Genomics annual report fnl by Mount Sinai Health System

2013

ICAHN INSTITUTE FOR GENOMICS AND MULTISCALE BIOLOGY DEPARTMENT OF GENETICS AND GENOMIC SCIENCES ANNUAL REPORT

The world is taking notice. Already our genetics and genomics department has jumped from 29th to 15th in independent rankings of genetics departments nationwide. We were also ranked by Fast Company in its list of the top 10 most innovative organizations in big data. ERIC E. SCHADT, PHD

Letter from the Chair

Basic Research Grants Spotlight on Alzheimerâ&#x20AC;&#x2122;s Disease Spotlight on the Microbiome K Awards

11 Cutting Edge Capabilities: Leveraging Big Data to Reveal Biological Insights & Identify Therapeutic Targets 15 Translational Research Inflammatory Bowel Disease Rare Metabolic Disorders Cancer 21 Patient Care Clinical Services 25 Diagnostic Testing 29 Recruiting Profiles 35 Education Highlights 39 In the News 43 Recognizing Our Partners

Letter from the Chair In 2013, our team in the Department of Genetics and Genomic Sciences continued its leadership role in the biomedical community, while the newly launched Icahn Institute for Genomics and Multiscale Biology began to hit its stride. Together, the Mount Sinai genomics group made significant advances in basic and translational research, clinical and diagnostic services, and educational achievements. The Icahn Institute—named in late fall 2012 thanks to the generosity and vision of Carl Icahn—was launched to build upon the well-known strengths of the Department of Genetics in translational research and clinical care. It was created around the idea that advancing the era of precision medicine will require completely new approaches: leading-edge technologies, novel partnerships between the public and private sector, alternative funding sources, and preeminent computational and analytical resources. We started by recruiting stellar people—more than 150 so far—from medical centers, academic institutions, and even Silicon Valley start-ups and major corporations. Our hires include rising stars, technology gurus, and seasoned talent, 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. This team complements the extraordinary talent in our established Department of Genetics of more than 200 people. Our faculty and staff accomplished great things in 2013, including elucidating genetic mutations or biological mechanisms related to cancer, schizophrenia, Alzheimer’s, congenital heart disease, autism, and multiple sclerosis, to name just a few. Our clinical team expanded its genetic screening offering and incorporated whole exome testing to help patients end their diagnostic odysseys. We partnered with biopharmaceutical companies Janssen (part of J&J) and Berg. We licensed targets to Plexcera, a company incubated in our own labs here at Mount Sinai. We also ran first-of-their-kind classes allowing medical students to sequence and analyze their own genomes, a key step toward shaping a new generation of physicians who embrace this nascent era of genomic information. The world is taking notice. Already our genetics and genomics department has jumped from 29th to 15th in independent rankings of genetics departments nationwide. We were also ranked by Fast Company in its list of the top 10 most innovative organizations in big data. Despite a sluggish grant funding environment, our genetics researchers have been quite successful in winning federal grants to support their groundbreaking efforts. This year, we will continue our quest to improve personalized cancer treatment and will expand our capabilities for large-scale genome sequencing in order to make major strides in advancing precision medicine and tailored treatment for each individual. In the pages that follow, I am pleased to share a sampling of our many promising programs (unfortunately not possible in one update to share all promising programs!), such as our efforts in Alzheimer’s disease, the human microbiome, and inflammatory bowel disease. You will also meet some of the people who make the genetics group at Mount Sinai such a remarkable team. Together, these stories illustrate the incredible potential we hold to change patient care for the better. I want to salute the vision and support of Mount Sinai’s volunteer and academic leadership, in particular Dr. Kenneth L. Davis and Dr. Dennis S. Charney, who consistently galvanize Mount Sinai’s research community to pursue innovation. Their efforts—inluding their encouragement of our generous philanthropists— have created the perfect environment for the unprecedented work we do. 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

k BASIC RESEARCH

Basic research to advance our understanding of the genetic underpinnings of human health and disease remains at the core of much of our work. Federal grant funding for such studies represents a crucial source of support for our researchers and, given the competitive nature of such funding, it also serves as a barometer of our relative standing within the academic community. 2013 was a particularly difficult year for researchers pursuing federal funding as the combination of the sequester and the government shutdown led to a ~5.5% decline in NIH budgets, which in turn drove a further reduction in the ratio of successful applications, which have now halved over the past decade. Given the context of this difficult funding environment, our grant awards in 2013 are even more impressive. We received total awards from federal sources of more than $22 million, a record for annual awards made to genetics at Mount Sinai. This success was reflected in our ranking relative to other academic genetics departments, where we leapfrogged nearly 15 spots in the national rankings, moving from the 29th to the 15th ranked genetics department nationwide. This increase demonstrates the strength of both our established and recently hired faculty, and the collaborations that are starting to emerge within our genetics researchers and across the wider Mount Sinai community. Going forward we anticipate another tough funding environment in 2014, but we remain confident of breaking into the top 10 ranked schools in the near term.

NATIONAL RANKINGS / FROM THE BLUE RIDGE INSTITUTE FOR MEDICAL RESEARCH 1 BAYLOR COLLEGE OF MEDICINE WASHINGTON UNIVERSITY

2 3 3

UNIVERSITY OF WASHINGTON STANFORD UNIVERSITY UNIVERSITY OF NORTH CAROLINA CHAPEL HILL DUKE UNIVERSITY

5 4 4 5 6 7

UNIVERSITY OF CHICAGO HARVARD UNIVERSITY (MEDICAL SCHOOL) UNIVERSITY OF PITTSBURGH AT PITTSBURGH YALE UNIVERSITY

8 9 10 27

OREGON HEALTH AND SCIENCE UNIVERSITY

UNIVERSITY OF CONNECTICUT SCH OF MED/DNT ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI

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Grants TITLE

PRINCIPAL INVESTIGATOR

The Genetics and Genomics of Allergic Rhinitis

Supinda Bunyavanich

Role of Glucocerebrosidase in Parkinson’s*

Manisha Balwani

Novel Strategy to Induce Islet Protective T Cells

Brian Brown

Genome-wide analyses of parent human disease

Andrew Sharp

Methods for Evolutionary Informed Network Analysis

Joel Dudley

Novel Oral Therapy for MPS (Mucopolysaccharidoses, a Lysosomal Storage Disorder)

Calogera Simonaro

Post-transcriptional regulation of the Dendritic Cell transcriptome

Brian Brown

Clinical and Molecular Studies of the Erythropoietic Protoporphyria.

Manisha Balwani

Identification of Genetic and Brain Molecular in Mouse

Andrew Karsarskis

Interdisciplinary Training in Systems and Developmental Biology

Ethylin Jabs

Pharmacogenomic Control of Clopidogrel Response in Acute Coronary Disease

Stuart Scott

Rapid and inexpensive epi/genetic profiling of human mitochondrial genome

Ravi Sachidanandam

Interplay of Gut Microbiome and Host Genes in Crohn’s Disease

Jianzhong Hu

Integrative Biology Approach to complexity of Alzheimer’s Disease

Eric Schadt

Sensor-seq: A genome-wide biological measure of microRNA activity

Brian Brown

Omics-Based predictive Modeling of Age Dependent to Influenza Infection*

Eric Schadt

TOTAL VALUE: $22.8 MILLION

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Three members of our AD “Dream Team” Drs. Jun Zhu, Sam Gandy (Mount Sinai Professor in Alzheimer’s Research), and Bin Zhang

This year, our team published research in the prestigious journal Cell demonstrating for the first time that a network of genes known to play a role in the brain’s inflammatory response is also a key mechanism in the development of late-onset Alzheimer’s disease. Whereas inflammation was once believed to be a result of Alzheimer’s disease damaging the brain, it is now shown as a contributing cause and not a consequence.

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Spotlight on Alzheimer’s Disease With 5 million Americans suffering from Alzheimer’s today and the number projected to rise dramatically as baby boomers age, insight into the disease is becoming more and more critical for the overall health of our population. This year, our team published research in the prestigious journal Cell demonstrating for the first time that a network of genes known to play a role in the brain’s inflammatory response is also a key mechanism in the development of late-onset Alzheimer’s disease. Whereas inflammation was once believed to be a result of Alzheimer’s disease damaging the brain, it is now shown as a contributing cause and not a consequence. Subsequently, the NIH awarded our team a multimillion-dollar grant to advance this research through the analysis of large-scale molecular, cellular, and clinical data from Alzheimer’s patients to identify therapeutic targets. This research is of paramount importance. Currently, no effective disease-modifying or preventive drugs exist for late-onset Alzheimer’s disease. Our novel approach is already providing clues to unanticipated pathways and new drug discovery opportunities. With this award, our team becomes one of the four US Alzheimer’s systems biology programs selected to constitute the new “Accelerated Medicines Partnership (AMP).” AMP was developed by a working group composed of NIH Director Francis Collins and the CEOs of the top pharmaceutical companies working in Alzheimer’s disease. AMP represents a new template for inter-institutional collaborative management of “big data,” wherein key molecular pathways underlying common forms of Alzheimer’s are identified and used to create predictive models for discovering Alzheimer’s new drugs. Our Alzheimer’s research program is an excellent example of cross-departmental collaboration at Mount Sinai, where our Icahn Institute faculty work closely with leading physician-scientists in our Neurology and Psychiatry departments to form a multidisciplinary team best able to tackle the most complex problems.

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Spotlight on the Microbiome The microbes that live in and on our bodies (our microbiota) influence our health in myriad ways, both beneficial and deleterious. This influence is particularly acute in our intestine, where microbes are so abundant they create one of the densest ecosystems on the planet. Each of our intestines harbors a few hundred species of bacteria, and typically these species remain stably colonized in our intestines for much of our adult lives. It is fundamentally important to ascertain which of these microbes are beneficial and which are harmful in the context of each personâ&#x20AC;&#x2122;s unique genome and lifestyle.

Dr. Jose Clemente & Carmen Haro Mariscal on the front lines of cutting edge research

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Analysis of individual’s microbiota compared to typical in USA and global

Ruminococcaceae 22.3%

“This shows that strains in our gut, and how they change over time, could act as a biomarker that helps us track our health status.”

Lachnospiraceae 13.0%

Prevotella 17.2%

Bacteroides 25.5%

Billy

Dr. Jeremiah Faith

At the Icahn Institute, we are developing the next generation of software tools, experimental technologies, and animal models to determine where and when changes in the microbiota are correlated with disease, to verify in animal models if those changes play a causative role in disease, and to identify which microbes are responsible. This work will set the stage for a new type of medicine that encompasses both our human genomes and the genomes of our microbes to understand how they combine to influence our health. Just as chemotherapy is more effective when targeted to a patient’s unique cancer, future treatments for many diseases will take into account our personal microbiome so that the right microbes (i.e., nextgeneration probiotics) can be added or removed from microbial communities to improve health. Our microbiome research is led by Drs. Jose Clemente, Jeremiah Faith, and their lab teams. Among the numerous diseases where the microbiome is thought to play an important role, our scientists are particularly interested in the role of our gut microbes in Inflammatory Bowel Disease, allergies, and cancer. The importance of the microbiome was seen in research led by Dr. Jeremiah Faith, and published in Science this year which revealed that most of the microbes in our guts appear to remain stable for most of our lives, for decades or more, directly contributing to our state of health. This finding could have a major impact on healthcare, by showing the value of monitoring an individual’s microbiome as part of their routine annual medical check-ups. In an interview with The Scientist, Dr. Faith said, “This shows that strains in our gut, and how they change over time, could act as a biomarker that helps us track our health status.”

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k BASIC RESEARCH Drs. Scott, Desnick, and Balwani

K Awards Given the challenging funding environment, one of the most pleasing elements of our 2013 grant awards was the success of many of our junior faculty members in receiving career awards (K awards) to establish them on a path toward research independence. These grants speak to both the exceptional ability of our junior faculty and the highquality mentoring they receive. Drs. Manisha Balwani and Stuart Scott, both mentored by Dr. Robert Desnick, received K awards to advance their work in erythropoietic protoporphyria and in the pharmacogenomics of antiplatelet compounds, respectively. These projects seek to translate research insights into improved patient care here at Mount Sinai. In addition, Dr. Jianzhong Hu received a K award to study the gut microbiome, in order to gain a better understanding of microbiome-host gene interaction associated with disease pathogenesis. The grant builds upon the extensive research of his mentor, Dr. Inga Peter, providing a strong multidisciplinary foundation for Dr. Huâ&#x20AC;&#x2122;s career in translational research. â&#x2013;

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Cutting Edge Capabilities

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Leveraging Big Data to Reveal Biological Insights & Identify Therapeutic Targets A key goal in both 2012 and 2013 was building and recruiting the key assets and people to fully unlock the potential of Big Data to drive both research discoveries and improvements to clinical care. Relative to our goal we enjoyed tremendous success in 2013, upgrading our physical assets, recruiting premier talent and beginning to gain external recognition of our enormous bet on the power of Big Data. Computational Infrastructure: We apply our scalable supercomputer resources for advanced quantitative analysis of massive and varied datasets to create predictive models of disease, and our two newest computing systems, Minerva and Demeter, rank among the largest in academic medicine in the U.S. and are capable of more than 100 million hours of computation per year. Our Minerva high-performance computing system provides a robust computational and data-intensive infrastructure geared specifically for genomics. Minerva has already analyzed thousands of human genome sequences, and we plan to handle hundreds of thousands of genomes in the near future. Minerva was recently expanded with new state-of-the-art Intel processors to over 400 servers, comprising over 12,000 cores, over 50TB of RAM, and 7.3 PB of raw storage capacity. Demeter is the core of our new Data Science Ecosystemâ&#x20AC;&#x201D;a Hadoop cluster we are building that will soon consist of 200 servers, 4,800 logical cores, 25 TB of RAM, and 8 PB of hard drive storage set up for integrated mining across all data assets at Mount Sinai. Demeter runs the same software that is used by companies such as Facebook and Walmart to improve business outcomes through the analysis of petabytes of data. Here at Mount Sinai, the system will be used to improve health outcomes.

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Dr. Rong Chen

Patricia Kovatch

Jeffrey Hammerbacher

Leading Big Data Talent: The leaders of our Big Data platform include Jeffrey Hammerbacher, Assistant Professor of Genomics and Genetics Sciences and former leader of the data team at Facebook, and Patricia Kovatch, Associate Dean for Scientific Computing, whose accomplishments include deploying the world’s third fastest machine while at Oak Ridge National Laboratory. In 2013 we were fortunate to recruit Dr. Rong Chen as our Director of Clinical Genome Informatics, who will lead the Icahn Institute team in interpreting the thousands of terabytes of genomic data. Dr. Chen is a world renowned expert in genome interpretation and translational bioinformatics, and has developed many databases, software tools, and patents being utilized to drive precision medicine and clinical diagnosis using genome and exome sequencing. Prior to joining Mount Sinai, Dr. Chen worked at Quest Diagnostics, Stanford University, and most recently, the startup company Personalis, which was founded to interpret personal genome and exome sequences for clinical diagnosis. ■

External recognition: Our combination of computing infrastructure and talent is truly unique within the Healthcare industry, and this was recognized by Fast Company who named the Icahn School of Medicine at Mount Sinai as one of the “World’s Top Ten Most Innovative Companies in Big Data” in its annual ranking of leading organizations in critical areas. The Icahn School of Medicine was ranked No. 5 on this Big Data sector list along with global corporations GE (No. 1) and IBM (No. 4) and start-up companies such as Kaggle (No. 2) and Ayasdi (No. 3). Notably Mount Sinai was the only health care provider to be included in the rankings.

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Translational Research

Drs. Cho, Sands, and Atreja (seated) and the IBD research team

These studies help us understand what causes IBD and how it works at the cellular level. This gives us real promise for further breakthroughs in treatment. DR. BRUCE SANDS Chief of the Division of Gastroenterology at The Mount Sinai Hospital Dr. Burrill B. Crohn Professor of Medicine

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More than a million Americans live with Inflammatory Bowel Disease (IBD), including Crohn’s disease and ulcerative colitis. Those with the disease find their immune systems attacking their digestive systems after being triggered by their bodies’ normal bacteria, and suffer from symptoms ranging from abdominal discomfort and diarrhea to skin lesions and even arthritis. In June of 2013, Janssen Biotech and the Icahn School of Medicine at Mount Sinai announced a first-ofits-kind IBD research alliance with the goal of providing the world’s best understanding of the molecular mechanisms underlying ulcerative colitis and Crohn’s disease. We are building a molecular interaction network of disease for IBD with the breadth and depth to yield high-confidence therapeutic targets to be tested. Using preclinical models, clinical study data, and patient samples, a dedicated group of Janssen and Mount Sinai researchers, computational biologists, and translational medicine scientists will develop clinical methodologies to identify potential therapeutic candidates and also progress them through drug development and trials. This work is a coordinated effort of the Icahn Institute, the Immunology Institute, and the Division of Gastroenterology at Mount Sinai. It is a prototype for the wide-ranging translational research we will do in the future that spans fundamental human disease biology and response to existing therapies in the clinic, animal models of disease, and robust modeling and data mining from the Icahn Institute to tie it all together. Industry partnerships such as this one are vital to our pursuit of next-generation therapeutic solutions.

A biological network model revealing key mechanisms in IBD

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Inflammatory Bowel Disease

It’s always been about taking results from the lab and translating that into better treatments for patients. That’s why I came to a medical center. DR. ED SCHUCHMAN

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Dr. Ed Schuchman, Professor and Vice Chair in the Department of Genetics, and Genetic Disease Foundation-Francis Crick Professor of Genetics and Genomic Sciences, has dedicated his career to translational research of rare metabolic disorders. This past summer, he led the creation of a new company named Plexcera Therapeutics LLC with Ivan Galanin, a pharmaceutical industry veteran and Mount Sinai Innovation Partners advisor. Their goal is to accelerate the development of discoveries made in Dr. Schuchman’s lab and advance them into clinical care.

In collaboration with QOL Medical LLC, a pharmaceutical company focused on rare pediatric diseases, Plexcera will undertake the large-scale clinical manufacturing of recombinant human acid ceramidase (rhAC). Acid ceramidase is an enyzme which breaks down ceramide, an essential lipid or fat, but which in excess causes cell death, and has been linked with hereditary disorders including Farber Disease, Spinal Muscular Atrophy and Cystic Fibrosis. An enzyme replacement therapy (of acid ceramidase) has proven effective in the lab against Farber Disease, which led to the founding of Plexcera to aggressively pursue the clinical development of this compound. While the company was only founded in 2013, it has managed to be highly productive in its first year, successfully negotiating a licensing deal with Mount Sinai, a development deal with QOL, and initiating the rhAC clinical manufacturing efforts. Most recently, orphan drug designation was obtained in the United States and EU for rhAC therapy for Farber Disease. Going forward, the company is seeking to identify patients and sites for an initial clinical trial, with the goal of initiating this trial within 18 months. They also are seeking partnerships with the NIH (through the Treat Rare and Neglected Disease Program; TRND) and Cystic Fibrosis Foundation to pursue their goals. In addition to work on Farber Disease, Plexcera also is in the process of licensing the rights from Mount Sinai to develop another drug developed in Dr. Schuchman’s laboratory with Dr. Calogera Simonaro, Associate Professor of Genetics & Genomic Sciences. This drug, Pentosan Polysulfate (PPS), is being “re-purposed” for a group of genetic disorders called the Mucopolysaccharidoses (MPS). QOL Medical will make an additional investment in Plexcera to develop this drug, and an initial clinical trial will begin in Spring 2014 in patients with one MPS subtype. Dr Schuchman’s research program also has led to a number of additional, exciting translational opportunities. Of note, his work on Farber disease was a serendipitous discovery made during investigative work on another lysosomal storage disease, Niemann-Pick Type B. His preclinical development of enzyme replacement therapy for this disorder led to a licensing agreement between Mount Sinai and Genzyme/Sanofi, and Phase 1 clinical studies have been successfully completed. In 2014, phase 2 clinical trails will begin.

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Rare Metabolic Disorders

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Cancer In cancer, our team is creating predictive, personalized diagnostic models that are able to uncover what is happening in a patient’s tumor, pinpoint which key driver genes are signaling pathways to grow the tumor, and then use that information to better match a patient’s condition to an appropriate treatment or to evolve a de novo treatment altogether for the patient (e.g., novel vaccine design to engage the patient’s immune system against the tumor, construct the patient’s tumor in a model system such as fly and perform high-throughput screening against all available drugs and drug combinations). Supercomputer resources for Big Data analysis are employed to build the complex predictive models for the personalized cancer therapy program. Our focus at present is on recurrent late-stage cancers, including head and neck, pancreatic, breast, ovarian, and multiple myeloma, but ultimately we see this being applied more routinely as a part of the standard of care for all cancer patients. Our personalized cancer therapy program has been featured on CBS News and in Esquire magazine. We are in the early days of our personalized cancer therapy program, with relatively small patient populations tested and the first few patients beginning to take drug cocktails identified by our analysis as potentially effective against their individual cancer. In 2014 and beyond, we will further refine our approach in the belief that these personalized models will be the future of cancer care at both Mount Sinai and beyond. ■

Personalized multiscale tumor networks to diagnose and treat cancers Tumor biopsy + normal

Genomics Core Facility (Illumina, PacBio, Ion)

RNA + DNA

= key driver

Patient network targeted therapy

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Patient-specific subnetwork Predictive network model of cancer

Patient Care

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Dr. Melissa Wasserstein, Director of the Program for Inherited Metabolic Diseases

Clinical Services While we strive to excel in our basic and translational research, the ultimate goal of everything we do is to have a positive and direct impact on patient care. Central to that is our clinical operation, which is one avenue through which we work directly with Mount Sinai patients today. The following developments in 2013 illustrate how our clinical programs continue to make a difference in patient treatment, screening, and care. Pilot Newborn Screen: Supported by an NIH grant, Dr. Wasserstein and team are leading a multi-hospital Pilot Newborn Screening for Lysosomal Storage Disorders program that will help us to identify and diagnose patients with severe inherited disease as early as possible. During the next four years, all babies born at Mount Sinai, Maimonides, New York University, and Elmhurst Hospitals will have the opportunity to be screened for Fabry, Gaucher, Niemann-Pick types A/B, and Pompe Diseases as part of their routine New York State newborn screening. Babies who are confirmed to be positive for one of these rare diseases will have the option to join a longitudinal follow-up study, which includes additional efforts to investigate the ethical, legal, and social issues related to screening newborns for later-onset phenotypes.Â This study complements our existing metabolic clinic, which is one of the countryâ&#x20AC;&#x2122;s largest referral centers for newborns with abnormal screening tests. 2013 ANNUAL REPORT / 23

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Metabolic Clinic: Our Metabolic Genetics Faculty Practice sees thousands of patients each year, providing advanced clinical and diagnostic services for children and adults with inborn errors of metabolism such as phenylketonuria, urea cycle defects, and glycogen storage disorders. This year, with the support of the hospital, we significantly added to the team of nutritionists in our program. In an effort led by Angela Kurtz, MS, we now provide a number of nutritional services to the program, including classes to teach patients about low-protein, modified foods that are an important part of health management for people with these diseases. We have also been fortunate to receive generous funding from the Genetic Disease Foundation to open a food pantry that makes these specialized but expensive foods freely available to patients in low-income families.

In 2013, we began to integrate this cutting-edge DNA sequencing approach into our clinical practice.

Whole Exome Sequencing: In 2013, we began to integrate this cutting-edge DNA sequencing approach into our clinical practice. We sequence all of the coding genes in a personâ&#x20AC;&#x2122;s genome, which often allows us to provide the first clear diagnosis for patients who have spent many years and tremendous expense on a diagnostic odyssey seeking a clinical explanation for their illness. Exome sequencing offers exciting potential for revealing medically relevant information and helping us better guide decision-making around therapeutic options for each patient. While we are currently running this test in relatively low volumes and for the neediest patients, we are encouraged by our high detection rate during this pilot phase. Implementing it now reflects the exceptional team work of our clinical geneticists, genetic counselors, lab directors, sequencing core technicians, and bioinformaticians; it further demonstrates our commitment to incorporate the latest genomic technologies in a rapid but responsible manner as they become useful for patient care. Clinical Trials: Our faculty is actively engaged in finding safe and effective treatments for patients with rare genetic diseases by working with industry sponsored clinical trials. Current clinical trials in the Department include evaluating novel treatments for type B Niemann Pick disease, phenylketonuria, porphyria, Gaucher disease, and lysosomal acid lipase deficiency. â&#x2013;

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Diagnostic Testing

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k DIAGNOSTIC TESTING

Diagnostic Testing The Mount Sinai Genetic Testing Laboratory has a considerable impact, providing high-quality genetic information to more than 22,000 patients in 2013. That represents growth of more than 150 percent over the past four years and is driven by both our investment in customer service and most recently the merger with the Continuum Health Partners, through which we are now the primary genetic testing lab for seven hospitals and 3,000,000 patient visits each year. In 2013, we again significantly strengthened our team, adding additional lab directors, account managers and lab-based genetic counselors. This expansion in capabilities ensures that we will continue to provide referring physicians with a commercial grade of customer service, and patients with a very high quality of genetic testing made possible through the expertise offered by the Laboratory Directors and Faculty in the Clinical Genetics Division.

25K 150%+ 22K+ 20K

15K

10K

2010

2011

2012

2013

A particular strength of our Genetic Testing Lab is the long standing commitment to excellence offered through our carrier screening program which involves testing adults that are of reproductive age to determine if they are carriers of recessive disorders which could be passed on to their future children. In 2013, we further strengthened our reputation in this space with the discovery and internal development of our enhanced test for spinal muscular atrophy, one of the most common and severe recessive disorders, with as many as 1 in 35 individuals carrying the mutated gene. This work, led by Dr. Lisa Edelmann and Dr. Bob Desnick and published in Genetics in Medicine, identified new variants in the causative gene, which allows for an improved test compared to existing tests that detects silent carriers of this severe disorder. This Mount Sinai-developed technology has since been licensed to multiple commercial labs in the US and internationally, who are rapidly deploying the technology to improve the accuracy of their testing.

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Our ever expanding Genetic Testing Lab team

Our commitment to keeping our Genetic Testing Lab at the leading edge of a rapidly evolving field means that we continually expand its capabilities and technology platforms. Our lab physically expanded this year in order to meet our increased demand, and our genome sequencing core has added the newest microarray and sequencing platforms over the past year. We are still in the early years of genome sequencing technologies being applied to clinical diagnostics, but with our Autism and Noonan Syndrome Next Generation Sequencing panels, as well as our whole exome tests experiencing rising demand, it is clear that this trend will further accelerate in 2014 and beyond. In 2013, we initiated a collaboration with the Mount Sinai pathology department to bring genomic information to cancer physicians and patients. Working together, we have developed gene-panel tests that can rapidly provide patient-specific genomic information to inform therapy selection decisions. The collaboration has been driven by Dr. Daniela Starcevic, Dr. Nina Longtine, and Dr. Robert Sebra, and represents a model we will seek to replicate to accelerate the application of new technologies. The initial test for colon cancer will launch in early 2014, to be followed by clinical tests for lung cancer and melanoma patients. â&#x2013;

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Recruiting

The state-of-the-art Windreich Center for Bioinformatics, established at the start of 2013, represents the hub for our newly recruited data scientists and bioinformaticians.

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Recruiting We have made tremendous progress in the past year in attracting world-class talent as a critical step towards accomplishing our ambitious goal to dramatically improve the treatment and prevention of diseases. In 2013, we grew our team of faculty, postdocs, students, and staff by 38% or a net increase of nearly 100 FTE’s. See chart below.

FACULTY POSTDOCS STAFF TOTAL

87 +12%

65 +48%

125

188 +50%

247

340 +38%

We have focused our recruiting in the following key areas: ® Data Scientists—to help us obtain, organize, and analyze staggering amounts of data. ® Disease-Focused Genomicists—Specialists in major disease areas from Cardiovascular to Gastroenterology to Neurology. ® Bioinformaticians—Experts who can interpret information from the genome and other biological sources, an essential step in making this information actionable for the clinic ® Clinical Lab Staff—As our patient volume ramps up dramatically, we have added the essential staff to handle the increased workload The state-of-the-art Windreich Center for Bioinformatics, established at the start of 2013, represents the hub for our newly recruited data scientists and bioinformaticians. On the next pages, we profile three of our new 2013 recruits; they exemplify the extraordinary talent that we are recruiting to our Icahn Institute and Department of Genetics and Genomic Sciences.

Judy Cho What I love about Mount Sinai is that there’s a real sense of innovation, that the sky’s the limit.

For Dr. Judy Cho, Ward-Coleman Professor in Translational Genomics, coming to Mount Sinai was all about the numbers. On the most basic level, her move from Yale University to the Genetics and Genomics Department gave her access to more patients and more clinical trials. On a more conceptual level, the Mount Sinai team offered a computational, statistical, and data mining core that is performing some of the most advanced analytical approaches in the world—an asset critical to continued innovation in healthcare. Now Vice Chair for Translational Genetics in the Mount Sinai Department of Genetics and Genomics, Judy is one of the leading experts in Inflammatory Bowel Disease, a syndrome with two common subtypes: Crohn’s disease and ulcerative colitis. Together, these diseases affect some 1.4 million Americans. Judy has been involved in some of the best gastroenterology programs in the US, but “Mount Sinai is the Mecca of IBD,” she says. After all, Crohn’s was first described by Mount Sinai doctors in 1932; since then, the hospital has seen more IBD patients and more distinguished physicians and faculty members than anywhere else. Judy adds to that list of distinguished faculty; she was part of the team that first identified NOD2 as a gene linked to IBD in 2001. At the time, the concept of finding a single gene related to a disease as complex as IBD was far from assured. “The idea of identifying genes linked to IBD lit my imagination—it was the perfect research direction for me as a physician-scientist,” she recalls. “But it was an enormous deductive leap from what had been accomplished at the time, namely, finding single genes linked to simple Mendelian diseases.” Since then, she has helped identify 163 genes associated with IBD. With a much clearer understanding of the genetics behind IBD, Judy believes the next step toward improved patient care will involve tapping Mount Sinai’s considerable arsenal of computational talent. “A big reason I came here was that they have the best statistical modelers. What I love about Mount Sinai is that there’s a real sense of innovation, that the sky’s the limit,” she says. “The medical leadership is truly visionary and wants to use modern data technologies to improve care at all levels.” This combination of exquisite data analysis together with a rich heritage of genetic information and patient data makes for IBD advances that are “uniquely possible at Mount Sinai,” Judy says.

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k RECRUITING: PROFILES

Jonathan Karr Mount Sinai has made a major institutional commitment to personalize medicine through data-driven computational models.

One of the newest members of the Icahn Institute is Jonathan Karr, a rising star in systems biology who joined Mount Sinai from Stanford University. His experience in modeling biological systems was a natural fit for the genomics group, which has industry-leading expertise in mining big data for translational research. Jonathan’s goal is to build predictive models that can accurately tell clinicians how each individual person would progress with an illness, respond to therapeutic treatments, and more. Today he is working toward that ambitious goal with smaller steps: developing highly accurate tools for predicting the phenotypes of simple single-celled bacteria. Jonathan hones the predictive abilities of his models by comparing their predictions to real-life bacteria. Ultimately, Jonathan envisions deploying this kind of tool in a clinical setting to model disease and drug response in a patient-specific way. “This will let us capture all of the genetic differences among patients that we know exist, but largely ignore,” he says, citing tumor variability as one well-established example. “We should be able to build models for each patient and use that to guide prognosis and treatment.” Jonathan chose to join Mount Sinai because its focus resonated with his own interests in applying math and computation to medicine. “Mount Sinai has made a major institutional commitment to personalize medicine through data-driven computational models,” he says. “We have world-class researchers who are going to lead medicine into a new personalized, predictive era.”

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Ariella Cohain Everyone here is brilliant. Everyone here is a genius.

A career in genomics wasn’t on Ariella Cohain’s radar until she attended a talk by Icahn Institute Director Eric Schadt just after completing here biomedical engineering undergraduate degree at Johns Hopkins. “It blew my mind,” she says. “Things just clicked, and I realized this is where it’s going.” After that, she headed to Mount Sinai to work in Eric’s institute as a data analyst. During the next two years, she worked on several different projects, all with the same approach: integrating many different types of data and mining them for advanced insights. Projects included studying gene expression in dendritic cells for immunology information, a translational research program for irritable bowel disease, and epigenetic analysis using single molecule DNA sequencing. This foundation convinced Ariella that she had found her career path, and she decided to apply to PhD programs. She applied to several schools, eventually choosing Mount Sinai over Harvard and Cornell. “Other PhD programs seemed competitive, but here the environment is collaborative and supportive in addition to having cutting-edge research,” says Ariella, now enrolled in her first year of PhD studies with the Genetics and Genomics Department. “I knew who I’d be working with and how great the projects were, so I decided to stay.” Ariella is currently progressing through three rotations that will help her choose the focus of her PhD studies. Network analysis and mining electronic medical records have both interested her, but she’s open to what the future holds—and to what she’s learning from her professors. “It’s incredible to be learning about something in biology directly from the people who discovered it in the lab,” she says. ■

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Education

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k EDUCATION

Education The way we make the most of every research and clinical advance is by passing it on to students who will build on it in their own budding careers. From starting the countryâ&#x20AC;&#x2122;s first medical genetics residency program, Mount Sinai has had a remarkable track record in its education initiatives. As genomic information becomes increasingly important to clinical practice, we consistently challenge ourselves to ensure that our educational programs are as creative and strong as they can be.

The Genetics and Genomics Department has contributed significantly to courses offered through the medical school. Faculty members including Andrew Kasarskis, Michael Linderman, George Diaz, Ali Bashir, and Randi Zinberg organized and taught the first class in which Mount Sinai medical students were able to fully sequence, analyze, and interpret their own genomes. For 20 students chosen through a highly selective admission process, that meant taking a summer prep session followed by the course, which demonstrated an encouraging improvement in participantsâ&#x20AC;&#x2122; knowledge of whole genome analysis. In a separate course, Dr. Diaz and Stuart Scott gave students firsthand insight into pharmacogenomics. Together, these classes are providing future generations of physicians with valuable exposure to genomic information now available in the clinic.

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k EDUCATION

In 2013, Dr. Ethylin Jabs launched our new NIH-sponsored predoctoral training program, through which 28 faculty members from 12 different departments, institutes, and centers work with and mentor students about systems biology, developmental biology, and birth defects. The goal is to address important research questions related to networks and processes of complex interactions underlying healthy and diseased states of cells, tissues, and organisms. Students participating in the program receive didactic and research training in quantitative reasoning, computational biology, bioinformatics, as well as developmental biology, birth defects, genomics, molecular biology, biochemistry, physiology, and pharmacology. Our Masters in Genetic Counseling program saw a notable enrollment increase last year. The program, led by Randi Zinberg, has been a staple of the department for 20 years and has adapted to the rapidly changing landscape of medicine. Coursework continues to emphasize a balance between the science and psychosocial aspects of patient care, and the recent addition of genomics courses has given students insight into genetic counseling in a variety of settings, including industry and biotech. Going forward, expansion goals include adding a PhD track to accommodate the growing opportunities for genetic counselors in traditional and nontraditional settings. Our postdoctoral clinical training programs continue to attract exceptional candidates who go on to great success. In 2013, our medical fellows and residents, and laboratory fellows achieved a 100 percent pass rate in their respective board exams, highlighting both their talent and application, and the quality of teaching and mentorship received. We expect to see even more great accomplishments in the years to come. â&#x2013;

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In the News

Marketing Highlights: August 2013

Pamela Sklar and Shaun Purcell and an internation published paper in Nature Genetics identifying 13 n schizophrenia. Pamela and Shaun played a critica in Sweden, data generation and analyses.

Genome-wide association analysis identifies 13 new schizophrenia. Nat Genet 2013 Aug 25. doi: 10.1038

http://www.genengnews.com/gen-news-highlights/investigators-fill-in-missing-pi

http://news.unchealthcare.org/news/2013/august/study-provides-strongest-clues-to-dat

Marketing Highlights: September 2013 Media Coverage re: our NIH Grant for Alzheimer’s Disease research

Drug Discovery and Development – September 18 NIH Awards $45 M for Alzheimer’s Prevention, Novel Drug Targets Researchers will test promising drugs aimed at preventing Alzheimer’s disease and identify and validate biological targets for novel therapies, with approximately $45 million in new funding from the National Institutes of Health (NIH). Studies focused on the identification and validation of novel therapeutic targets for Alzheimer’s disease include the Integrative Biology Approach to Complexity of Alzheimer’s Disease — Eric Schadt, PhD, Director the Icahn Institute of Multiscale Biology, Chair of Genetics and Genomic Sciences, and Jean C. and James W. Crystal Professor of Genomics at the Icahn School of Medicine at Mount Sinai, and a team of investigators, who are being funded $1.6 million in fiscal 2013, with the potential of $8.2 million over five years.

Bio-IT World – September 18 NIH Distributes $45 Million for Alzheimer's Research At Mount Sinai, the NIH grant will enable the research team and partner institutions to build upon the discovery published earlier this year in the journal Cell of a network of genes as a key mechanism driving Late Onset Alzheimer’s Disease (LOAD) through involvement in the inflammatory response in the brain. Eric Schadt, The Jean C. and James W. Crystal Professor of Genomics at the Icahn School of Medicine at Mount Sinai, and Director of the Icahn Institute for Genomics and Multiscale Biology, will be a principal investigator in the study. “With this grant, we can continue to build and refine our predictive model of Alzheimer’s disease to yield valuable insights into the complex mechanism of the disease and potential therapies. In the same way that sophisticated predictive mathematical models drive decision making in the global financial markets, our field of medical research has begun to rely on network models to derive meaning from vast amounts of patient data, enabling better understanding and treatment of human disease,” Schadt said in a statement. 14

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part of our Personalized Cancer Therapy program, featuring patient Mark Beeninga

Marketing Highlights: September 2013 Media Coverage re: our NIH Grant for Alzheimer’s Disease research

Marketing Highlights: September 2013 Media Coverage: NIH Announces Alzheimer’s Grant

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MAJOR MEDIA COVERED OUR KEY PROJECTS: CBS News, Katie Couric on ABC, Charlie Rose on PBS, Dr. Drew on CNN, Bloomberg TV, New York Times, Esquire Magazine, Huffington Post, US News & World Reports, NPR, Oprah Magazine, Delta Sky Magazine Strong Industry Press Coverage in MIT Technology Review, GEN, Drug Discovery & Development, GenomeWeb, Bio-IT World, The Scientist, FierceHealthIT, CruxialCIO

Recognizing Our Partners Leadership gifts to the Campaign for Mount Sinai allowed us to advance the innovative efforts of the Icahn Institute for Genomics and Multiscale Biology and the Department of Genetics and Genomic Sciences. We want to thank all those whose gifts made possible the significant accomplishments below; to acknowledge the vision and active participation of the Genomics Advisory Board; and to extend appreciation for the support of our foundation and corporate partners. ® The creation of the Icahn Institute for Genomics and Multiscale Biology, supported by Carl Icahn ® The recruitment of Eric Schadt, PhD, Jean C. and James W. Crystal Professor of Genomics, supported by Jean C. and James W. Crystal ® The Windreich Center for Bioinformatics, created by a gift from the Windreich Family Foundation ® Research in genomics, focused on inflammatory bowel disease and Alzheimer’s disease, supported by the Litwin Foundation, Carole and Ira Pittelman, and Howard and Michelle Swarzman ® DNA sequencing and computational analysis to predict individual risk of metastatic melanoma, while developing personalized therapies, made possible through the support of Kimberly and Eric J. Waldman ® Network modeling in genomics with a focus on Chronic Fatigue Syndrome, supported by a gift from Dwight Merriman ® Unrestricted support for innovative projects and the creation and expansion of the Genomics Advisory Board, made possible through the support and leadership of Chair Gerald J. Cardinale ® Playing a leadership role in the New York Genome Center, an influential organization transforming biomedical research and clinical care in New York and beyond, with support from Betty and John A. Levin ® State-of-the-art equipment that has helped expedite diagnosis and research for a range of genetic diseases, and expansion of our whole genome sequencing (WGS) program for healthy subjects, a fundamental part of our work to advance precision medicine, supported by the Genetic Disease Foundation

k FOR MORE INFORMATION:

icahn.mssm.edu/genomics

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Icahn School of Medicine at Mount Sinai One Gustave L. Levy Place, Box 1107 New York, NY 10029-6574