was an eventful year for the clinical side of the Department of Genetics and Genomic Sciences. Dr. George Diaz was appointed as Chief of the Division of Medical Genetics to lead our clinical faculty in their efforts to integrate the fruits of the genomics revolution into practical applications that will benefit our patients. The year also saw an expansion in the number of trainees admitted to our Genetic Counseling Master’s Program, led by Randi Zinberg, an increase in the number of new patients seen by our Lysosomal Infusion Program, led by Dr. Manisha Balwani, and by our Clinical Genetics Program, led by Dr. Lakshmi Mehta. In the coming year, the Division will continue to grow our programs that service the Mount Sinai community and beyond. New Faces: In the past year we welcomed three new faculty to the Division. Dr. Noura Abul-Husn is a graduate of the Mount Sinai MD, PhD program and of the combined Internal Medicine/Medical Genetics residency program. She is pursuing a research path in translational genomics in the Institute for Personalized Medicine while developing an adult medicine clinical genetics clinic in the Division of Medical Genetics. Dr. Kimihiko Oishi also trained at Mount Sinai in Pediatrics and in Medical Genetics after doing a post-doctoral fellowship developing mouse and fruitfly models of human genetic disorders. He will focus on translational research in inborn errors of metabolism. Dr. Pankaj Prasun joins our Division after completing a combined Pediatrics/ Medical Genetics Residency at the Children’s Hospital of Michigan and a Medical Biochemical Genetics Fellowship at Duke University. He will expand the Program for Inherited Metabolic Diseases’ clinical focus on mitochondrial disorder.
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Â New Spaces: As in years past, the Division was a beneficiary of the tireless efforts of the Genetic Disease Foundation (GDF). Building upon their generous donation to start up a low-protein food pantry to help families of patients with inborn errors of metabolism, the Food for Life Program, GDF board members partnered with Division faculty and staff to redesign the main waiting room for the Medical Genetics clinical office. This initiative engaged designer Edin Rudin to create a more colorful and engaging environment for the patients who are seen in our clinic, particularly children followed by our clinical programs who require frequent visits. In addition to the funding for the project, GDF Board members Lorie Broser and Sue Preziotti were on hand to help paint and redecorate the office space. Our patients love the new look!
We are integrating cutting-edge DNA sequencing and analysis into our clinical practice.
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Continuing Excellence: Faculty in the Division continue to lead in their fields and to contribute importantly to Medical Genetics. In this past year several programs were recognized with grant funding for their ongoing contributions to rare disease research. Dr. Ethylin Jabs, Director of the Congenital Anomalies and Craniofacial Program, was awarded a program project grant, the Craniosynostosis Network, that will study the biology and genomics of skull malformations. Two NIH-funded Rare Disease Clinical Research Network projects were renewed in this past yearâ€™s funding cycle. Dr. Robert Desnick and Dr. Manisha Balwani continue to lead the RDCRN Porphyrias Consortium and Dr. George Diaz continues to lead the Urea Cycle Disorders Consortium site at Mount Sinai. Other clinical work of note includes publications by Drs. Jabs and Mehta describing a quarter million craniofacial reconstruction surgeries at Mount Sinai over the past decade and work describing a founder RTEL1 mutation responsible for dyskeratosis congenita and which is present in over 1% of the Ashkenazi Jewish population. This work contributed directly to the expansion of the Ashkenazi screening panel offered by the Mount Sinai Genetic Testing Laboratory and is an excellent example of the productive interaction between the clinical and laboratory experts in the Department fostering ongoing innovation in genetic testing.
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k DIAGNOSTIC TESTING
Diagnostic Testing In 2014 the Mount Sinai Genetic Testing Laboratory (MGTL) continued itâ€™s exceptional track record of growth, achieving new milestones in both test volumes and revenue with a 50%+ increase in both measures relative to the prior year. To accommodate growth, additional faculty and staff were hired and the Client Services area, the hub of MGTL, received a facelift to re-organize space and layout. We envision this growth will continue throughout 2015. Some highlights from this past year include: In 2014, MGTL launched the largest Ashkenazi Jewish Carrier Screening panel currently on the market. After careful research and compilation of the findings of over 2,000 Ashkenazi Jewish individuals, MGTL compiled a list of genetic diseases with founder-based mutations in this ethnic group. The Ashkenazi Jewish panel has now grown to 36 diseases, which are now routinely run on almost all individuals of Ashkenazi Jewish ancestry to ensure informed reproductive decision making. This assay truly sets our lab apart from competitors, and as a result we have received patient samples from across the country seeking to access this test. We also rolled out 3 new Sequencing Panels: FGFR3 common mutation testing (with reflex to full gene sequencing) was welcomed by those in the prenatal field as not many options existed for patients with pregnancies that warranted such testing. Our Noonan Syndrome Disease (NSD) Next Generation Sequencing (NGS) Panel was increased from 12 genes to 14 â€“ this makes it the most comprehensive NSD panel on the market. Finally, an NGS Limb Defects Panel was added to our menu to aid in the diagnosis of prenatal and postnatal patients with limb defects of unknown etiology. These panels all provide patients with additional genomic insight into their conditions, and provide more precise input to the clinician when making therapeutic selections. MGTL had a national presence at all 3 major annual education conferences in Genetics in 2014: American College of Medical Genetics in Nashville, TN; National Society of Genetic Counselors in New Orleans, LA; and American Society of Human Genetics in San Diego, CA. Exhibiting at these national conferences gave the laboratory exposure on the National level, and establishes us within the top tier of academic genetic testing laboratories.
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Our ever expanding Genetic Testing Lab team
Our growing team of Laboratory Directors representing our Biochemical, Cytogenetic, and Molecular Divisions
40000 35000 30000 25000 20000 15000 10000 5000 0 2010
Clinical lab Annual Patient Samples, 2010 to 2014
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The Genetic Testing Laboratory underwent a major renovation to enhance workflow efficiency
The state-of-the-art Windreich Center for Bioinformatics represents the hub for our talented data scientists and bioinformaticians.
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The previous pages describe the enormous range of developments across all of the areas of our operations in this past year, whether it be our grant funded research, our diagnostic testing lab, genetics clinic or core infrastructure. Achieving that level of output has necessitated a significant recruitment effort in order to have the leadership and horsepower to drive the growth. In 2014 we grew our team of faculty, postdocs, students, and staff by 21% or a net increase of over 75 FTE’s. See chart below.
We have focused our recruiting in the following key areas: Bioinformaticians - Scientists with deep skill sets in both the biology of disease but also the mathematical/computational skills needed to analyze and interpret the enormous flow of genomic and clinical data Clinical Lab Staff - As our diagnostic testing volume continues to increase significantly , we have added the essential faculty and staff to handle the increased workload while continuing to innovate and develop more complex/advanced tests, and launch our CT lab Project Management – We now have the support of a group of talented project managers, drawn largely from industry, to ensure that across our portfolio we are hitting project deliverables and outcomes In the following pages we profile 3 of our new recruits in 2014, who nicely demonstrate the extraordinary talent that we are recruiting to our Icahn Institute and Department of Genetics and Genomic Sciences.
Alison Goate Working with the Icahn Institute faculty, I expect to use whole genome and exome sequence information together with other systems biology data to identify pathways that are dysregulated in Alzheimer’s disease. Ultimately we could understand a person’s risk for the disease as well as find drugs that could protect individuals from developing it.
Claim to fame: Discovered the very first genetic mutation linked to Alzheimer’s disease, and has continued to shape the neurodegenerative research field ever since. Recruited from: Washington University in St. Louis, January 2015 Alison Goate had her first encounter with Alzheimer’s disease research as a postdoctoral fellow in 1987. In the nearly three decades since, she has delivered some of the most important discoveries in the field, shedding light on disease genetics and possible treatment avenues. “Alzheimer’s disease is an extremely important public health problem,” says Goate, who is now a senior faculty member in the Department of Genetics and Genomic Sciences and director of the Ronald M. Loeb Center for Alzheimer’s Disease at Mount Sinai. “It’s already the sixth leading cause of death, and it’s the only disease in the top 10 killers that doesn’t have any kind of treatment and whose prevalence is increasing.” At least one form of the disease is caused by changes in a single gene, which allowed scientists to study it even with the basic tools available in the 1980s. Goate helped find that first genetic mutation, and in the following years her lab helped identify other genes with a significant role in disease onset or progression. More recently, she has turned to whole genome sequencing to discover additional genetic variants linked to the disease. As Goate has shaped the Alzheimer’s research field over the years, she has also developed a very personal connection to the disease, studying a handful of families for more than 20 years — first with pure research, later with clinical studies. “It’s a really satisfying thing to be able to see your research go from the bench all the way potentially to the bedside,” Goate says. “We are now doing clinical trials for these families that have done so much to help my research over the years.” Goate was attracted to Mount Sinai in part by the opportunity to direct a dedicated research center for Alzheimer’s, where she envisions further elucidating biological mechanisms behind the disease and using that information to identify promising drug targets. The research avenue she finds most exciting today is trying to uncover natural defenses that protect some people from the debilitating disease. “We’re designing our studies now to find those protective factors,” she says. Success in this arena could lead to therapies that would prevent people from ever developing the disease.
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k RECRUITING: PROFILES
Jason Bobe The Icahn Institute is the most dynamic place I could imagine for exploring how sharing can really enhance our ability to do research and translate those findings into improved wellness for people
Claim to fame: A pioneer of interactive, participatory research, Bobe heads up the now-global Personal Genomes Project. Previous post: Harvard Medical School, June 2014 If Jason Bobe gets his way, it could one day be as appealing to participate in a health research study as it is to score premiere tickets to a new exhibit at the Met. As director of the new Sharing Lab at the Icahn Institute for Genomics and Multiscale Biology, Bobe aims to figure out better ways of connecting researchers to patients and to each other. “From the participants’ perspective, the current state of the health research enterprise is deplorable. It’s so transactional: you sign a consent form and give a tube of blood. It’s not surprising that participation rates in research are so low,” Bobe says. The way he sees it, there is virtually limitless opportunity for new approaches that will be far more engaging and personalized for participants. His Sharing Lab aims to prototype various methods to see which ones successfully accelerate research while appealing to patients and consumers. “Sharing is the fundamental lever that will get us from this period of very little participation to one where research participation is a cultural activity that everybody wants to do,” Bobe says. “This is an idea that keeps me up at night and gets me up in the morning.” He is also interested in encouraging scientists to share more with each other, and he’s betting on a few pioneering research projects to help spread his message. The Resilience Project, a unique initiative launched by the Icahn Institute in 2013 to find novel biological mechanisms that prevent disease, is an excellent springboard for Bobe’s work. Scientists who join the project get research access to a unique group of people from around the world — but to be involved, they have to agree to collaborate and share results with the whole team. Bobe is no stranger to game-changing research paradigms: he’s a longtime leader of the Personal Genomes Project, which he grew from a single site at Harvard Medical School to a global network of participating institutions. His move to Mount Sinai came from his desire to parlay that experience into a role with more direct impact on healthcare. “Being able to be part of a translational system has become really important to me,” he says. “The world that Eric Schadt is setting up — with such an emphasis on biomedical big data and this diverse expertise in consumer health apps and devices, mining electronic medical records, biobanking, and genomics research — seemed like an amazing opportunity for launching cutting-edge research projects.” 2014 ANNUAL REPORT / 35
Zeynep H. Gümüş Mount Sinai is a dynamic hub for innovative research in genomics right now, and that was very attractive
Claim to fame: Developed an immersive 3D visualization platform to explore and manipulate complex biological networks from massive datasets. Recruited from: Weill Cornell Medical College, July 2014 It will be many years before babies routinely have their whole genome sequenced at birth, but Zeynep H. Gümüş is already preparing for the data onslaught that will follow. “It’s going to lead to massive amounts of data, but there are still questions about how we’re going to make sense of these data,” she says. Gümüş, an Assistant Professor in the Department of Genetics and Genomic Sciences who joined the institute in July of 2014, has already taken the data interpretation world by storm with a unique tool for the interpretation of large, complex data sets. She developed data visualization software that lets users explore massive biological networks and other information in a fully immersive, 3D experience. Using the tool, known as iCAVE, feels like being inside Star Trek’s holodeck. With the software and a pair of 3D glasses, users can interact with data in ways that 2D images simply don’t allow. Scientists can manipulate and explore complex networks, such as protein-protein interactions, drug responses, and genetic pathways — even layering those networks together to see how they affect each other. It’s more than a party trick: being able to visualize the data differently from, say, an Excel spreadsheet allows users to quickly spot elements in a network that are controlling other elements, or to see what kinds of unique structures they form. It’s a way for scientists to home in on the particular genetic mutation causing a disease without getting sidetracked by all the benign genetic mutations. “You can look at a table of interactions, but that’s not fun or useful,” Gümüş says. “Since the data are massive, they just look like a hairball in 2D. In 3D you can embed yourself inside data while interacting with it in real time, and stitching together multitudes of complex information in a user-friendly way.” Data visualization is just one area of interest for Gümüş, who also develops algorithms to address questions in genomics and deploys them for challenges in both basic research and the clinic. With a background in applied mathematics and chemical engineering, she has an interdisciplinary approach to genomics and enjoys being able to connect with colleagues and seeing her research evolve toward having a real impact on patients. In one project, she is exploring methods for early discovery of people at high risk for lung cancer, the leading cause of cancer death in the United States. Gümüş aims to identify genes that, when mutated, increase the risk of developing lung cancer. Gümüş earned her PhD from Princeton University, and came to the Icahn Institute from a faculty post at Weill Cornell Medical College. “The array of resources at Mount Sinai for genomics— from top-of-the-line computational infrastructure to expert software developers — is truly world class.”
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In the News
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MAJOR MEDIA COVERED OUR KEY PROJECTS: The New York Times, CBS TV News, The Wall Street Journal, NBC TV News, Bloomberg Businessweek, Fox News, Forbes, The Atlantic, Reuters, US News & World Reports, Fortune Strong Industry Press Coverage in Fast Company, Scientific American, MIT Technology Review, GenomeWeb, GEN, Bio-IT World, Techonomy, Wired, New Scientist, Business Insider
Recognizing Our Partners We are enormously thankful to the many donations, both large and small received during 2014 which provide the necessary fuel to drive the amazing research and care described in the previous pages
k FOR MORE INFORMATION:
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Icahn School of Medicine at Mount Sinai One Gustave L. Levy Place, Box 1107 New York, NY 10029-6574
Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences