2006 Distinguished Clinical Scientist Awards
$10,500,000 over 5 to 7 years
In 2006, seven outstanding physician-scientists at the mid-career level each received grants of $1.5 million to be used over five to seven years.
2006 DCSA Grantees
David M. Altshuler, M.D., Ph.D.
Broad Institute of MIT and Harvard
Friedhelm Hildebrandt, M.D.
University of Michigan
William G. Kaelin, M.D.
Dana-Farber Cancer Institute
Elizabeth M. McNally, M.D., Ph.D.
University of Chicago
Christopher V. Plowe, M.D., M.P.H.
University of Maryland School of Medicine
David Relman, M.D.
Joyce Slingerland, M.D., Ph.D.
University of Miami Miller School of Medicine
2006 DCSA Continuation Grants
Olufunmilayo I. Olopade, M.D.
University of Chicago
Robert Siliciano, M.D.
Johns Hopkins University
Bruce D. Walker, M.D.
Massachusetts General Hospital
2006 DCSA Grantees
Dr. Altshuler's laboratory aims to characterize and catalogue patterns of human genetic variation, and to apply this information to understand the inherited contribution to common diseases.
Dr. Altshuler was a leader in the SNP Consortium and International HapMap Consortium, public-private partnerships that created genome-wide maps of human genetic diversity that now guide the design and interpretation of genetic association studies. Dr. Altshuler's group has also contributed to identifying the role of common genetic variants in type 2 diabetes, prostate cancer, and lupus.
Dr. Altshuler is a Clinical Scholar in Translational Research of the Burroughs Wellcome Fund, a Charles E. Culpeper Medical Scholar, and winner of the Stephen Krane Award of the Massachusetts General Hospital. He received the Richard and Susan Smith Pinnacle Award of the American Diabetes Association, and the "Freedom to Discover" Award from the Foundation of Bristol-Myers Squibb. He is a member of Advisory Boards at The National Institutes of Health, The Juvenile Diabetes Research Foundation, The Wellcome Trust and Merck Research Laboratories, on the Editorial Board of Annual Reviews of Human Genetics and Genomics, and the Board of Reviewing Editors at Science. Professor Altshuler is one of four Founding Members and Director of the Program in Medical and Population Genetics of The Broad Institute of Harvard and MIT, a unique research collaboration of Harvard, MIT, The Whitehead Institute, and the Harvard Hospitals.
Discovery and Clinical Application Type 2 Diabetes Genes
Despite great progress in biomedical research, the root causes of common diseases remain largely unknown; we have limited ability to prevent disease before it occurs, and few cures to offer once present. The long-term objective of our research is to identify inherited DNA variations that predispose to type 2 diabetes (T2D), and using this information, deploy existing treatments more effectively and design more effective interventions.
Our work is based on the observation that family history is one of the strongest influences on any disease: that is, rates of disease are more correlated in first degree relatives than in unrelated individuals, and strikingly more so in identical twins. Our past efforts have helped create a foundation of knowledge and methods that make possible systematic study of human genome sequence variation for its contribution to T2D and other diseases. We are currently testing 500,000 common genetic variations for association to T2D in 1,500 cases and 1,500 matched controls, and other such studies are ongoing. It is reasonable to expect that these (and even more powerful methods to come) will soon yield novel insights into the biological basis and population risk of T2D. Translating this information to clinical medicine is the goal of this proposal.
First, we will study whether and how DNA variants associated with risk of T2D might offer clinical information about progression from impaired glucose tolerance to T2D, and response to interventions. Specifically, single nucleotide polymorphisms found to be reproducibly associated with T2D in the whole genome scans will be genotyped in DNA samples from the Diabetes Prevention Program (DPP), a randomized intervention trial of patients with impaired glucose tolerance (IGT), with progression to T2D as an endpoint. Together with colleagues in the DPP we will ask whether these genetic variants predict progression from IGT to T2D, and of altered response to lifestyle and pharmacological interventions that delay onset of T2D. Based on these findings we will design a clinical trial asking whether genetically tailored diagnosis and therapy improves outcomes compared to standard care.
Second, we will develop new therapeutic leads based on novel information about inherited variants that predispose to risk of T2D. Specifically, we will study cells from carriers of specific risk genotypes, and in which the level of confirmed risk genes have been modified using RNAi and over-expression. Using genome-wide expression profiling we will search for signatures of altered gene sequence and activity. We will then use gene-expression high throughput screening (GE-HTS) to search for small molecules that reverse the signature of the at-risk genotypes or altered level of gene function, aiming to identify lead compounds for future study.
Third, we will create a suite of educational programs to enhance the mentoring and training of clinical investigators interested in applying genetics and genomics to clinical practice. Specifically, we will develop educational materials tailored for use on the wards, and organize an annual symposium for investigators who are embarking on careers in clinical genomic research, with the goal of having them get to know one another, to share ideas, and to brainstorm together about important goals and how to overcome obstacles to progress.
The proposed research aims to translate genetic information into more effective use of existing therapies, to catalyze discovery of new therapies, and to train the next generation of clinical genetic investigators.
Dr. Hildebrandt is a Professor of Pediatrics and of Human Genetics at the University of Michigan. He has studied medicine and psychology at the Universities of Marburg and Heidelberg (Germany) and at the Middlesex Hospital Medical School (London). He received his M.D. degree from the University of Heidelberg (1984) and performed a postdoctoral research fellowship with Peter Aronson and Peter Igarashi at the Yale University School of Medicine (1987-1990). He received his clinical training in general pediatrics and pediatric nephrology at Freiburg University Children's Hospital. In 2001, Dr. Hildebrandt joined the faculty of the University of Michigan as a full professor and holds an endowed chair as the First Frederick G.L. Huetwell Professor for the Cure and Prevention of Birth Defects. He continues to treat Pediatric Nephrology patients, teach graduate and medical students, and leads a basic science research group that identifies by positional cloning and functionally characterizes novel genes mutated in kidney diseases of children. Dr. Hildebrandt has received multiple awards for basic science-related clinical research including a Heisenberg Scholarship by the German Research Foundation (1998-2001), the Franz Volhard Award from the German Society of Nephrology (1997), the E. Mead Johnson Award for Pediatric Research from the Society for Pediatric Research (2004), and was elected Member of the Association of American Physicians in 2005. He lives with his wife Sabine Hildebrandt and their two children in Ann Arbor, Michigan.
New Treatment of Childhood Genetic Kidney Diseases
Dr. Hildebrandt's laboratory has advanced the understanding of disease mechanisms of hereditary kidney diseases in childhood that are associated with blindness or hearing loss. This includes cystic kidney diseases, nephrotic syndrome, and urinary tract malformations. His laboratory has identified by positional cloning ten novel genes. The identification of six genes mutated in nephronophthisis with retinitis pigmentosa contributed to a new unifying pathogenic concept of cystic kidney diseases that is based on the function of primary cilia, a sensory organelle.
Dr. Hildebrandt's laboratory identified the first gene mutated in a treatable form of nephrotic syndrome and in focal segmental glomerulosclerosis. Insights into kidney development were gained through positional cloning of the BSND gene mutated in Bartter syndrome with deafness, and of SIX1 mutations in Branchio-oto-renal syndrome. These studies helped elucidate the pathogenesis of developmental defects of the kidney, the eye, and auditory system, and allow for the generation of disease models to test new treatment approaches. Dr. Hildebrandt's laboratory provides molecular genetic diagnostics on an experimental basis for children with hereditary kidney disease worldwide.
William G. Kaelin Jr., M.D., is a Professor in the Department of Medicine at the Dana-Farber Cancer Institute and at the Brigham and Women's Hospital, Harvard Medical School. He obtained his undergraduate and M.D. degrees from Duke University and completed his training in internal medicine at the Johns Hopkins Hospital, where he served as chief medical resident. He was a clinical fellow in medical oncology at the Dana-Farber Cancer Institute and later a postdoctoral fellow in the laboratory of David Livingston, during which time he was a McDonnell Scholar.
Dr. Kaelin is a member of the American Society of Clinical Investigation and the American College of Physicians. He recently served on the National Cancer Institute Board of Scientific Advisors, the AACR Board of Trustees, and the Institute of Medicine National Cancer Policy Board. He is a recipient of the Paul Marks Prize for cancer research from the Memorial Sloan-Kettering Cancer Center and the Richard and Hinda Rosenthal Prize from the AACR.
A Howard Hughes Medical Investigator since 1998, Dr. Kaelin's research seeks to understand how, mechanistically, mutations affecting tumor-suppressor genes cause cancer. His laboratory is currently focused on studies of the VHL, RB-1, and p53 tumor suppressor genes. His long-term goal is to lay the foundation for new anticancer therapies based on the biochemical functions of such proteins. His work on the VHL protein led to new insights into how cells sense and respond to changes in oxygen, and thus has implications for diseases beyond cancer, such as myocardial infarction and stroke.
Translational Studies Based on Tumor Suppressor Proteins
Over 30,000 Americans are diagnosed with kidney cancer each year resulting in approximately 12,000 kidney cancer-related deaths per year. About 1 in 35,000 people are born with a defective copy of the VHL gene and are at increased risk of kidney cancer. Importantly, acquired (rather than inherited) mutations of the VHL gene are also very common in non-hereditary kidney cancer. In short, inactivation of the VHL gene is a common event in both hereditary and non-hereditary kidney cancer. Genes are usually 'blueprints' for making particular proteins. The VHL gene contains the information for making the VHL protein ('pVHL'), which inhibits a protein called 'HIF'. HIF, in turn, activates ~ 100 genes implicated in cell growth and angiogenesis (the process of making new blood vessels), including VEGF. Most successful drugs work by binding to, and inhibiting, a specific cellular protein (its 'target'). Drugs that inhibit VEGF have demonstrated significant activity as treatments for kidney cancer, in terms of tumor shrinkage and delayed tumor growth, but are not curative. This proposal seeks to build upon these results. One set of experiments seeks to identify new kidney cancer drug targets by systematically searching for genes that are essential for survival in cells lacking pVHL, but not in normal cells. In theory, drugs that inhibited the proteins encoded by such genes should selectively kill tumor cells bearing VHL mutations. Inactivation of the VHL gene is not sufficient to cause kidney cancer; mutations of additional genes are also clearly required.
State of the art techniques will be used to try to identify such genes because they should define additional molecular circuits that are abnormal in kidney cancer cells. These circuits could then be targeted with drugs. This proposal will also attempt to identify proteins ('biomarkers') that can be easily measured in clinical samples (such as blood or urine) to monitor the presence of kidney cancers in patients and/or to document that kidney cancer drugs have successfully inhibited their targets. In some cases drugs will already be available, or in development, for the targets identified in this proposal. In other cases partnerships with the private sector will be required to develop such drugs. The final goal of this proposal is to perform kidney cancer clinical trials with novel drugs that are based on knowledge of the genes that are altered in this disease, as outlined above.
Elizabeth McNally is a professor at the University of Chicago where she studies the genetics of inherited heart disease and inherited muscle disease. Dr. McNally was born in Chicago and received her undergraduate degree at Barnard College majoring in Philosophy and Biology. She received her M.D. and Ph.D. degrees participating in the Medical Scientist Training Program at Albert Einstein College of Medicine. Dr. McNally was clinically trained at the Brigham and Women's Hospital in Internal Medicine and Cardiovascular Diseases. She was a fellow in Genetics at Children's Hospital in Boston and the Howard Hughes Medical Institute.
Dr. McNally studies the genetic defects that lead to heart and muscle weakness. She directs the Cardiovascular Genetics Clinic at the University of Chicago that specializes in inherited cardiomyopathies, the cardiomyopathy that accompanies neuromuscular disease and other inherited cardiovascular disorders. The discovery of gene defects in patients and families with inherited heart disease helps identify those that are at higher risk of developing disease. Dr. McNally is now planning to study the epigenetic mechanisms that lead to cardiomyopathy and to combine genetic studies with imaging to identify the earliest markers of cardiomyopathy. These studies will also test whether early treatment can slow or prevent the onset of cardiomyopathy and heart failure. Dr. McNally was a Culpeper Medical Scholar and received a Clinical Translational Award from the Burroughs Wellcome Foundation. Dr. McNally is also supported by the National Institutes of Health. She is a member of the American Society for Clinical Investigation and the Association of American Physicians. Dr. McNally works closely with the Muscular Dystrophy Association serving on its Scientific Advisory Board. Dr. McNally is also dedicated to training physician scientists by directing the Cardiovascular Sciences Training Program at the University of Chicago.
Epigenetics of Heart Failure
Cardiomyopathy, or weakness of the heart muscle, is a leading cause of congestive heart failure, one of the most common hospital diagnoses in the United States. Cardiomyopathy can be caused by mutations in single genes, where it can lead to heart failure and life-threatening irregular heart rhythms. Most of the genes that are associated with cardiomyopathy encode proteins that are specifically important for heart muscle function. One gene that is associated with cardiomyopathy encodes a protein of the nuclear membrane that is thought to have a role in regulating nuclear function such as the expression of genes. Dr. McNally will study patients with mutations in genes that cause cardiomyopathy to try to understand new mechanisms of heart failure. Dr. McNally will also work to identify how the nuclear membrane is important for the proper function of heart cells. Lastly, Dr. McNally will work with patients and families who are at risk of developing heart failure to identify new markers and determine therapy that can slow or halt the progression of cardiomyopathy.
Chris Plowe is a physician and malariologist who leads a multidisciplinary clinical translational malaria research at the University of Maryland's Center for Vaccine Development, with field sites in Mali, West Africa and Malawi, Central Africa. He is best known for his work on the molecular epidemiology of drug resistant malaria. Working with African colleagues, his group at the University of Maryland developed rapid molecular assays to detect drug resistant malaria using dried blood spots on paper. These tests have been used to understand the population genetics of malaria and to control malaria outbreaks and inform treatment policy decisions. Dr. Plowe's work encompasses malaria drug resistance, molecular epidemiology, molecular evolution, rapid diagnostics, pathogenesis, immunology, international research ethics, interactions between HIV and malaria, and clinical trials of drugs and vaccines. His group is currently concentrating on understanding and mitigating the impact of genetic diversity on malaria vaccine efficacy and on developing strategies to deter the emergence and spread of drug resistant malaria.
Dr. Plowe was born and raised in South Dakota, the second of six children of a clergyman/farmer and a Vassar-educated housewife. He is a tenured Professor of Medicine and Chief of the Malaria Section in the Center for Vaccine Development at the University of Maryland School of Medicine in Baltimore. He received a BA in Philosophy from Cornell University in 1982, an MD from Cornell in 1986, and an MPH in Tropical Medicine from Columbia University in 1991. After training in malaria research at the National Institutes of Health and in infectious diseases at Johns Hopkins University he joined the University of Maryland faculty in 1995. He was awarded the Ashford Medal for distinguished work in tropical medicine from the American Society of Tropical Medicine and Hygiene in 2002 and was elected to the American Society for Clinical Investigation in 2005. He provides expert advice on malaria research and control to national and international agencies and has testified before Congress on tropical medicine research priorities and before a Presidential commission on international research ethics. He divides his time between his laboratories in Baltimore, the Bandiagara Malaria Project in Mali and the Blantyre Malaria Project in Malawi. He enjoys playing music with his children and riding motorcycles with his wife.
Antigenic Diversity and Malaria Vaccine Efficacy
"Malaria parasites mutate and evolve so quickly that drugs and vaccines are always chasing a moving target," says Dr. Chris Plowe, Professor of Medicine and Chief of the Center for Vaccine Development's Malaria Section at the University of Maryland School of Medicine. Dr. Plowe's project, "Genetic Diversity and Malaria Vaccine Efficacy", will combine molecular studies in the Center for Vaccine Development with clinical trials in Mali, West Africa, to understand how malaria parasites evolve to evade attack from the human immune system. Plowe's team at the University of Maryland and colleagues at the University of Bamako in Mali hope that learning how the malaria parasite genome is shaped by both natural and vaccine-induced immunity will lead to a vaccine that protects people against genetically diverse malaria parasites.
"This award will help us exploit the amazing advances in malaria genomics to improve a malaria vaccine we are testing now in Mali," says Plowe. "It's as if malaria parasites can change their coats so that they aren't recognized. We need to beat the parasite at its own game by making a vaccine that helps the body's defenses recognizes malaria parasites whether they are wearing a red parka or a blue blazer."
The Doris Duke award will also support research training for medical students and young doctors to work with Dr. Plowe and his team both at the University of Maryland and in Africa.
David Relman, M.D., is associate professor of medicine, and of microbiology and immunology at Stanford University. He is also chief, infectious diseases section, at the VA Palo Alto Health Care System in Palo Alto, California.
A native of Boston, Massachusetts, Dr. Relman holds an S.B. degree from the Massachusetts Institute of Technology and received his M.D. degree, magna cum laude, from Harvard Medical School in 1982. Following postdoctoral clinical training at Massachusetts General Hospital in Internal Medicine and in Infectious Diseases, Dr. Relman served as a postdoctoral research fellow in microbiology at Stanford University in the laboratory of Stanley Falkow from 1986 until 1992. He joined the Stanford University faculty in 1992 and was appointed associate professor (with tenure) in 2001.
His research is directed towards the characterization of the human indigenous microbial communities of the mouth and gut, with emphasis on understanding variation in diversity, succession, the effects of disturbance, and the role of these communities in oral and intestinal disease. Experimental approaches include molecular phylogenetics, ecological statistics, single cell genomics, and community-wide metagenomics. A second area of research concerns the classification structure of humans and non-human primates with systemic infectious diseases, based on patterns of genome-wide gene transcript abundance in blood and other tissues. The goals of this work are to recognize classes of pathogen and predict clinical outcome at early time points in the disease process, as well as gain further insights into virulence (e.g., of variola and monkeypox viruses). Past achievements include the description of a novel approach for identifying previously-unknown pathogens, the identification of a number of new human microbial pathogens, including the agent of Whipple's disease, and the most extensive descriptions to date of the human indigenous microbial community.
Dr. Relman received the Squibb Award from the Infectious Diseases Society of America (2001), the Senior Scholar Award in Global Infectious Diseases from the Ellison Medical Foundation (2002), and is a recipient of an NIH Director's Pioneer Award (2006). He is a member of the American Society for Clinical Investigation and was named a Fellow of the American Academy of Microbiology in 2003.
Dr. Relman currently serves on the Board of Scientific Counselors of the National Institute of Dental and Craniofacial Research and was a member of the Board of Directors of the Infectious Diseases Society of America (2003-2006), and co-chair of the National Academy of Sciences' Committee on Advances in Technology and the Prevention of Their Application to Next Generation Biowarfare (2004-2006). He is a member of the National Science Advisory Board for Biosecurity, the Institute of Medicine's Forum on Microbial Threats, and advises several U.S. Government departments and agencies on matters related to microbial pathogen detection and future biological threats.
Microbial Ecology of the Human Intestinal Tract
The human body is a consortium between human cells and microbial cells. The latter outnumber the former by approximately ten-fold. Each cell type depends upon the other. Although we know that our microbial inhabitants provide a number of critical functions, we know little about the make-up of our microbial communities in health, and how they may contribute to a variety of disease states. The broad, long-term objectives of the proposed work are a more complete understanding and definition of human health based on the patterns of diversity within indigenous microbial community, the identification of microbial community "signatures" that predict the development or course of local disease, and strategies for the maintenance or restoration of health that involve well-informed manipulations of the human microbial communities. The specific aims of this work are to characterize the composition of the human gut microbial communities in health, the changes in these communities during inflammatory bowel disease, and the responses of the distal gut microbial communities to antibiotic exposure.
Dr. Slingerland received her M.D. from the University of Toronto in 1983. She is certified in Internal Medicine by the American Board in Internal Medicine and in Canada, and in Medical Oncology by the Royal College of Physicians and Surgeons. In 2002, Dr. Slingerland came to the University of Miami Miller School of Medicine as the Director of the Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center where she is working to expand and coordinate multidisciplinary breast cancer research. She has published over 60 articles and reviews in addition to several book chapters and has received numerous awards. Dr. Slingerland continues her medical practice devoted entirely to breast cancer patients at the Sylvester Comprehensive Cancer Center and the Jackson Memorial Hospital.
Dr. Slingerland's lab research has provided insights into how cancers escape negative growth controls. Following her discovery of a key cell cycle inhibitor, p27, she found that p27 levels are reduced in up to 60% of common human cancers (breast, prostate, lung, ovarian and others) in association with poor patient prognosis. She also showed that cell cycle inhibitors p15 and p27 cooperate to cause G1 arrest by transforming growth factor-beta (TGF-beta) and that cancer cells lose responsiveness to TGF-beta through loss or deregulation of p27. Current work addresses how p27 function is impaired in human breast and other cancers. Functional inactivation of p27 in human cancers can either occur through accelerated p27 degradation or through altered p27 phosphorylation leading to p27 mislocalization. Slingerland's group demonstrated that antiestrogen drugs require the cdk inhibitors p21 and p27 to arrest breast cancer growth. She showed that oncogenic signaling via the Src and MEK pathways deregulate p27 function causing tamoxifen resistance in breast cancer. Efforts to prevent or reverse hormone independent, antiestrogen resistant breast cancer growth using EGFR, MEK and Src inhibitors are under investigation in pre-clinical studies and clinical trials.
Molecular Therapies for Hormone Resistant Breast Cancer
About two-thirds of breast cancers express the estrogen receptor (ER). These ER positive breast cancers can be treated with antiestrogen drugs like tamoxifen or aromatase inhibitors. Unfortunately, most breast cancers develop resistance to these drugs. Our lab has shown that estrogen promotes breast cancer growth by causing the degradation of a key cell cycle inhibitor, p27. We also showed that estrogen deprivation and drugs that block the ER, like tamoxifen, depend on p27 to cause breast cancer cells to stop growing. p27 levels are often reduced in human breast cancers and this predicts poor patient outcome and poor response to tamoxifen therapy. Our recent work showed that the oncogene Src acts on p27 to change its shape and function and promotes p27 degradation in breast cancer cells. This grant will investigate further how Src alters both where p27 is in the cell and how its function is regulated. We will examine a series of tissues from human breast cancer samples to test whether Src activation is associated with reduced p27 protein and if both of these findings together may predict poor patient outcome. Given the strength of our observations in the laboratory, we plan to test if a new Src inhibitor drug can delay or prevent resistance to antiestrogens therapy. We will carry out a Phase I-II clinical trial of the Src inhibitor, AZD0530, together with antiestrogens therapy for metastatic and locally advanced breast cancer. These studies will increase our understanding of the relationship between Src activation and loss of the growth inhibitory effect of p27 in human breast cancer, and apply this knowledge to design new more effective strategies to treat women with antiestrogens resistant breast cancer.
2006 DCSA Continuation Grants
In addition to supporting a new roster of Distinguished Clinical Scientists in 2006, the Medical Research Program also awarded continuation grants of $200,000 each to support the exceptional mentoring projects of three past DCSA recipients.
"Translational Research Career Development Program for Physician Scientists"
Dr. Olopade will support a Translational Research Career Development Program at the University of Chicago, which will foster the careers of clinical fellows and young faculty members in hematology/oncology and support a summer internship program for high school and college students.
"Bench to Bedside Training in HIV Therapeutics"
Dr. Siliciano will continue a novel mentoring program at Johns Hopkins developed during his DCSA grant, which provides medical students and infectious disease fellows with training in bench-to-bedside research in HIV therapeutics. This integrated program provides trainees with exposure to patient care in the HIV clinic under seasoned clinicians as well as direct involvement in laboratory work on HIV drug resistance under Dr. Siliciano.
"Capacitating Research in Africa"
Dr. Walker will continue training Ph.D. candidates and postdoctoral fellows at the Doris Duke Medical Research Institute in Durban, South Africa, who are focusing on the AIDS and tuberculosis epidemics in South Africa. In addition, he will provide fellowships for African trainees to come to the U.S. and participate in summer training courses at the Harvard School of Public Health.