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May 28, 2002
HHMI Announces Selection of New Investigators Who Conduct Patient-Oriented Research
From left (row 1): Katherine A. High, Emmanuel J. Mignot, Brendan H.L. Lee, Charles L. Sawyers; (row 2): Robert B. Darnell, Bruce D. Walker, Helen H. Hobbs, Todd R. Golub; (row 3): Robert F. Siliciano, Edwin M. Stone, Christopher A. Walsh, Brian J. Druker.
The Howard Hughes Medical Institute has selected 12 of the
nation’s top physician-scientists to be appointed as HHMI
investigators in an innovative program to improve the translation of
basic science discoveries into enhanced treatments for patients.
They will join 324 HHMI investigators across the United States, a
group whose recent honors include the National Medal of Science and the
Lasker Award. Earlier this month, nine HHMI investigators were elected
to membership in the National Academy of Sciences.
“This group of physician-scientists has already made
impressive contributions to understanding some of society’s most
vexing health problems, including AIDS, cardiovascular disease and
cancer,” said HHMI President Thomas R. Cech. “We believe
that they have the potential to continue to improve healthcare by
finding new ways to translate basic science discoveries into useful
therapy for patients.”
"Medical research is thriving today, primarily as a result of the
powerful new tools of molecular biology that have revealed new concepts
about the inner workings of the human cell,” said Joseph L.
Goldstein of the University of Texas Southwestern Medical Center at
Dallas and chairman of HHMI’s Medical Advisory Board. “What
are crucially needed are more patient-oriented researchers with the
expertise to translate and transform these molecular advances into the
realities of clinical medicine. In the conquest of any disease,
patient-oriented researchers are essential at every stage — from the
delineation of a new syndrome, to elucidation of pathogenesis, to
design and evaluation of a new drug.”
With the completion of the human genome sequence and the advent of
other technological advances such as those in the area of biomedical
imaging, there are new opportunities for bridging the gap between
advances in basic science and clinical research. The purpose of this
investigator competition was to identify researchers whose scientific
work is guided by their interaction with patients or other human
subjects.
Although several of the 324 current HHMI investigators are doing
patient-oriented research on diseases such as colon cancer,
hypertension, and hypertrophic cardiomyopathy, the majority of Hughes
scientists focus on basic research directed toward understanding the
genetic, molecular and cellular bases of human disease. This type of
research is generally characterized as being disease-oriented rather
than patient-oriented, because the research does not require
significant contact with patients.
In June 2001, letters inviting nominations were sent to 119
institutions, including medical schools, research institutes, schools
of public health and some independent hospitals. By September 10, 2001,
the closing date for nominations, 138 nominations had been received. A
review committee of distinguished biomedical scientists evaluated the
nominations. Following the recommendations of the advisors, 12
physician-scientists were selected for appointment.
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Robert B. Darnell, M.D., Ph.D.
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The Rockefeller University
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Brian J. Druker, M.D.
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Oregon Health & Science University
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Todd R. Golub, M.D.
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Harvard Medical School
Dana-Farber Cancer Institute
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Katherine A. High, M.D.
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The Children’s Hospital of Philadelphia
University of Pennsylvania School of Medicine
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Helen H. Hobbs, M.D.
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University of Texas Southwestern Medical Center
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Brendan H. L. Lee, M.D., Ph.D.
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Baylor College of Medicine
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Emmanuel J. Mignot, M.D., Ph.D.
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Stanford University School of Medicine
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Charles L. Sawyers, M.D.
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Jonsson Comprehensive Cancer Center
David Geffen School of Medicine at the University of California, Los
Angeles
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Robert F. Siliciano, M.D., Ph.D.
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The Johns Hopkins University School of Medicine
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Edwin M. Stone, M.D., Ph.D.
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University of Iowa Roy J. and Lucille A. Carver
College of Medicine
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Bruce D. Walker, M.D.
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Harvard Medical School
Massachusetts General Hospital
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Christopher A. Walsh, M.D., Ph.D.
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Harvard Medical School
Beth Israel Deaconess Medical Center
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The Institute is a medical research organization that enters into
long-term collaboration agreements with universities and other academic
research organizations, where its investigators hold faculty
appointments. Under these agreements, HHMI investigators, all of whom
are employees of the Institute, carry out their research with
considerable freedom and flexibility in HHMI laboratories located on
various campuses. This model emphasizes “people, not
projects” and differs from the grant-based approach used
elsewhere. The Institute expects to provide initial research budgets of
up to $1 million annually for each of its new investigators, plus
payments to the host institutions for laboratory space.
The Institute’s biomedical research expenditures this fiscal
year will total about $450 million. In addition to conducting medical
research, the Institute has a large grants program that supports
science education in the United States and the research of a select
group of biomedical scientists in other countries. HHMI grants will
total more than $100 million during the current fiscal year.
Established in 1953 by the aviator-industrialist for whom it is
named, the Institute maintains its headquarters and conference center
in Chevy Chase, Maryland, just outside Washington, D.C.
Investigators and Research
Descriptions
Robert B. Darnell, M.D.,
Ph.D.
The Rockefeller University
New York, NY
Dr. Darnell studies paraneoplastic neurologic disorders (PNDs), which
are believed to arise when tumor cells abnormally produce proteins that
are usually made only in neurons. In PND patients, the immune system
produces antibodies and T cells that effectively attack the patient's
own tumor. But the same immune cells can also attack healthy neurons,
in what is termed an autoimmune response, which can lead to neuronal
degeneration in specific regions of the brain.
One of the goals of Dr. Darnell's research is to learn more about
the neuronal proteins that are attacked by the immune system. Using
serum from patients with PND, Dr. Darnell's research team has
identified a series of genes that encode previously undiscovered
neuron-specific proteins. Recent work has focused on the role that
neuronal RNA binding proteins play in the brain and in disease. By
studying the PND antigens, Dr. Darnell and colleagues have found that
neurons are unique in the way they regulate gene expression through
their processing of RNA. These findings are relevant for a number of
diseases. For example, the Darnell laboratory recently discovered how
the RNA binding protein associated with fragile X mental retardation
might cause the range of cognitive and behavioral abnormalities
characteristic of this disease.
A second goal is to understand the nature of the anti-tumor and
autoimmune response, with the aim of developing new immunotherapies. By
starting with the unique set of PND patients, the Darnell laboratory is
working its way back toward understanding how people's immune system
may normally suppress cancer as well as how autoimmune diseases, such
as multiple sclerosis, arise — two pursuits that may lead to novel
strategies for treating these life-threatening conditions.
Brian J. Druker, M.D.
Oregon Health & Science University
Portland, OR
One of the most exciting recent advances in cancer treatment is the
development of STI571, commonly known as Gleevec, a drug that inhibits
the activity of specific proteins called tyrosine kinases that promote
the formation of chronic myelogenous leukemia (CML) and
gastrointestinal stromal tumors (GIST). Working from the premise that
the leukemia-cell-specific Bcr-Abl tyrosine kinase caused CML, Dr.
Druker searched for a molecule that would block the action of this
altered kinase without interfering with other normal kinases. His
search led to scientists at Novartis, who provided a number of chemical
compounds that Dr. Druker tested to see whether they blocked the
activity of the wayward kinase. The studies turned up STI571, a
compound that Dr. Druker played a key role in shepherding through
development — from early experimental therapy to large-scale clinical
trials in patients.
As the STI571 studies have shown, tyrosine kinases make excellent
targets for new cancer therapies. Dr. Druker and his colleagues are
continuing to study how tyrosine kinases spur cellular transformation.
His group is now studying the FLT3 tyrosine kinase, which is mutated in
30 percent of patients with acute myeloid leukemia. Using the STI571
studies as a road map for drug development, Dr. Druker and his
colleagues hope to design an effective FLT3 kinase inhibitor.
Todd R. Golub, M.D.
Dana-Farber Cancer Institute
Boston, MA
Dr. Golub is addressing clinical problems in cancer medicine by
studying primary patient material at the genetic level. He and his
colleagues are developing diagnostic and prognostic tests for childhood
leukemia based on the cloning of genes involved in chromosome
translocations; they are devising strategies for predicting responses
to chemotherapy based on DNA microarray gene expression patterns; and
they are exploring novel therapeutic strategies based on whole genome
analyses of patient samples.
Dr. Golub and his colleagues have shown that children with acute
lymphoblastic leukemia (ALL) carry a rearrangement of the TEL
gene. They demonstrated that 27 percent of patients they studied
carried a specific TEL/AML1 fusion gene that can be used as a
diagnostic marker to predict a favorable response to therapy.
TEL/AML1 testing is now being used at some medical centers to
tailor individual treatment plans for patients with ALL in the hope of
reducing toxicity caused by chemotherapy.
Unlike acute leukemias, most adult solid tumors are characterized by
more complex gene rearrangements. Dr. Golub is now taking a number of
different approaches that will yield a more accurate picture of how
these tumors develop by taking a "whole genome" look at cancer. His
research team is bringing the power of genomic technologies to bear on
clinical dilemmas in cancer treatment, with an eye toward developing
more rational approaches to treatment planning and drug
development.
Katherine A. High, M.D.
The Children's Hospital of Philadelphia
Philadelphia, PA
For the past 16 years, Dr. High has studied the molecular basis of
blood coagulation, with an emphasis on hereditary bleeding disorders.
Approximately 10 years ago, she became interested in developing a gene
transfer approach to the treatment of hemophilia B, a bleeding disorder
caused by a deficiency of clotting factor IX. Gene therapy is a novel
area of therapeutics in which the active agent is a DNA sequence rather
than a protein or small molecule. The therapeutic possibilities for
gene therapy are enormous, but they have been limited by practical
difficulties related to inefficient gene transfer, transient gene
expression or unacceptable toxicities.
In 1999, Dr. High's research team showed that gene therapy could
achieve long-term improvement in a naturally occurring hemophilia that
affects dogs. Using a genetically engineered virus, called
adeno-associated virus, as a vector to deliver therapeutic genes, Dr.
High and her colleagues continued to improve results in the hemophilia
dog model, and have recently demonstrated high-level expression of
clotting factor in these animals. Concurrently, they have carried out
the first studies of parenterally administered adeno-associated virus
vectors in humans. These clinical studies are ongoing in patients with
severe hemophilia B.
Helen H. Hobbs, M.D.
University of Texas Southwestern Medical Center
Dallas, TX
Dr. Hobbs and her colleagues are studying how abnormalities in the
processing of dietary lipids cause human diseases. Her research team is
identifying the genetic factors that influence how low-density
lipoprotein (LDL) and high-density lipoproteins (HDL), the two major
cholesterol-carrying lipoproteins, accumulate in the blood. Many
different genes and environmental factors contribute to the variations
in levels of LDL and HDL. In an effort to identify genetic factors that
lead to variations in lipoproteins levels, Dr. Hobbs and her colleagues
have collected and characterized the plasma lipoprotein levels in over
500 families in which multiple family members have elevated plasma
levels of lipoproteins. Her group has also recently identified genes
that play critical roles in limiting the amount of dietary cholesterol
that accumulates in the body. Dr. Hobbs is investigating why some
individuals are more likely than others to develop high plasma
cholesterol levels on a high cholesterol diet.
Levels of lipoprotein(a) [Lp(a)]— which at high levels can increase
one's risk of developing heart disease — can differ dramatically
between individuals and ethnic groups. Dr. Hobbs and her research team
have shown that sequence variations in the apo(a) gene are the major
determinant of plasma concentrations of Lp(a) within ethnic groups, but
it is not known why individuals of African descent have about a
three-fold higher mean plasma level of Lp(a) or whether high levels of
Lp(a) in African-Americans are a risk factor for heart disease. Her
group is examining these questions by performing family studies and by
studying the relationship between plasma levels of Lp(a) and
atherosclerosis in African-Americans.
As principal investigator of the Dallas Heart Disease Prevention
Project, Dr. Hobbs and her colleagues are studying heart disease in a
population of 3,000 randomly selected individuals who are being
characterized for behavioral, environmental, metabolic and genetic risk
factors for cardiovascular disease. The extensive database generated
from this study will be used to identify new predictive cardiac risk
factors and to explore the relationship between the metabolic syndrome
X, which is characterized by obesity, insulin resistance, high
triglyceride levels, high blood pressure, and heart disease.
Brendan H. L. Lee, M.D., Ph.D.
Baylor College of Medicine
Houston, TX
Dr. Lee is studying the developmental and biochemical pathways that
regulate mammalian tissue and organ development. He is applying
knowledge from these studies to the design of new diagnostic and
therapeutic tools for disorders that result from abnormalities in these
pathways.
In pathways that are not well understood, such as those that
regulate the early development of organs, Dr. Lee and his colleagues
have focused on the transcriptional networks that govern pattern
formation and cell differentiation. In their studies on skeletal and
kidney development, they have correlated human genetic disease
phenotypes with mouse models to elucidate the regulators and targets of
key transcription factors specifying unique developmental programs.
These basic and translational studies in the laboratory are linked with
clinical research coordinated from the Texas Children's Hospital
Skeletal Dysplasia Clinic. In this environment, the multidisciplinary
care of pediatric patients with skeletal malformations is closely
linked with studies aimed at understanding the consequences of gene
mutations on craniofacial/limb skeletal development, and at
quantitation and treatment of osteopenia (less than normal amount of
bone) associated with skeletal dysplasias.
Dr. Lee and his colleagues are also studying patients who have
disorders in the urea cycle, which is responsible for removing ammonia
that is generated by protein intake in food and by the breakdown of
proteins in the body during illness. If ammonia is not cleared from the
blood, it can reach toxic levels, causing brain damage and death. Since
much basic information about the urea cycle is already available, Dr.
Lee has attempted to translate that information into stable
isotope-based metabolic protocols in patients with urea cycle defects
to develop new tools to diagnose and manage the disorders. By
understanding the underlying gene-nutrient interactions in these
disorders, Dr. Lee and his colleagues may develop new strategies
important for the nutritional management of both healthy and acutely
ill children. The ultimate goal of Dr. Lee's research in this area is
to translate information from these pathways into treatment, including
gene replacement therapy, for urea cycle disorders.
Emmanuel J. Mignot, M.D.,
Ph.D.
Stanford University School of Medicine
Palo Alto, CA
Dr. Mignot and his colleagues are studying narcolepsy, a severe sleep
disorder that usually manifests during a person's teens or early 20s.
With little or no warning, a narcoleptic person feels irrepressibly
sleepy and quickly falls into deep sleep.
In 1999, Dr. Mignot's research team and another group led by HHMI
investigator Masashi Yanagisawa at the University of Texas Southwestern
Medical Center converged on a faulty neuropeptide system that induced
narcolepsy in dogs and mice. Dr. Mignot, whose group has been studying
narcolepsy for more than a decade, showed that molecules, which they
called hypocretins, were absent in the brain of patients with
narcolepsy.
Dr. Mignot is now investigating whether narcolepsy is exacerbated by
an autoimmune response against specific cells in the brain. The
scientists are also studying the underlying pathophysiology of
narcolepsy in two animal models, zebrafish and mice, and they are
planning studies to map narcolepsy genes in humans. The studies
underway in Dr. Mignot's laboratory may provide information that can
improve the treatment of a number of sleep disorders that afflict
humans.
Charles L. Sawyers, M.D.
Jonsson Comprehensive Cancer Center
David Geffen School of Medicine at the University of California, Los
Angeles
Los Angeles, CA
Dr. Sawyers is investigating how molecular abnormalities in leukemia
and prostate cancers lead to abnormal growth and cellular
transformation. The leukemia studies focus on signal transduction
pathways involving the Abl gene. The c-Abl tyrosine kinase is
involved in a chromosome translocation, which creates the
Bcr-Abl oncogene in patients with chronic myelogenous leukemia
(CML).
In collaboration with Dr. Brian Druker at Oregon Health &
Science University (see above), Dr. Sawyers designed and conducted the
phase I-II clinical trials of STI571 (Gleevec) for treatment of CML.
Dr. Sawyers recently showed that resistance to STI571 occurs through
mutation or amplification of the Bcr-Abl gene.
Building on the lessons learned in the development and clinical
trials of STI571, Dr. Sawyers is now developing kinase inhibitor
therapy for other cancers. Currently he is studying how the PTEN
tumor suppressor gene restricts access to the Akt pathway, which
regulates growth signals. When PTEN is mutated, the Akt pathway
promotes rapid cell growth, which may lead to cancer. Since 1997, Dr.
Sawyers and his colleagues have learned critical information about how
PTEN and Akt interact. The studies may help identify the molecular
changes that accompany a form of brain cancer called glioblastoma and
prostate cancer, a disease that kills 40,000 men in the United States
every year.
Robert F. Siliciano, M.D.,
Ph.D.
The Johns Hopkins University School of Medicine
Baltimore, MD
Dr. Siliciano's laboratory is searching for ways to prevent or treat
HIV infection through the development of new vaccine or drug therapies.
Combination drug therapy for HIV-1 infection can reduce the amount of
virus in the blood to undetectable levels in many patients. However,
Dr. Siliciano and his colleagues have shown that HIV-1 can persist in a
silent, or latent, form in a long-lived population of memory T cells.
Since this reservoir of HIV-1 decays very slowly, latent infection of
these so-called memory CD4+ T cells provides a mechanism for lifelong
persistence of HIV-1, even in patients on effective antiretroviral
therapy.
A major goal of Dr. Siliciano's laboratory is to understand the
mechanisms by which the latent T cell reservoir is established and
maintained. This information will aid in developing approaches for
eradicating or containing the virus in CD4+ T cells. His group is also
studying how drug therapy affects the evolution of HIV-1. HIV-1 can
mutate rapidly to evade drug therapy, so understanding how to measure
and control HIV-1 evolution may lead to improved treatment for HIV-1
infection.
Edwin M. Stone, M.D., Ph.D.
University of Iowa Roy J. and Lucille A. Carver College of
Medicine
Iowa City, IA
Dr. Stone's research interests are in inherited eye diseases. He
established the Molecular Ophthalmology Laboratory at the University of
Iowa in 1987 to facilitate the diagnosis and treatment of human eye
diseases. Since1990, Dr. Stone has collaborated with HHMI investigator
Dr. Val Sheffield at the University of Iowa in identifying the
chromosomal location of genes that cause 14 different eye diseases and
over 70 different mutations that cause a range of disease, including
hereditary obesity, corneal dystrophies, vitreoretinopathy, optic
neuropathy, deafness, and Pendred Syndrome.
Dr. Stone and his colleagues have also created the first
international center for ophthalmic molecular diagnosis and have
provided expert diagnostic assistance to physicians throughout the
United State and fifteen foreign countries. The group has also
initiated strategies to develop vectors for gene transfer to the eye
for treatment of a variety of inherited eye diseases.
Bruce D. Walker, M.D.
Harvard Medical School
Massachusetts General Hospital
Charlestown, MA
Dr. Walker and his colleagues are investigating the cellular immune
response to human viral pathogens, particularly HIV-1, HIV-2, and
hepatitis C virus. Numerous studies in mouse models of viral infection
have shown that virus-specific cytotoxic T lymphocytes form a strong
natural defense mechanism against viruses. Dr. Walker has been
investigating the role of these cells in chronic human viral
infections, and is particularly interested in translational studies to
answer basic questions related to viral pathogenesis in humans.
Dr. Walker's group has focused their research efforts on persons in
the earliest stages of HIV infection to determine how the immune system
fights the virus during the initial encounter. In addition, they have
followed a group of people who have been infected with HIV for more
than two decades and yet remain well. This is a special group because
their illness has not progressed despite the fact that they have never
been treated with antiviral drugs. By understanding how the immune
systems of these people effectively cope with the virus, the
researchers hope to learn how to neutralize or kill HIV-infected cells,
and how to boost immunity to viruses as a means of combating these
infections.
As director of the Harvard Medical School Division of AIDS and of
the Partners AIDS Research Center, Dr. Walker has actively encouraged
collaboration within the AIDS research community at Harvard and abroad.
He and his colleagues have initiated studies in Uganda to test
candidate HIV vaccines and have set up a fully functioning laboratory
in Kampala to support these studies. Dr. Walker and his colleagues are
also aiding several institutions in South Africa (Universities of Cape
Town, Natal and Witwatersrand) to expand their immunology programs and
to provide new opportunities for African scientists who are studying
virology.
Christopher A. Walsh, M.D.,
Ph.D.
Harvard Medical School
Beth Israel Deaconess Medical Center
Boston, MA
Dr. Walsh's laboratory is interested in the causes of mental
retardation and epilepsy in children. Although these common conditions
impact many children and their families, we know little about what
causes them and in many cases lack specific diagnostic tests.
Increasingly, children with mental retardation and epilepsy are being
discovered to have abnormal development of the largest structure of the
human brain, the cerebral cortex. The cerebral cortex, or "gray
matter," is a folded sheet of neurons that forms a wrapping around the
outside of the brain. Abnormal development of the cerebral cortex in
humans can also result in autism, dyslexia and other learning
disorders, and perhaps some psychiatric conditions as well.
By identifying the genes that are mutated in patients with disorders
of brain development, Dr. Walsh and his colleagues are learning what
proteins are involved, as well as where and how they function. For
example, some of the gene mutations they have already identified result
in brains that are too small, or abnormally patterned, or show
accumulation of cortical cells in abnormal locations. The different
disorders reflect the site of action and function of the genes
involved, and other members of his lab study the function of these
genes in normal development.
Dr. Walsh has ongoing collaborations with clinical geneticists and
pediatric neurologists around the world to improve diagnosis of
childhood brain disorders. His group is pioneering an "Internet
Clinic," in which the clinical histories and magnetic resonance (MRI)
images of patients are received via email. Dr. Walsh, a genetic
counselor, neuroradiologists and other specialists then review the
information. Working closely with the referring physician, Dr. Walsh
and his colleagues refine the diagnosis, and in some cases work with
the physician and family to obtain additional MRI images and obtain DNA
samples for genetic mapping. The collaboration has led to the clinical
description of more than a dozen new neurological syndromes whose
genetic bases are currently being investigated.
Photo: Paul Fetters
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Versión en español
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Avice Meehan
