2012
2013
Weill Cornell Medical College
Research Highlights
Weill Cornell Medical College
Research Highlights
2012
2013
On the Cover:
Glutamate transporters are
a major focus of study in the
laboratory of Dr. Olga Boudker.
In the central nervous system,
glutamate transporters are
responsible for the uptake of the
neurotransmitter glutamate
following rounds of synaptic
signaling. Dysfunction of these
transporters is implicated in
numerous disorders such as
neurodegenerative diseases,
stroke, traumatic brain injury,
epilepsy, and schizophrenia.
Message from the Dean
1
Major Grants
3
Centers and Institutes
4
Research and Training Collaborations
9
Research Profiles
13
Core Facilities
72
Research Environment
74
Faculty Honors and Distinctions
76
Research Faculty
77
Leadership
Senior Administration
Department Chairs
Board of Overseers
84
Message from the dean
Well into my first year as Dean, I continue to discover the greatness
that is Weill Cornell Medical College. The scientific endeavors of our
faculty span an amazing range of disciplines across the research
continuum. Their work is further advanced through innovative
collaborations and groundbreaking partnerships with institutions of
note – from The Rockefeller University and Memorial Sloan-Kettering
Cancer Center in our own neighborhood to Cornell University in Ithaca,
The Methodist Hospital Research Institute in Texas, and as far away as
our sister institution in Qatar, to name just a few.
In this report, we are pleased to highlight the work of nearly 60
outstanding, highly funded physicians and scientists, and their
research laboratories, who are making exceptional contributions
to science and medicine at every level. Some of these individuals
are working at the molecular biological level, while others carry on
investigations in experimental pre-clinical models and others through
human clinical trials. The ultimate goal, of course, is to provide novel
therapeutics and better ways to fight human disease. Critical to
continuing to develop these new treatments is the ability of our
clinicians, translational researchers, and basic scientists to meld ideas
and share discoveries. This interdisciplinary model is the future of
biomedicine.
Healthcare in this country is facing a watershed moment, and the
challenges posed will require bold new ideas and a commitment to
excellence. At Weill Cornell, a solid foundation is in place to further the
institution as a world-class research enterprise. In 2014, we will open
the Belfer Research Building that will usher in a new era in biomedical
research. The building will double the Medical College’s available
research space and is allowing us to actively recruit some several
dozen top-tier, well-funded junior and senior physicians, physicianscientists, and PhD scientists who will become the next generation
of clinical and research leaders. This effort has commenced with the
recent appointment of Dr. Lewis Cantley, one of the world’s most
preeminent scientists in translational research, who will direct our
newly established Cancer Center.
Today, we have a unique opportunity available to very few American
medical colleges: to bend the curve in clinical care, graduate education,
and biomedical research. I am delighted to be here at this pivotal
juncture in the history of Weill Cornell Medical College.
Laurie H. Glimcher, MD
Stephen and Suzanne Weiss Dean
Weill Cornell Medical College
Provost for Medical Affairs
Cornell University
2012-2013 Research highlights
1
2012-2013 Research Highlights
Major Grants
This is an unprecedented time in biomedical research. From initiating breakthroughs in stem cell research to
pioneering therapeutic applications of genomic and proteomic sciences to cultivating cutting-edge technology that
is changing the way discoveries are made and analyzed, Weill Cornell Medical College is playing a considerable role
in guiding the future of medicine.
In 2012, the Medical College received $49.6 million from the National Center for Advancing Translational Sciences of
the National Institutes of Health to fund its Clinical and Translational Science Center. This Clinical and Translational
Science Award is a five-year renewal of the largest Federal grant ever awarded to the Medical College by the NIH.
As the Medical College enters the final phase of its $1.3 billion Discoveries that Make a Difference campaign, its Research
Leads to Cures initiative is focused on recruitment of distinguished scientists in a number of important fields of study.
These individuals will join an impressive faculty whose efforts are currently supported by a research budget of more than
$200 million, including an impressive roster of National Institutes of Health R01 grants and MERIT Awards. Some of
the major grants received by Medical College scientists include over 250 R01 grants in awards of up to $5.4 million and
10 MERIT Awards in amounts up to $3.2 million. Following are a sampling of grants active in 2011-2012 (FY12).
R01 Grants
• Epigenome Interactions in Complex
Neurogenetic Disorders: $5.4 million
(Transformative R01)
• Biology of Lipoamide Dehydrogenase
and 2-Hydroxy-3-Oxoadipate Synthase
in Mtb: $4.4 million
MERIT Awards
• Receptor-Mediated Endocytosis –
Mechanism and Function: $3.2 million
• Cell-Cell Interactions in Thrombosis:
$2.5 million
• Biomolecular Markers for Safe
Minimization of Immunosuppression:
$2.1 million
• Overlapping Airway Basal Cell
Transcriptome Reprogramming in COPD
and Lung Cancer: $4.2 million
• Sphingolipid Modulators of Vascular
Growth and Homeostasis: $2.1 million
• Gene Therapy for Batten Disease:
$3.7 million
• Neutralization of Primary HIV-1 Viruses:
$2.1 million
• A Collaborative System Approach to
Diffusion of Evidence-Based Prevention:
$3.7 million
• Diabetic Vasculopathy and Mitochondrial
eNOS: $2.1 million
• Molecular Basis of Protein Transport in
Photoreceptor: $3.2 million
Other Major Grants
The National Institute of Neurological
Disorders and Stroke awarded a
$6.7 million grant to the Department of
Neurology and Neuroscience to study
proliferation, specification, and brain
function, and a $4.9 million grant to
the Department of Genetic Medicine to
study gene therapy for metachromatic
leukodystrophy. In addition, a $5.3
million grant was received by the
• Central Thalamic Deep Brain
Stimulation: $3.2 million
• Hepcidin Therapy for Iron Overload and
Hematologic Disorders: $3.2 million
• Drug Targets in Mtb Gluconeogenesis:
$3.1 million
• Biotin Synthesis and Biotin Ligation in
Mtb: $3.1 million
Department of Genetic Medicine from
the National Heart, Lung, and Blood
Institute to study COPD metabolome,
smoking oxidants, and aberrant ciliated
cell function, and the National Institute
of Child Health & Human Development
awarded a $5.8 million grant to
the Department of Neurology and
Neuroscience to investigate risk genes
and environmental interactions in neural
tube defects.
American Recovery and
Reinvestment Act
Since the American Recovery and
Reinvestment Act – also known as
the economic stimulus package – was
enacted in February 2009, Weill Cornell
Medical College has received $48 million
to fund 112 projects. Stimulus funding
is supporting work in AIDS, kidney
disease, cancer, Parkinson’s disease, with
the single largest grant – $3.8 million
from the National Institute on Drug
Abuse – funding the development of an
adenovirus-based anti-cocaine vaccine.
2012-2013 Research highlights
3
CENTERS AND INSTITUTES
Major research is taking place throughout the biomedical community at Weill Cornell
Medical College. Through the establishment of specialized centers and institutes,
and collaborations among some of the world’s foremost and prolific scientists, great
strides are being made in areas as diverse as bench-to-bedside research; psychological,
sociological, and societal based studies; and innovations in computational biomedicine
and healthcare informatics. Following are some of the many programs that
demonstrate the influential work that is underway at Weill Cornell.
Cancer Center
Lewis C. Cantley, PhD
Director
Cancer cells engage in a metabolic program to
enhance biosynthesis and support cell proliferation.
The regulatory properties of pyruvate kinase M2
(PKM2) influence altered glucose metabolism
in cancer. The interaction of PKM2 with
phosphotyrosine-containing proteins inhibits
enzyme activity and increases the availability of
glycolytic metabolites to support cell proliferation.
This suggests that high pyruvate kinase activity
may suppress tumor growth. Shown here is the
activator-bound structure of human pyruvate kinase.
(Courtesy of Dr. Lewis Cantley)
The newly established Cancer Center at Weill Cornell Medical College and
NewYork-Presbyterian Hospital marks a critical step in the transformation
and acceleration of personalized translational medicine, research, and clinical
care for cancer patients. The Center’s mission is to ensure that patients can
have immediate access to emerging new therapies in a supportive and caring
environment, while training future researchers and recruiting leaders in cancer
research and clinical care.
The Cancer Center, which will be headquartered in the new Belfer Research Building,
will provide research space, resources, and access to the latest state-of-the-art
technologies for basic, clinical, and translational cancer research, as well as support
for initiating and conducting novel clinical trials. A centralized cancer tumor tissue
bank and patient database and system will enable the rapid evaluation of each
patient’s cancer tumor for its genetic profile, associated gene expression, and
mutations to accelerate the development of a personalized treatment plan or
enrollment in clinical trials based on the individual’s genetic information.
As a collaborative, multidisciplinary research enterprise, the Cancer Center will
organize Weill Cornell’s current efforts under a centralized structure, across faculty
and departments. This will enable basic, translational, and clinical researchers to
collaborate and efficiently convert conceptual breakthroughs into novel therapies
and bridge the work of scientists and clinicians in the design and execution
of investigator-initiated clinical trials. The Cancer Center will initially focus on
colorectal, lung, melanoma, and hematopoietic cancers and expand to all cancers
where there is a risk that standard of care will not lead to a cure, such as breast,
prostate, pancreatic, endometrial, and ovarian cancers, and glioblastoma.
The Cancer Center's researchers will conduct more detailed exploration of the
molecular abnormalities in cancer cells and tumors to gain new insight into the
underlying mechanisms of drug resistance or acquired resistance to therapies and
test novel drug combination therapies to combat resistance. Also, identifying new
biomarkers for resistance will help researchers more effectively triage patients into
the specific therapies that will benefit them the most.
Brain and Mind Research Institute
Costantino Iadecola, MD
Director
In 2012, Weill Cornell Medical College and NewYork-Presbyterian Hospital came
together to create the Brain and Mind Research Institute – a major initiative that
will serve as the hub for neuroscience research and for training the next generation
of basic, translational, and clinical scientists. With faculty from neuroscience,
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WEILL CORNELL MEDICAL COLLEGE
CENTERS AND INSTITUTES
neurology, psychiatry, psychobiology, neurosurgery, and radiology, the Institute
will integrate expertise from multiple specialties to focus on:
• neurovascular conditions such as stroke, hypertension, and dementia
• neurodegenerative conditions such as Alzheimer’s, Parkinson’s, ALS, and aging
• neuroplasticity development, including learning, memory, brain malformations,
pain, and addiction
• neuroimmunological conditions, such as multiple sclerosis
• mind and consciousness, including neurophysiology, coma, vegetative state, and
minimally conscious state
The Institute provides a focal point for clinical and research faculty across the
Medical College and the Hospital to pursue their areas of interest and expertise in
neuroscience and related fields under one umbrella and facilitate the translation
of discoveries into novel therapeutics for brain diseases. Neuroimaging modalities,
including cell imaging, optogenetics, and functional brain imaging, will be used
to identify biomarkers and advance novel diagnostics. The Institute builds on the
groundbreaking interdisciplinary work of Weill Cornell faculty who conducted the
first clinical trial of gene therapy for Parkinson’s disease and performed the world’s
first successful use of deep brain stimulation to treat a minimally conscious braininjured patient.
Clinical and Translational Science Center
Julianne Imperato-McGinley, MD
Director
This complex of three proteins, called retromer, is
one of the traffic directors inside all mammalian
cells, including neurons. The drug in the center of
the picture was designed in the Petsko/Ringe lab by
graduate student Vincent Mecozzi to redirect traffic
away from those places in the cell where toxic forms
of Abeta are produced in Alzheimer's disease. In tests
in neuronal cell culture it is able to reduce Abeta levels
by up to 70 percent. (Courtesy of Dr. Gregory Petsko)
In 2007, the National Institutes of Health awarded $49 million to Weill Cornell
Medical College to establish the Clinical and Translational Science Center (CTSC) –
one of 60 translational centers nationwide that brings together researchers and
clinicians to advance community health. The multi-institutional consortium –
Memorial Sloan-Kettering Cancer Center, Hospital for Special Surgery, Cornell
University Cooperative Extension in New York City, Hunter College School of
Nursing, Hunter College Center for the Study of Gene Structure and Function,
NewYork-Presbyterian Hospital/Weill Cornell Medical Center, and Weill Cornell
Graduate School of Medical Sciences – is yielding new patient treatments, educating
translational research scientists, and enhancing healthcare for the underserved.
Since its inception, the CTSC has supported over 140 pilot, planning, community
engagement, and novel research and methodology projects in departments
throughout the partner institutions. Projects include human and animal
studies; basic, translational, and clinical research; community-based outcomes
studies and registries; and novel uses for devices and technologies. The CTSC
continues to serve as a source for essential resources, technological tools, and
education programs, helping to accelerate the clinical application of basic
science discoveries and creating an ideal multicenter clinical trials network. By
providing an environment that allows optimal use of the Center’s considerable
multi-institutional assets and diverse patient populations, research transitions
seamlessly from bench to bedside to the community.
In 2012, the CTSC received renewed funding for an additional five years of the
NIH’s Clinical and Translational Science Awards program. During the next funding
period, the CTSC will build on the varied accomplishments achieved during the
initial funding period, focusing on advancing translational science discoveries.
2012-2013 Research highlights
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CENTERS AND INSTITUTES
The renewed funding will also expand and enrich programs in drug discovery,
education, and mentoring; increase research resources; and enhance healthcare
to underserved communities of New York City.
Institute for Computational Biomedicine
Harel Weinstein, MSc, DSc
Director
The Weill Cornell visualization facility in the ICB uses
the highest resolution blended images possible,
projected on three walls and a walk-on floor. An
interactive tracking device, worn by the primary
user, coupled with a hand-held electronic wand to
manipulate the images, allows multiple researchers
to “move around” simultaneously within a threedimensional data set or structure.
The detailed understanding of complex interactions among genes and between
proteins and other cell components that underlie normal and pathophysiological
states of cells, tissues, and organs remains a significant challenge in biomedical
sciences. The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for
Computational Biomedicine (ICB) is an academic and research unit presenting
a novel approach to biomedicine that addresses that challenge. Its special
perspective is mathematical modeling, large-scale computational simulation, and
information management of genomes, proteomes, and complex physiological
systems. The computational models of biological systems are created, using
computer and informatics technology, from the analysis of the large amounts
of data that are now available to scientists. The evolution of each biological
system can thus be evaluated in space and time using simulation with powerful
computational approaches. The results are tested in newly designed experiments
based on the hypotheses generated from the computational models, and these
are iteratively probed and refined in the lab.
Created less than a decade ago, the ICB enables physician-scientists to attack
complex medical problems formerly beyond their reach by integrating genomic
and cellular data with the larger issues of biomedicine. Scientists can pursue
fundamental study and practical use of the basic, quantitative understanding of
physiological function and disease in an integrative, multi-scale approach. The
ICB has established the computational means for using the abundant genomic
information to guide decisions for medical care and preventive medicine, placing
it among the leaders in uncovering new capabilities of genomic tools, especially
their ability to identify individual genetic variations that can guide medical care.
The ICB is home to the world’s highest-definition 3D virtual reality environment.
Here, images of tissues and biological objects such as chromosomes and ion channels
can be “entered” and explored, turned, expanded, and viewed layer by layer, bringing
the scientists to the molecular and cellular level with exquisite clarity and precision.
Ansary Stem Cell Institute
Shahin Rafii, MD
Director
The Ansary Stem Cell Institute was established in 2004 with a $15 million grant
from Shahla and Hushang Ansary. The Institute’s scientists are leaders in stem cell
and developmental biology research. Their goal is to be able to use a patient’s own
stem cells as treatment in a number of areas such as brain recovery following stroke,
wound healing in diabetics, and heart muscle regeneration after a heart attack.
In the seven years since its creation, the Ansary Institute has realized significant
breakthroughs, including the discovery that endothelial cells have the potential to
grow large amounts of adult stem cells, potentially offering therapeutic applications
for organ regeneration and cancer cell inhibition. In addition, the Institute’s scientists
have shown how endothelial cells influence the self-renewal of certain stem cells and
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WEILL CORNELL MEDICAL COLLEGE
CENTERS AND INSTITUTES
have an “instructive role” in blood, liver, and lung regeneration. In the past year, the
Ansary Stem Cell Institute has made progress on several projects.
Generation of lineage-specific tissues from hESC and iPSC. The group has
demonstrated, for the first time, the potential for hESC-derived endothelium to
generate hematopoietic derivatives.
Repository for varied adult stem cells for scientific and therapeutic applications.
Ansary Stem Cell Institute scientists have established methods for providing
unlimited sources of human embryonic, fetal, amniotic, and organ-specific adult
stem cells to Tri-SCI researchers. Specifically, they have the capacity to generate
GMP-grade validated stem cells and feeder support cells for scientists who
envision translation of their studies to pre-clinical and clinical settings.
Novel platform to generate tissue specific cell types via reprogramming of
amniotic cells. The Institute’s scientists have developed a novel approach for
generating virtually unlimited quantities of engraftable, functional endothelium
from amniotic cells that can be generated for a vast diversity of genotypes.
Combining this with the increased potential for amniotic cells to generate
endothelium and perhaps other lineage-specific specialized cell types, amniotic
cells may provide an “off the shelf” resource for cell-based therapies.
Center for Vascular Biology
Timothy Hla, PhD
Director
The Center for Vascular Biology, founded in 1995, is dedicated to biomedical
research into vascular biology and disease. The vascular system permeates all
organ systems; indeed, vascular health is essential for overall well-being of the
organism. Physicians have come to realize that abnormal changes in the vascular
system contribute critically to many serious diseases, including cancer, heart
disease, stroke, and diabetes. Vascular biologists at Weill Cornell have been
at the forefront of several aspects of vascular research, including the cell and
molecular biology of endothelial cells, angiogenesis (also known as new blood
vessel formation), and lipid mediators in vascular disease. The Center is also an
intellectual home for scientists interested in vascular biology and disease from
Weill Cornell and neighboring institutions. Cutting-edge research in the areas of
regenerative biology, inflammatory vascular diseases, tumor microenvironment,
lipid mediators, vascular cell biology, developmental biology and signaling,
metabolomics, and hypertension are conducted. In addition to novel research
discoveries that are making an impact on our knowledge base as well as on
therapeutic approaches, the vascular biology community provides a superb
training environment in basic and translational research endeavors.
Brain imaging shows an imbalance between
prefrontal cortical control regions (top image) and
subcortical emotional regions (bottom image) in
individuals with the brain-derived neurotrophin
factor (BDNF) genotype. BDNF is a focus of several
projects in the Sackler Institute for Developmental
Psychobiology, including one looking at the impact
of BDNF genotype and early life stress on learning in
adolescents. (Courtesy of Dr. B.J. Casey)
Sackler Institute for Developmental Psychobiology
B.J. Casey, PhD
Director
The Sackler Institute for Developmental Psychobiology – established more than
two decades ago – focuses on human behavioral and brain development. It has
garnered an international reputation for research and training using the techniques
of brain imaging, human genetics, and behavioral methods in the domains of
perceptual, cognitive, and emotional development. In addition, the Sackler Institute
is rapidly establishing a high profile in genomic research, translating transgenic
2012-2013 Research highlights
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CENTERS AND INSTITUTES
mouse models to human behavior and disease. The Institute is using this approach
to delineate the biological mechanisms underlying mental health and illness and to
optimize both the type and timing of treatments and interventions for individuals
with mental illness. Studies currently underway focus on risk factors related to
anxiety, depression, and addiction and are moving the field toward preventive and
personalized medicine for these disorders.
Comprehensive Center of Excellence in
Disparities Research and Community Engagement
Carla Boutin-Foster, MD
Director
Cardiovascular and cancer diseases are among the most prevalent healthcare
challenges confronting the nation’s racial and ethnic minorities. Reducing the
profound disparity in health status of these and other populations with limited
resources and access to healthcare is the focus of the Comprehensive Center for
Excellence in Health Disparities Research and Community Engagement (CEDREC)
established in 2010. Created through an $8 million grant from the National Center
on Minority Health and Health Disparities, a division of the National Institutes of
Health, the Center is a consortium comprised of the Medical College, Hunter College
School of Nursing, City University of New York, Lincoln Medical and Mental Health
Center, and the Center for Healthful Behavior Change at New York University
Langone Medical Center. CEDREC is conducting two randomized trials to improve
blood pressure control and colon cancer screening, thereby improving health. With
the understanding that nobody knows the problems in a community better than
the people who live and work there, CEDREC developed a community engagement
and outreach core to provide the infrastructure for improving the health of the
community through sustained and expanded community partnerships.
Center for Healthcare Informatics and Policy
Rainu Kaushal, MD, PhD
Executive Director
The new Center for Healthcare Informatics and Policy (CHiP) provides an exciting
platform that will take technology and its role in the healthcare arena to a
transformative level. Bringing together faculty with expertise that crosses multiple
fields – informatics, clinical medicine, health services research, biostatistics, public
health, healthcare policy, healthcare analytics, computer science, economics, and
decision science – CHiP will foster the growth and effective use of technology,
buttressing the healthcare industry for decades to come.
The Center’s experts will develop and evaluate innovations that improve healthcare,
such as mobile devices, novel graphical interfaces, and natural language processing.
Collaborative research through CHiP is focusing on a number of areas, including
the effectiveness, cost-effectiveness, and comparative effectiveness of a variety
of healthcare interventions. Researchers will measure the effects of health
information technology on such outcomes as clinical quality and safety, economic
value, technology adoption, consumer satisfaction, and provider experiences.
In addition, CHiP offers a two-year Fellowship in Healthcare Quality and Medical
Informatics emphasizing research methods and a five-month, executiveformat Health IT Certificate Program emphasizing pragmatic training to address
the technical, legal, social, financial, and clinical environment surrounding
implementation of electronic health records systems.
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WEILL CORNELL MEDICAL COLLEGE
Research and Training Collaborations
Collaborations among Weill Cornell Medical College faculty and their colleagues at
other major institutions continue to provide extraordinary training for the physicians
and scientists of tomorrow and unique opportunities for advancing medicine across
the basic, translational, and clinical research arenas.
Tri-Institutional MD-PhD Program
Weill Cornell Medical College, The Rockefeller University, and the Sloan-Kettering
Institute comprise an inter-institutional collaboration for joint MD/PhD training.
These biomedical research and educational institutions, which are geographically
adjacent to each other in New York City, are home to more than 35 members of
the National Academy of Sciences. The program awards an MD degree from Weill
Cornell Medical College and a PhD degree from either Weill Cornell Graduate
School of Medical Sciences (formed by Weill Cornell Medical College and the SloanKettering Institute), Gerstner Sloan-Kettering Graduate School, or The Rockefeller
University. Now in its 40th year, the Tri-Institutional MD-PhD Program continues
to draw on the unique resources available in the three institutions with a goal to
educate tomorrow’s biomedical investigators. Each year over 500 students apply
for an average of 14 positions per year, which are fully funded by the National
Institutes of Health Medical Scientist Training Program. Students receive an
advanced understanding of biomedical science and master state-of-the-art research
skills in basic biological processes pertaining to human health and disease, working
and training side-by-side with renowned investigators from around the world.
Approximately 80 percent of graduates of the
Tri-Institutional MD-PhD Program who have completed
their residency and fellowship training are in full-time
faculty positions in basic science and clinical departments. Shown here is the graduating class of 2012
with (far right) Dr. Olaf S. Andersen, Program Director.
Tri-Institutional Stem Cell Initiative
The Tri-Institutional Stem Cell Initiative (Tri-SCI) is a major collaborative endeavor
made possible by an initial $50 million gift in 2005 from The Starr Foundation,
followed by a new $50 million gift awarded in 2012 to continue the work of this
multi-campus program. Together, Weill Cornell Medical College, Memorial SloanKettering Cancer Center, and The Rockefeller University are providing resources to
support a broad portfolio of stem cell research, including funds for projects using
both registered and non-registered human embryonic stem (hES) cell lines, and for
work with human pluripotent stem (hPS) cells. As part of this initiative, support
is also provided for three state-of-the-art core facilities to derive, maintain, and
characterize human embryonic stem cells for the tri-institutional investigators. This
includes the development of cell lines that model genetic diseases.
Recognizing the need to train the next generation of stem cell scientists, the TriSCI continues to sponsor the Tri-Institutional Starr Stem Cell Scholars Fellowship
program and also provides support for lectures and seminars in the field that are
of interest both to the scientific community and to the public.
Studies currently underway in laboratories on each of the three member
campuses are generating new insights into basic stem cell biology and exploring
the translational potential of stem cells in human disease, with a major focus
on cancer, neurosciences, cardiovascular and angiogenesis, ophthalmology, and
regenerative medicine and cell therapy. With more than 60 scientists involved in
the Tri-SCI, breakthroughs have already begun to be realized.
2012-2013 Research highlights
9
Research and Training Collaborations
Center on the Microenvironment and Metastasis
With funding of $13 million over five years from the National Cancer Institute,
the Center on the Microenvironment and Metastasis at Cornell University (CMM),
in partnership with Weill Cornell Medical College and the University at Buffalo,
focuses on using nanobiotechnology and other related physical science approaches
to advance research on cancer. The Center, one of 12 such Physical Sciences
Oncology Centers across the country, deciphers the complexities of cancer
using the insights and methods of physical sciences and engineering to further
understand how cancer travels through the human body and how it acquires
resistance to commonly used chemotherapy. Research advances are leading to new
drug strategies to inhibit metastasis and tumor growth.
Close-up of primary tumor cell cultures
(Courtesy of Dr. Steven Lipkin)
The CMM brings together a multidisciplinary team of 27 faculty and over 70
researchers from engineering, physics, biomedical sciences, and medicine in
the pursuit of experimental and theoretical approaches to the major questions
and barriers in the treatment of cancer. The CMM’s innovative in vitro and
in vivo approaches and techniques promote our understanding of the tumor
environment, yielding new pathways with which to intervene in the progression
of cancer.
During the past year there were over 52 collaborations with the Center, with 30
researchers from 30 research centers. There has also been an increasing impact
of the Center’s research through publications and presentations, with 19 peerreviewed papers published, 15 manuscripts at press, accepted or submitted, and
30 papers presented at conferences.
Translational Research Institute on Pain in Later Life
Created in response to the millions of older adults experiencing persistent pain,
the Translational Research Institute for Pain in Later Life (TRIPLL) seeks effective
solutions to the problem of later-life pain, moving basic behavioral and social science
and medical research findings more rapidly into programs, practices, and policies
targeting older adults. A National Institute of Aging-funded Edward R. Roybal Center,
TRIPLL is a collaboration among investigators at Weill Cornell Medical College, Cornell
University College of Human Ecology, Columbia University’s Mailman School of Public
Health, Hospital for Special Surgery, Visiting Nurse Service of New York, and the
Council of Senior Centers and Services of New York City, Inc. TRIPLL focuses on:
1) building evidence-based pain prevention and reduction, and management practices,
treatments, and interventions; 2) developing and translating research-based
methods, tools, and strategies that facilitate successful translation of evidence
into practice; and 3) developing and maintaining an effective infrastructure for
conducting translational research on aging and pain in New York City.
Cornell Center for Behavior Intervention Development
With a $6 million grant from the National Heart, Lung, and Blood Institute, the
Cornell Center for Behavior Intervention Development seeks to reduce obesity
and obesity-related deaths in New York City’s African-American and Latino
communities. The program is a joint endeavor of Weill Cornell Medical College,
Cornell University, Lincoln Hospital in the Bronx, and Renaissance Health Systems
in Manhattan in partnership with faith-based and community organizations. One
of the Center’s studies, SCALE: Small Changes and Lasting Effects, takes an
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WEILL CORNELL MEDICAL COLLEGE
Research and Training Collaborations
interdisciplinary approach to lifestyle changes. Drawing on the expertise of
psychologists, medical sociologists, nutritionists, and other experts working
directly with community members in Harlem and the South Bronx, the initiative
incorporates individually tailored programs that are more likely to be successful
for participants. The study team is developing strategies aimed at reducing
weight through small, sustained changes in eating behavior, coupled with
sustained increases in physical activity.
Cornell IMAGINE:
Ithaca-Manhattan Graduate Initiative in Neuroscience
This joint graduate training initiative combines the strengths of the psychology
and cognitive science programs at Cornell University with the expertise of
the neuroscience program at Weill Cornell Medical College. Cornell IMAGINE,
based at Cornell University, specializes in basic analysis of perception, cognition,
communication, and decision making, grounded in developmental and
evolutionary perspectives, with a strong computational emphasis. The training
facility is integrated by its focus on development, learning, and trajectories
of behavioral change. The faculty are segmented into three interest clusters
spanning both campuses. These include memory, attention and learning systems;
communication systems focusing on language and emotional communication;
and sensory and perceptual systems.
Kawthar Al-Dabhani and Nawaf Al-Taweel, the first
graduates of WCMC-Q’s Biomedical Research Training
Program for Qatari Nationals, intend to pursue careers
in the field.
Weill Cornell Medical College in Qatar
Weill Cornell Medical College in Qatar (WCMC-Q) is a prominent example of a
national investment in biomedical research and education, creating world-class
facilities and research infrastructure. In accordance with the research priorities of
Qatar and the Qatar Foundation, the WCMC-Q research program is well on its way
to achieve three major objectives: 1) develop biomedical research capacity for the
country; 2) develop sustainable human capacity; and 3) address pressing health
needs in Qatar.
In the span of three years, the biomedical research program has grown to 28
active research labs that target multiple areas of biomedical research, providing
significant breadth to tackle complex diseases such as diabetes. The idea is that
complex multifactorial diseases will be dealt with in a multi-pronged approach at
the molecular, cellular, biochemical, organismal, translational, and clinical levels.
WCMC-Q researchers together with their research partners in Qatar, such as the
clinicians at Hamad Medical Corporation (Qatar’s national health provider), have
the expertise and the resources to make this happen.
The program’s success to date is evident in the faculty’s ability to garner
significant extramural funding (totaling $50 million since the start of the
program) and publish extensively in peer-reviewed journals (totaling 55 articles
in 2010-11), several in high-impact journals such as PNAS, Nature Biotechnology,
Journal of Cell Biology, American Journal of Human Genetics, and the Journal of
Biological Chemistry. WCMC-Q faculty are also building a pipeline of patents
with the goal of commercializing them in the future – ideally through Qatar
Science & Technology Park – thus closing the research innovation circle and truly
contributing toward building Qatar’s knowledge-based economy.
(continued on page 12)
2012-2013 Research highlights
11
Research and Training Collaborations
(continued from page 11)
The research effort at WCMC-Q remains in its early stages of development.
However, a combination of factors has resulted in a productive research
environment. At the national level, Qatar has invested significantly in research.
This, coupled to well-equipped core labs at WCMC-Q and the unwavering
commitment of its scientists to high quality research, is already producing
internationally noted research and more is set to follow. Having established a
strong administrative infrastructure and state-of-the-art core labs, WCMC-Q is
now in a position to make an impact at the national and regional levels in the
biomedical arena.
The Methodist Hospital Research Institute
The Methodist Hospital Research Institute in
Houston, Texas
Weill Cornell Medical College is affiliated with The Methodist Hospital Research
Institute in Houston, Texas, actively collaborating on interdisciplinary research
projects and training of the next generation of translational scientists. Laurie H.
Glimcher, MD, the Stephen and Suzanne Weiss Dean of Weill Cornell Medical
College, joined the Research Institute Board of Directors in 2012. The affiliation is
also supported by former Weill Cornell Medical College Dean Antonio M. Gotto, Jr.,
MD, DPhil, serving as the head of the Research Institute Council of Deans, and
Harold G. Craighead, PhD, of Cornell University serving as the Research Institute
Dean of Physics.
The two institutions support joint collaboration of their researchers with
reciprocity agreements for shared core technology facilities on the iLab
platform, collaborative seed grant programs, and joint Institutional Review
Board procedures to streamline clinical trials approvals. The Methodist Hospital
Research Institute and Weill Cornell Medical College are also working together
to create a de-identified clinical data repository as part of the National Center for
Biomedical Computing i2B2 project to share data resources from The Methodist
Hospital with the multi-institutional consortium of the Weill Cornell Medical
College Clinical and Translational Science Center.
With this administrative and joint infrastructure support, The Methodist Hospital
Research Institute and Weill Cornell Medical College joint research programs and
centers are rapidly expanding, including:
• Development
of a joint National Cancer Institute (NCI) designated
comprehensive cancer center
•N
etworked NCI Physical Sciences in Oncology Centers, dedicated to
understanding the physical principles of cancer development
• J oint program project grant applications
• J oint research projects:
– Strategies to eliminate leukemia stem cells during remission, supported by
the Leukemia & Lymphoma Society
– Nanoparticle-mediated targeting of molecules for breast cancer treatment,
supported by the New York State Department of Health
– D
evelopment of live imaging techniques, miRNA-based therapeutics, and
tumor-stroma cross-talk in primary and metastatic breast cancer, supported
by the National Cancer Institute
12
WEILL CORNELL MEDICAL COLLEGE
Research
Research
Highlights
Profiles
Scott C. Blanchard, PhD
John A. Boockvar, MD
Olga Boudker, PhD Carla Boutin-Foster, MD
Martha L. Bruce, PhD, MPH
Lewis C. Cantley, PhD
B.J. Casey, PhD
Mary E. Charlson, MD
Selina Chen-Kiang, PhD
David J. Christini, PhD
Ronald G. Crystal, MD
Anna Di Gregorio, PhD
Sabine Ehrt, PhD
Todd R. Evans, PhD
Joseph J. Fins, MD, MACP
Daniel W. Fitzgerald, MD
Paraskevi Giannakakou, PhD
Laurie H. Glimcher, MD
Lorraine J. Gudas, PhD
David P. Hajjar, PhD
Katherine A. Hajjar, MD
Hugh C. Hemmings, Jr., MD, PhD
Barbara L. Hempstead, MD, PhD
Timothy Hla, PhD
Xin-Yun Huang, PhD
Costantino Iadecola, MD
Samie R. Jaffrey, MD, PhD
Rainu Kaushal, MD, MPH
Francis S. Lee, MD, PhD
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John P. Leonard, MD
Steven M. Lipkin, MD, PhD
David C. Lyden, PhD, MD
Khaled Machaca, PhD
Frederick R. Maxfield, PhD
Ari M. Melnick, MD
Anant K. Menon, PhD
Teresa A. Milner, PhD
John P. Moore, PhD
Anne Moscona, MD
Carl Nathan, MD
Steven M. Paul, MD
Gregory A. Petsko, DPhil
Shahin Rafii, MD
M. Cary Reid, MD, PhD
Enrique J. Rodriguez-Boulan, MD
M. Elizabeth Ross, MD, PhD
Mark A. Rubin, MD
Timothy A. Ryan, PhD
Bruce R. Schackman, PhD
Nicholas D. Schiff, MD
Dirk Schnappinger, PhD
Heidi Stuhlmann, PhD
Tao Sun, PhD
Manikkam Suthanthiran, MB, BS
Jonathan D. Victor, MD, PhD
Yi Wang, PhD
Harel Weinstein, MSc, DSc
Pengbo Zhou, PhD
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2012-2013 Research highlights
13
Research PROFILES
Scott C. Blanchard, PhD
Associate Professor of Physiology and Biophysics
SELECTED Publications
Dunkle JA, Wang L, Feldman MB, Pulk A,
Chen VB, Kapral GJ, Noeske J, Richardson
JS, Blanchard SC, Cate JH. Structures of the
bacterial ribosome in classical and hybrid states
of tRNA binding. Science. 2011 May 20;
332(6032):981-84.
Zhao Y, Terry DS, Shi L, Quick M, Weinstein H,
Blanchard SC*, Javitch JA*. Substrate-modulated
gating dynamics in a sodium-coupled transporter.
Nature. 2011 Jun 2;474(7349):109-13.
(*co-corresponding authorship)
Altman RB, Terry DS, Zhou Z, Zheng Q, Geggier
P, Kolster RA, Zhao Y, Javitch JA, Warren JD,
Blanchard SC. Cyanine fluorophore derivatives
with enhanced photostability. Nature Methods.
2011 Nov 13;9(1):68-71.
Altman RB, Zheng Q, Zhou Z, Terry DS, Warren
JD, Blanchard SC. Enhanced cyanine-class
fluorophore photostability across the visible
spectrum. Nature Methods. 2012 April 27;9(5):
428-29.
Wang, L, Pulk A, Wasserman MR, Feldman MB,
Altman RB, Cate JHD, Blanchard SC. Allosteric
control of the ribosome by small-molecule
antibiotics. Nature Structural & Molecular
Biology. 2012 Aug 19. [Epub ahead of print.]
Dr. Scott Blanchard and his team focus on the molecular mechanisms governing
enzyme function and regulation for the purpose of developing therapeutic strategies
for the treatment of human infection and disease. The studies undertaken employ
an integrated battery of molecular, structural, biophysical, and chemical strategies,
including the development and advancement of single-molecule imaging methods
that yield unprecedented insight into the dynamic properties underlying the functions
of biological machines. Single-molecule imaging enables the observations from the
perspective of motion. Consequently, the dynamic properties of single molecules
can be tracked over time and in response to stimuli to quantitatively reveal the
structure-function relationship. Perhaps most critically, the single-molecule imaging
approaches under development can be applied to investigations of many biological
systems that have proven difficult or impossible to study using traditional methods.
The Blanchard lab has already developed the first single-molecule methods used to
explore the structural and mechanistic determinants of aminoacyl-tRNA selection
and substrate translocation on bacterial and mammalian ribosomes – reactions
critical to determining the rate and fidelity of protein synthesis. Dr. Blanchard's
group was also the first to successfully extend such lines of investigation to
integral membrane proteins involved in solute transport across lipid bilayers.
This includes proteins such as the Na+-coupled neurotransmitter transporters, a
family of proteins targeted by a broad array of mood-altering agents in humans.
Pioneering technological efforts in the lab have also shown that single-molecule
measurements can be used as a tool to streamline the determination of highresolution structures of macromolecular complexes. This has led to the atomic
resolution structures of functional configurations of the ribosome that have
provided unprecedented insight into mechanisms of antibiotic actions blocking
normal functions of the translation machinery.
To enable translational efforts centered on whole cells, the Blanchard lab has
pursued a battery of investigations aimed at understanding the photophysical
properties of the fluorescent compounds that are essential for whole-cell imaging.
Technological developments on this front have played a key role in the publication
of the first three-color, single-molecule fluorescence imaging studies of the bacterial
ribosome and the continued advancement of new imaging and site-specific
labeling modalities. By creating a new suite of organic fluorophores ("self-healing"
dyes) spanning the visible spectrum, the lab ultimately plans to empower the
examination of biological processes in vivo at the single-molecule scale using realtime super-resolution and multicolor fluorescence imaging.
Because it appears that physical and functional distinctions of the ribosome within
the cancerous cell can be specifically targeted by small-molecule therapies, a key goal
of the Blanchard lab is to address the misregulation of translation in the cancerous
state and to understand how ribosomopathies alter the cellular proteome. The lab’s
application of single-molecule imaging to dynamic processes of integral membrane
protein function also has the potential to shed critical new insights on signaling
processes at the membrane directly contributing to neurodegenerative disease.
Correspondingly, the lab also plans to use single-molecule imaging to improve the
search for new pharmacologic interventions that specifically regulate these critical
information transfer processes.
14
WEILL CORNELL MEDICAL COLLEGE
RESEARCH PROFILES
John A. Boockvar, MD
Associate Professor of Neurological Surgery
Dr. John Boockvar and his colleagues have focused on studies of brain tumor
formation and brain tumor and stem cell survival, with a particular interest in
improving how drugs are delivered to the brain and spinal cord. During the past
five years, they have pursued research into better therapies for glioblastoma
multiforme (GBM), a common primary brain tumor that has not responded well to
currently available medical and surgical therapies.
In 2009, Dr. Boockvar, who directs Weill Cornell’s Brain Tumor and Stem Cell
Research Laboratory and the Brain Tumor Research Group, and his neurological
surgery colleagues performed the world’s first intra-arterial cerebral infusion of
bevacizumab directly into a patient’s malignant brain tumor. The goal of the novel
intra-arterial (IA) technique was to expose the tumor to higher doses of the drug
therapy with less toxicity to the patient then administering the drug intravenously
(IV). Because the blood-brain barrier prevents many IV-administered drugs from
penetrating the blood vessel walls sufficiently, it is unclear if IV infusion enables
current drugs to enter the brain. Since these agents are less toxic and their delivery
leads to a higher tumor-drug concentration, this combination may provide a better
outcome in patients with high-grade glioma.
Dr. Boockvar is now the principal investigator of several clinical trials using super
selective intra-arterial infusion – a technique that can effectively increase the
concentration of drug delivered to the brain while sparing the body of systemic
side effects – for the delivery of novel therapeutics such as bevacizumab (Avastin®),
temozolomide (Temodar®), or cetuximab. These Phase I clinical trials are testing
the hypothesis that the drugs can be safely used by direct intracranial superselective intra-arterial infusion and ultimately enhance survival of patients with
relapsed/refractory GBM. The trials will enable the researchers to determine the
toxicity profiles and maximum tolerated doses and may alter the way the drugs are
delivered to patients in the near future.
A Phase I/II trial of erlotinib (Tarceva®) is also underway for the treatment of
relapsed/refractory GBM and anaplastic astrocytoma (AA). Erlotinib belongs to
a class of drugs called epidermal growth factor receptor (EGFR) tyrosine kinase
inhibitors and is approved for the treatment of non-small cell lung cancer. A
percentage of malignant brain tumors, such as GBM and AA, express EGFR and
therefore, by inhibiting this receptor, the researchers predict that they may be able
to slow or arrest the growth of the tumor. Previous studies performed elsewhere
indicate that erlotinib is safe to use in patients with brain tumors and may also
have anti-tumor effects. The specific objective of this trial is to determine the rate of
response and patient survival time to oral erlotinib in patients with and without the
EGFRvIII and PTEN brain tumor mutation and to assess quality of life and survival.
In the laboratory, Dr. Boockvar and his team are investigating the link between brain
tumor formation and adult human central nervous system stem cells. They seek to
understand the differential sensitivity of patients with glioma to targeted therapeutics
and whether tumor stem cells play a role in this response. By manipulating normal
and tumor-derived stem cell signaling, Dr. Boockvar studies neural stem cell migration
and invasion as this has relevance to glioma invasion and response to therapy.
SELECTED Publications
Riina HA, Fraser JF, Fralin S, Knopman J, Scheff
RJ, Boockvar JA. Superselective intra-arterial
cerebral infusion of bevacizumab: a revival of
interventional neuro-oncology for malignant
glioma. Journal of Experimental Therapeutics &
Oncology. 2009;8(2):145-50.
Boockvar JA, Tsiouris AJ, Hofstetter CP,
Kovanlikaya I, Fralin S, Kesavabhotla K, Seedial SM,
Pannullo SC, Schwartz TH, Stieg P, Zimmerman RD,
Knopman J, Scheff RJ, Christos P, Vallabhajosula
S, Riina HA. Safety and maximum tolerated dose
of superselective intraarterial cerebral infusion
of bevacizumab after osmotic blood-brain barrier
disruption for recurrent malignant glioma. Journal
of Neurosurgery. 2011 Mar;114(3):624-32.
Gürsel DB, Beyene RT, Hofstetter C, Greenfield
JP, Souweidane MM, Kaplitt M, Arango-Lievano
M, Howard B, Boockvar JA. Optimization of
glioblastoma multiforme stem cell isolation,
transfection, and transduction. Journal of
Neurooncology. 2011 Sep;104(2):509-22.
Burkhardt JK, Riina H, Shin BJ, Christos P,
Kesavabhotla K, Hofstetter CP, Tsiouris AJ,
Boockvar JA. Intra-arterial delivery of
bevacizumab after blood-brain barrier disruption
for the treatment of recurrent glioblastoma:
progression-free survival and overall survival.
World Neurosurgery. 2012 Jan;77(1):130-34.
Jeon JY, Kovanlikaya I, Boockvar JA, Mao X, Shin
B, Burkhardt JK, Kesavabhotla K, Christos P, Riina
H, Shungu DC, Tsiouris AJ. Metabolic response
of glioblastoma to superselective intra-arterial
cerebral infusion of bevacizumab: a proton
magnetic resonance spectroscopic imaging study.
American Journal of Neuroradiology. 2012 May 10.
[Epub ahead of print]
Hofstetter CP, Burkhardt JK, Shin BJ, Gürsel DB,
Mubita L, Gorrepati R, Brennan C, Holland EC,
Boockvar JA. Protein phosphatase 2A mediates
dormancy of glioblastoma multiforme-derived
tumor stem-like cells during hypoxia. PLoS One.
2012;7(1):e30059.
2012-2013 Research highlights
15
Research PROFILES
Olga Boudker, PhD
Associate Professor of Physiology and Biophysics
Living cells are surrounded by lipid membranes, which are fundamental to their
integrity. Membrane integrity is essential for compartmentalized life preventing an
uncontrolled diffusion of proteins, metabolites, signaling molecules, and ions. The
lipid bilayers of membranes represent formidable barriers for polar molecules, and
cells have evolved an array of specialized proteins, transporters, and channels to
assist their controlled trans-membrane passage.
SELECTED Publications
Yernool D, Boudker O, Jin Y, Gouaux E. Structure
of a glutamate transporter homologue from
Pyrococcus horikoshii. Nature. 2004 Oct 14;
431(7010):811-18.
Boudker O, Ryan RM, Yernool D, Shimamoto K,
Gouaux E. Coupling substrate and ion binding
to extracellular gate of a sodium-dependent
aspartate transporter. Nature. 2007 Jan 25;
445(7126):387-93.
Reyes N, Ginter C, Boudker O. Transport
mechanism of a bacterial homologue of
glutamate transporters. Nature. 2009 Dec 17;
462(7275):880-85.
Boudker O, Verdon G. Structural perspectives
on secondary active transporters. Trends in
Pharmacological Sciences. 2010 Sep;31(9):
418-26.
Verdon G, Boudker O. Crystal structure of an
asymmetric trimer of a bacterial glutamate
transporter homolog. Nature Structural &
Molecular Biology. 2012 Feb 12;19(3):355-57.
Dr. Olga Boudker and her lab are interested in understanding the structure
and mechanism of these proteins, focusing primarily on the gradients-driven
transporters. These transporters are miniature molecular machines that are
thought to undergo at least one critical conformational transition: from a state
in which they are open to one side of the membrane, to a state in which they are
open to the other side. During this transition, the substrate is sequestered from
the aqueous solution on one side and released on the other. The Boudker lab’s
central goal is to understand in structural detail the conformational states of the
transporters and their dynamic properties.
The Boudker lab’s central goal is to understand in structural
detail the conformational states of the transporters and their
dynamic properties.
In the central nervous system, glutamate transporters are responsible for the
uptake of the neurotransmitter glutamate following rounds of synaptic signaling.
Rapid clearance of the transmitter is essential not only to allow for repeated rounds
of neurotransmission, but also to prevent excessive stimulation of the glutamate
receptors, which leads to cytotoxicity and neuronal death. Dysfunction of these
transporters is implicated in numerous disorders such as neurodegenerative
diseases, stroke, traumatic brain injury, epilepsy, and schizophrenia. Located in
the plasma membranes of glial cells and neurons, the transporters couple uptake
of a glutamate to the co-transport of three sodium ions and a proton and to
the counter-transport of one potassium ion. The crystal structures of a bacterial
homologue from Pyrococcus horikoshii, determined by Dr. Boudker and colleagues,
revealed the transporter in a state in which the substrate-binding site is close
to the extracellular solution, and in a state in which it is close to the cytoplasm.
These structures showed that glutamate transporters function as miniature
elevators with a central rigid scaffold and three cabins, which are loaded with the
transported substrate and coupled ions and which traverse the thickness of the
membrane.
Dr. Boudker and her colleagues have recently reported another structure of the
transporter in which it was captured in an intermediate state. The intermediate
state shows a cavity in the thinnest region of the transporter that is potentially
accessible to extracellular and cytoplasmic solutions. This structure suggests a
structural principle by which transport intermediates may mediate permeation of
polar solutes other than the primary transporter substrates, such as chloride ions,
a well-known property of the mammalian transporters of potential importance in
modulating synaptic transmission.
16
WEILL CORNELL MEDICAL COLLEGE
Research profiles
Carla Boutin-Foster, MD
Associate Professor of Medicine
Associate Professor of Public Health
Dr. Carla Boutin-Foster is the Director and Principal Investigator of the
Comprehensive Center of Excellence in Disparities Research and Community
Engagement (CEDREC) at Weill Cornell. The mission of CEDREC is to improve
minority health and eliminate health disparities by conducting innovative,
cutting-edge transdisciplinary research; providing strong mentorship for junior
investigators; and fostering community-academic partnerships that build
community capacity for research. This year a new core was funded under CEDREC.
The Environmental Health Disparities Core lends an environmental justice
perspective to disparities research.
Dr. Boutin-Foster’s research focuses on addressing the psychosocial determinants
of health disparities in cardiovascular disease and includes studies that focus on the
association between cardiovascular disease and depressive symptoms, perceptions
of stress, and social support. The common theme is to understand and intervene
upon those factors that help to drive or motivate the adaptation and maintenance
of healthy behaviors. Among Dr. Boutin-Foster’s most recently NIH-funded grants
is TRIUMPH (Trial Using Motivational Interviewing and Positive Affect and Selfaffirmation in Hypertension). This randomized, controlled trial is designed to
improve blood pressure control in hypertensive black patients. Participants are
recruited from medically underserved communities in the South Bronx and Harlem
in New York City. The goal is to achieve improvements in medical adherence, reduce
the rates of uncontrolled hypertension in African-Americans, and ultimately reduce
the disproportionate rates of adverse hypertension-related events in African-Americans.
TRIUMPH applies three interrelated behavioral techniques to motivate health
behavior change: positive affect induction, self-affirmation induction, and motivational
interviewing. Trained research assistants deliver these techniques via telephone.
Positive affect is a state of pleasurable engagement with the environment and reflects
the extent to which a person feels enthusiastic, active, and alert. Positive affect may
exert its impact on behavior by increasing the expectation that a specified health
behavior change will result in a desirable outcome. Self-affirmation is a theory that
describes the motivation to preserve a positive image and self-integrity when one’s
self-identify is threatened. Self-affirmation can be induced through the active use
of positive statements or memories about one’s accomplishments or successes to
build self-confidence. This helps to build confidence in one’s ability to achieve a
desirable health outcome. Motivational interviewing is a directive, patient-centered,
counseling technique designed to motivate health behavior change. The goal is to
facilitate patients to recognize and resolve the discrepancy between their present
behavior and a desired future goal or outcome.
Dr. Boutin-Foster was recently appointed Assistant Dean for Faculty Diversity with
a goal to develop a cadre of talented research faculty from diverse backgrounds
who can contribute to biomedical research at Weill Cornell. She founded the annual
Tri-Institutional SPARC Conference (Achieving Successful and Productive Academic
Research Careers) in collaboration with The Rockefeller University and Memorial SloanKettering Cancer Center to provide a forum for junior faculty all over New York City to
enhance their knowledge of research, networking, and career development awards.
SELECTED Publications
Boutin-Foster C, Phillips E, Palermo AG, Boyer
A, Fortin P, Rashid T, Vlahov D, Mintz J, Love G.
The role of community-academic partnerships:
implications for medical education, research,
and patient care. Progress in Community Health
Partnerships: Research, Education, and Action.
2008 Spring;2(1):55-60.
Boutin-Foster C, Ravenell JE, Greenfield VW,
Medmim B, Ogedegbe G. Applying qualitative
methods in developing a culturally tailored
workbook for black patients with hypertension.
Patient Education and Counseling. 2009 Oct;
77(1):144-47.
Boutin-Foster C, McLaughlin N, Gray A,
Ogedegbe A, Hageman I, Knowlton C,
Rodriguez A, Beeder A. Reducing HIV and AIDS
through Prevention (RHAP): a theoretically
based approach for teaching HIV prevention to
adolescents through an exploration of popular
music. Journal of Urban Health. 2010 May;
87(3):440-51.
Miller SA, Mancuso CA, Boutin-Foster C,
Michelen W, McLean-Long C, Foote B, Charlson
ME. Associations between posttraumatic
stress disorder and hemoglobin A1(C) in
low-income minority patients with diabetes.
General Hospital Psychiatry. 2011 Mar-Apr;
33(2):116-22.
Patel M, Phillips-Caesar E, Boutin-Foster C.
Barriers to lifestyle behavioral change in
migrant South Asian populations. Journal of
Immigrant and Minority Health. 2011 Dec 17.
[Epub ahead of print]
Ogedegbe GO, Boutin-Foster C, Wells MT,
Allegrante JP, Isen AM, Jobe JB, Charlson ME. A
randomized controlled trial of positive-affect
intervention and medication adherence in
hypertensive African Americans. Archives of
Interal Medicine. 2012 Feb 27;172(4):322-26.
Aponte J, Boutin-Foster C, Alcantara R.
Knowledge, perceptions, and experiences
of Dominicans with diabetes. Journal of
Immigrant and Minority Health. 2012 May 5.
[Epub ahead of print]
2012-2013 Research highlights
17
Research PROFILES
Martha L. Bruce, PhD, MPH
Professor of Sociology in Psychiatry
Clinically significant depression affects a significant number of older adults.
Consistent with the complex interaction of biological and psychosocial factors that
contribute to depression, it is especially prevalent in older adults who are already
vulnerable due to disability, medical illnesses, social isolation, and poverty. But despite
evidence of effective pharmacological and psychosocial treatments, depression is
commonly undetected, untreated, or poorly treated in these older adults.
SELECTED Publications
Bruce ML, Brown E, Raue P, Mlodzianowski A,
Meyers B, Leon A, Heo M, Byers A, Greenberg R,
Rinder S, Katt W, Nassisi P. A randomized trial
of depression assessment intervention in home
healthcare. Journal of the American Geriatric
Society. 2007 Nov;55:1793-800.
Sheeran T, Byers AL, Bruce ML. Depression and
increased short-term hospitalization risk among
geriatric patients receiving home healthcare
services. Psychiatric Services. 2010 Jan;61:78-80.
Raue PJ, Morales KL, Post EP, Bogner HR, Ten
Have R, Bruce ML. The wish to die and five-year
mortality in elderly primary care patients.
American Journal of Geriatric Psychiatry. 2010
Apr;18(4):341-50.
Bao Y, Alexopoulos GS, Casalino LP, Ten Have TR,
Donohue JM, Post EP, Schackman BR, Bruce ML.
Collaborative depression care management and
disparities in depression treatment and outcomes.
Archives of General Psychiatry. 2011 Jun;68:627-36.
Bruce ML, Bartels SJ, Lyness JM, Sirey JA,
Sheline YI, Smith G. Promoting the transition
to independent scientist: a national career
development program. Academic Medicine. 2011
Sep;86(9):1179-84.
Bao Y, Shao H, Bishop TF, Schackman BR, Bruce ML.
Inappropriate medication in a national sample of
U.S. elderly patients receiving home healthcare.
Journal of General Internal Medicine. 2012
Mar;27(3):304-10.
Pickett YR, Weissman J, Bruce ML. Racial differences
in antidepressant use among older home
healthcare patients. Psychiatric Services. 2012
Aug;63.
18
WEILL CORNELL MEDICAL COLLEGE
The target of Dr. Martha Bruce’s research is this gap between research and “real
world” practice. She focuses specifically on depression in older adults, working in
partnership with primary care and other community-based settings, to develop
and implement workable strategies to improve depression care and outcomes.
Her interest in homebound older adults started with her analyses of epidemiologic
data demonstrating that being homebound was both a powerful risk factor
for depression, but also a significant barrier to receiving depression care in
traditional outpatient settings. The premise of the research that followed was that
organizations that provide other services to the homebound could also provide
mental health services.
The science of mental health services delivery spans much of the translational
research spectrum, beginning with epidemiology to describe the problem,
intervention development, effectiveness trials, and then implementation trials.
Dr. Bruce began by documenting that almost 15 percent of older patients of a typical
home healthcare agency suffered from major depression. In most cases, depression
was not identified and fewer than one in five received adequate treatment.
Dr. Bruce’s research builds on the premise that if we want the community practices
to use evidence-based interventions, then we need to involve the community
practices in intervention development and testing. With NIH funding, her group
worked in partnership with three home healthcare agencies to adapt evidencebased interventions from primary care to fit the patients, practice, and organization
of home healthcare. The purpose of improving an intervention’s fit is to increase its
acceptability, feasibility, and sustainability in real world settings across the nation.
Dr. Bruce’s group has used this approach successfully in home healthcare, aging
services, and community-based primary care. They are completing an NIH-funded
randomized trial of their Depression CAREPATH (Depression Care for Patients at
Home) intervention in collaboration with eight home health agencies located in
Florida, Arkansas, Michigan, Vermont, Philadelphia, and the Bronx.
From a public health perspective, improving real world practice requires not only
effective and sustainable interventions, but also strategies to promote their uptake
and use. Dr. Bruce’s current research focuses on implementation strategies that
can be used in home healthcare and other sectors of care where the agencies are
decentralized, resource poor, and widely dispersed. With NIH funding, the group has
developed a web-based platform, including e-learning modules, to help agencies
implement the Depression CAREPATH. This long-distance implementation strategy
is being tested in a randomized trial of home healthcare agencies spread across
the nation, with the goal of improving depression care and outcomes of as many
homebound older adults as possible.
Research profiles
Lewis C. Cantley, PhD
Director, Cancer Center
The research of Dr. Lewis Cantley, newly appointed Director of the Cancer Center
of Weill Cornell Medical College and NewYork-Presbyterian Hospital, is focused on
understanding the biochemical pathways that regulate normal mammalian cell
growth and the defects that cause cell transformation. Dr. Cantley, whose early work
was on the structure and mechanism of enzymes that transport small molecules
across cell membranes, pioneered the application of fluorescence resonance energy
transfer (FRET) for studying such processes.
In the mid 1980s, Dr. Cantley conducted research on biochemical mechanisms of
cellular responses to hormones and growth factors that led to the discovery of the
phosphoinositide 3-kinase (PI3K) signaling pathway. Dr. Cantley and his colleagues
at Tufts University School of Medicine identified PI3K as an enzyme that co-purified
with a variety of oncoproteins. Subsequent research from their laboratory and
other laboratories showed that PI3K activation is critical for oncogene-mediated cell
transformation, as well as for insulin-dependent stimulation of glucose uptake and
metabolism, with the subsequent revelation that lipid products of PI3K directly activate
the AKT/PKB protein kinase to provide a cell survival signal. This discovery, as well as
subsequent discoveries from other laboratories that human cancers frequently have
activating mutations in PI3K genes and/or inactivating mutations in the PTEN gene
(encoding a phosphatase that degrades PI3K lipid products), stimulated pharmaceutical
companies to develop PI3K pathway inhibitors for cancer therapy.
At Harvard Medical School, Dr. Cantley’s laboratory has been utilizing mouse
models, genetically engineered with mutations in the PI3K pathway, to investigate
opportunities for therapeutic intervention in diseases that result from defects in the
PI3K pathway. Recent studies from this laboratory have revealed that growth factors,
through activation of PI3K and other signaling pathways, cause major changes in
cellular metabolism that are critical for the growth of cancer cells. Of particular
interest, cancer cells invariably utilize an embryonic form of pyruvate kinase (PKM2)
to channel glucose metabolites for optimal cell growth. Ongoing studies are defining
how oncogene transformation of cells alters the flux of metabolites such as glucose
and glutamine and how these changes enhance cell growth and cell survival.
In 2009, Dr. Cantley received one of only five grants from Stand Up 2 Cancer, a highprofile initiative created to bring new cancer treatments to patients in a faster time
frame. The $15 million, three-year grant funded a team of researchers under Dr.
Cantley’s leadership to investigate the role of PI3K in the development of breast,
ovarian, and endometrial cancers.
Dr. Cantley has also pursued major research on the structural basis for specificity in
protein/protein interactions in signal transduction cascades that control cell growth
and survival. In particular, Dr. Cantley and his research team focused on the mechanism
by which protein phosphorylation can control the assembly of signaling complexes.
This technique was subsequently modified to determine optimal substrates for protein
kinases. A novel oriented peptide library technique was developed to determine
optimal phosphopeptides for binding to various protein domains. The identification of
optimal peptides has facilitated the determination of the structure of protein-peptide
complexes and explained how specificity in signaling is maintained. These studies led
to a bioinformatics approach (Scansite) for predicting sites of protein phosphorylation
and protein interaction from primary sequences.
SELECTED Publications
Whitman M, Downes, CP, Keeler M, Keller T,
Cantley LC. Type I phosphatidylinositol kinase
makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature. 1988 Apr 14;
332(6165):644-46.
Franke TF, Kaplan DR, Cantley LC, Toker A. Direct
regulation of the AKT proto-oncogene product by
phosphatidylinositol-3,4-bisphosphate. Science.
1997 Jan 31;275(5300):665-68.
Obenauer JC, Cantley LC, Yaffe MB. Scansite
2.0: proteome-wide prediction of cell signaling
interactions using short sequence motifs. Nucleic
Acids Research. 2003 Jul 1;31(13):3635-41.
Benes CH, Wu N, Elia AE, Dharia T, Cantley LC,
Soltoff SP. The C2 domain of PKCdelta is a
phosphotyrosine binding domain. Cell. 2005
Apr 22;121(2):271-80.
Engelman JA, Chen L, Tan X, Crosby K, Guimaraes
AR, Upadhyay R, Maira M, McNamara K, Perera
SA, Song Y, Chirieac LR, Kaur R, Lightbown A,
Simendinger J, Li T, Padera RF, García-Echeverría
C, Weissleder R, Mahmood U, Cantley LC, Wong
KK. Effective use of PI3K and MEK inhibitors to
treat mutant Kras G12D and PIK3CA H1047R
murine lung cancers. Nature Medicine. 2008
Dec;14(12):1351-56.
Anastasiou D, Poulogiannis G, Asara JM, Boxer
MB, Jiang J-K, Shen M, Bellinger G, Sasaki AT,
Locasale JW, Auld DS, Thomas CJ, Vander
Heiden MG, Cantley LC. Inhibition of PKM2 by
reactive oxygen species contributes to cellular
antioxidant responses. Science. 2011 Dec 2;
334(6060):1278-83.
Juvekar A, Burga LN, Hu H, Lunsford EP, Ibrahim
YH, Balmañà J, Rajendran A, Papa A, Spencer K,
Lyssiotis CA, Nardella C, Pandolfi PP, Baselga J,
Scully R, Asara JM, Cantley LC, Wulf GM.
Combining a PI3K inhibitor with a PARP inhibitor
provides an effective therapy for a mouse model
of BRCA1-related breast cancer. Cancer Discovery.
2012 Aug 22. [Epub ahead of print]
2012-2013 Research highlights
19
RESEARCH PROFILES
B.J. Casey, PhD
Sackler Professor of Developmental Psychobiology
Professor of Psychology in Psychiatry
Dr. B.J. Casey is a world leader in pediatric neuroimaging and its application to
understanding typical and atypical human brain development. She uses brain
imaging to uniquely examine transitions into and out of stages of development,
especially the period of adolescence. Dr. Casey grounds this work in translational
studies from rodent to human, developing models for several major developmental
disorders with implications for targeted individualized treatment. The collaborative
and highly interdisciplinary work in her laboratory broadly spans three key areas.
SELECTED Publications
Liston C, Matalon S, Hare TA, Davidson MC,
Casey BJ. Anterior cingulate and posterior
parietal cortices are sensitive to dissociable
forms of conflict in a task-switching paradigm.
Neuron. 2006 May 18;50(4):643-53.
Galvan A, Hare T, Parra CE, Penn J, Voss H,
Glover G, Casey BJ. Earlier development of
the NAcc relative to OFC may underlie risk
taking in adolescence. Journal of Neuroscience.
2006 Jun 21;26(25):6885-92.
Hare TA, Tottenham N, Galvan A, Voss H,
Glover GH, Casey BJ. Biological substrates
of emotional reactivity and regulation in
adolescence during an emotional go-nogo task.
Biological Psychiatry. 2008 May 15;63(10):927-34.
Liston C, McEwen B, Casey BJ. Psychosocial
stress reversibly disrupts prefrontal processing
and attentional control. Proceedings of the
National Academy of Sciences. 2009 Jan 20;
106(3):912-17.
Soliman F, Glatt CE, Bath KG, Levita L, Jones
RM, Pattwell SS, Jing D, Tottenham N, Amso D,
Somerville L, Lee FS, Casey BJ. A genetic variant
BDNF polymorphism alters extinction learning
in both mouse and human. Science. 2010 Feb 12;
327(5967):863-66.
Pattwell SS, Bath KG, Casey BJ, Ninan I, Lee FS.
Selective early-acquired fear memories
undergo temporary suppression during adolescence. Proceedings of the National Academy of
Sciences USA. 2011;Jan 18;108(3):1182-87.
Casey BJ, Somerville LH, Gotlib H, Ayduk O,
Franklin N, Askren MK, Jonides J, Berman
MG, Wilon NL, Teslovich T, Glover G, Zayas V,
Mischel W, Shoda Y. Behavioral and neural
correlates of delay of gratification 40 years
later. Proceedings of the National Academy of
Sciences USA. 2011 Sep 6;108(36):14988-15003.
Somerville L, Hare T, Casey BJ. Frontostriatal
maturation predicts cognitive control failure
to appetitive cues in adolescents. Journal of
Cognitive Neuroscience. 2011 Sep;23(9):2123-43.
20
WEILL CORNELL MEDICAL COLLEGE
First, her seminal neuroimaging studies have moved the field of adolescent human
brain development from simplistic notions of “aberrant” behavior in adolescents
being attributed to delayed prefrontal cortical development to one that acknowledges
an imbalance among regions within maturing frontolimbic circuitry during this
developmental period. This imbalance leads to primitive limbic systems hijacking
slower maturing, rational prefrontal systems in emotionally charged situations
and resulting in less optimal actions and choices. These findings are relevant for
understanding the inflection in substance abuse, affective disorders, and criminal
behavior during adolescence that markedly differ from childhood or adulthood.
Dr. Casey’s studies have shown divergence in the typical
progression of functional brain development in individuals
with ADHD and those with anxiety disorders. These findings
are important for understanding both pathways to these
disorders and targeted treatments.
A second significant area of research by Dr. Casey has been in exploiting functional
neuroimaging to develop biologically based theoretical models of normal and
abnormal brain development. She establishes normative developmental trajectories
of brain circuitry and then examines how children with clinical disorders either
deviate or show a delay in the development of this circuitry. Her studies have shown
divergence in the typical progression of functional brain development in individuals
with ADHD and those with anxiety disorders. These findings are important for
understanding both pathways to these disorders and targeted treatments.
A third area of research that reflects Dr. Casey’s most recent work is using human
imaging and mouse genetics to identify the role of specific genes as a first step
toward individualized and biologically targeted treatments of psychiatric disorders
across development. In collaborative studies examining genetically altered mice
and humans with allelic variance in neurotrophin and serotonin related genes, she
is making new discoveries that could significantly change the way a clinician treats
his or her patient. Her work is providing evidence for when during development an
individual may be most responsive to cognitive behavioral therapies, and what type
of therapy will be most effective for whom. This work is moving psychiatric practice
into a new and exciting era of personalized and preventive medicine.
RESEARCH PROFILES
Mary E. Charlson, MD
William T. Foley Distinguished Professor of Medicine
Professor of Complementary and Integrative Medicine
Dr. Mary Charlson is an internationally recognized clinical epidemiologist and
methodologist who leads a multidisciplinary research team conducting a broad
array of clinical trials, outcomes research, and population-based studies designed
to improve outcomes in patients with chronic illness. Among her many original
contributions, she has developed new strategies for measuring the prognostic
burden of chronic illness, including the widely used Charlson Comorbidity Index.
Dr. Charlson has shown that patients with multiple chronic illnesses are driving
a significant portion of healthcare costs, and how an adapted comorbidity index
can predict the longitudinal costs of caring for patients with chronic disease.
Dr. Charlson has also shown why disease management programs structurally
cannot reduce costs of care because most of the costs are incurred by patients with
multiple chronic diseases. She is currently working on strategies to manage such
complex patients to improve outcomes and reduce costs.
Dr. Charlson’s research team has developed prognostic models for identifying
patients with chronic disease at high risk of adverse events. Based on these models,
they developed and evaluated innovative strategies for improving outcomes
in randomized trials. Their research has resulted in significant improvement in
outcomes in patients with coronary artery disease, hypertension, and asthma.
Recently, Dr. Charlson and her multidisciplinary team have tested a novel psychosocial intervention combining positive-affect and self-affirmation to help motivate
behavior change in patients with chronic cardiovascular disease. This National Heart,
Lung, and Blood Institute-sponsored consortium conducted three parallel studies,
with a qualitative phase, pilot phase, and randomized trial phase. After completing
extensive interviews and pilot studies to optimally tailor the intervention for
application in ethnically and racially diverse populations, three parallel randomized
trials were conducted that involved over 750 patients. Three papers published in the
Archives of Internal Medicine detailed these first large, randomized trials, showing
that people with chronic cardiovascular disease can use positive-affect and selfaffirmation to help them make and sustain behavior change.
The combined findings of the consortium led Dr. Charlson and her team to develop
an intervention to help motivate behavior change in overweight black and Latino
adults, who have a disproportionate burden of health consequences from obesity.
The project entitled, “SCALE: Small Changes and Lasting Effects,” an NHLBI-funded
randomized controlled trial, is currently testing a small change approach to eating
and physical activity behavior to produce 7 percent weight loss in black and Latino
adults. Small changes include using smaller plates and drinking water rather than
sweetened beverages. The multidisciplinary team involves faculty from both the
Weill Cornell and Cornell University-Ithaca campuses. Dr. Charlson is also the CoPrincipal Investigator on the NIMHD Weill Cornell Center of Excellence in Disparities
Research and Community Engagement (CEDREC). The goal of this Center is to
create an interdisciplinary academic and community research enterprise that will
expand the capacity for conducting cutting-edge and trans-disciplinary research
that will contribute to improving minority health and reducing health disparities in
cardiovascular disease and cancer in Central Harlem and the South Bronx.
SELECTED Publications
Charlson ME, Boutin-Foster C, Mancuso C,
Peterson J, Ogedegbe G, Briggs W, Robbins L,
Isen A, Allegrante J. Randomized controlled
trials of positive-affect and self-affirmation to
facilitate healthy behaviors in patients with
cardiopulmonary patients: rationale, trial design,
and methods. Contemporary Clinical Trials. 2007
Nov;28:748-62.
Charlson ME, Charlson RE, Briggs WM, Hollenberg
JP. Can disease management target patients
most likely to generate high costs? The impact of
comorbidity. Journal of General Internal Medicine.
2007;22:464-69.
Charlson ME, Peterson J, Boutin-Foster C, Briggs
W, Ogedegbe G, McCulloch C, Hollenberg JP,
Wong C, Allegrante J. Changing healthy
behaviors after angioplasty: a randomized trial
of net-present value versus future-value risk
communication to improve health outcomes.
Health Education Research. 2008 Apr;23(5):826-39.
Charlson ME, Peterson JC, Marinopoulo SS,
Briggs WM, Hollenberg JP. The comorbidity
index is adapted to predict costs of chronic
disease in primary care patients. Journal of
Clinical Epidemiology. 2008 Dec;61(12):1234-40.
Mancuso CA, Choi TN, Westermann H,
Wenderoth S, Hollenberg JP, Wells MT, Isen AM,
Jobe JB, Allegrante JP, Charlson ME. Increasing
physical activity in patients with asthma
through positive affect and self-affirmation: a
randomized trial. Archives of Internal Medicine.
2012 Feb 27;172(4):337-43.
Ogedegbe GO, Boutin-Foster C, Wells MT,
Allegrante JP, Isen AM, Jobe JB, Charlson ME. A
randomized controlled trial of positive-affect
intervention and medication adherence in
hypertensive African Americans. Archives of
Internal Medicine. 2012 Feb 27;172(4):322-26.
Peterson JC, Charlson ME, Hoffman Z, Wells MT,
Wong SC, Hollenberg JP, Jobe JB, Boschert KA,
Isen AM, Allegrante JP. A randomized controlled
trial of positive-affect induction to promote
physical activity after percutaneous coronary
intervention. Archives of Internal Medicine. 2012
Feb 27;172(4):329-36.
2012-2013 Research highlights
21
RESEARCH PROFILES
Selina Chen-Kiang, PhD
Professor of Pathology
Professor of Immunobiology and Microbial Pathogenesis
Dr. Selina Chen-Kiang has long studied cell cycle control of B cell immunity and
cancer. Cancer is fundamentally a disease of uncontrolled cell division, due to
the loss of orderly programmed gene expression and checkpoints that normally
regulate the cell cycle. Cyclin-dependent kinases (CDKs) power progression
through phases of the cell cycle. CDK4 and CDK6 in particular are required for
entry and progression through the G1 phase. In many cancers, these two enzymes
are over-expressed, ensuring continual growth. Targeting CDK4/CDK6 therefore
represents a rational approach for cancer therapy.
SELECTED Publications
Menu E, Garcia J, Huang X, Di Liberto M, Toogood
P, Chen I, Vanderkerken K, Chen-Kiang S.
A novel therapeutic combination using PD
0332991 and bortezomib: study in the 5T33MM
myeloma model. Cancer Research. 2008;68:
5519-23.
Baughn LB, Di Liberto M, Niesvizky R, Cho HJ,
Jayabalan D, Lane J, Liu F, Chen-Kiang S. CDK2
phosphorylation of Smad2 disrupts TGF-beta
transcriptional regulation in resistant primary
bone marrow myeloma cells. Journal of
Immunology. 2009 Feb 15;182(4):1810-17.
Bretz J, Garcia J, Huang X, Kang L, Zhang Y,
Toellner KM, Chen-Kiang S. Noxa mediates
p18INK4c cell-cycle control of homeostasis in
B cells and plasma cell precursors. Blood. 2011
Feb 17;117(7):2179-88.
Leonard JP, LaCasce AS, Smith MR, Noy A,
Chirieac LR, Rodig SJ, Yu JQ, Vallabhajosula S,
Schoder H, English P, Neuberg DS, Martin P,
Millenson MM, Ely SA, Courtney R, Shaik N,
Wilner KD, Randolph S, Van den Abbeele AD,
Chen-Kiang SY, Yap JT, Shapiro GI. Selective
CDK4/6 inhibition with tumor responses by
PD0332991 in patients with mantle cell lymphoma. Blood. 2012 May 17;119(20):4597-607.
Huang X, Di Liberto M, Jayabalan D, Liang J,
Ely S, Bretz J, Shaffer AL 3rd, Louie T, Chen I,
Randolph S, Hahn WC, Staudt LM, Niesvizky R,
Moore MA, Chen-Kiang S. Prolonged early G1
arrest by selective CDK4/CDK6 inhibition
sensitizes myeloma cells to cytotoxic killing
through cell cycle-coupled loss of IRF4. Blood.
2012 Jun 20. [Epub ahead of print]
22
WEILL CORNELL MEDICAL COLLEGE
Using PD 0332991, the only known selective and potent inhibitor of CDK4/CDK6
that is also reversible and orally bioavailable, Dr. Chen-Kiang and her colleagues
have developed the first mechanism-based therapy to both inhibit tumor cell
division and sensitize them to diverse, clinically relevant cytotoxic agents. They
demonstrated that: 1) selective inhibition of CDK4/CDK6 leads to early G1 arrest;
2) upon release of the G1 block, a synchronized progression to S phase occurs;
3) prolonged G1 arrest (pG1) sensitizes tumor cells to cytotoxic killing, and
4) pG1 sensitization to cytotoxic killing is augmented in the subsequent S phase
synchronization (pG1-S) when metabolic demands are heightened.
Dr. Chen-Kiang’s team was also the first to demonstrate that negative control of
CDK4 and CDK6 by their physiologic inhibitor, p18INK4c, is required for homeostasis
in B cell activation and for terminal differentiation to non-cycling plasma cells.
They were also the first to show that CDK4 and CDK6 are dysregulated in the
plasma cell cancer multiple myeloma (MM), as in the B cell cancer mantle cell
lymphoma (MCL). Both are currently incurable diseases. On this basis, Dr. ChenKiang has implemented the novel CDK4/CDK6 combination therapy in treating
MCL and MM, in collaboration with Drs. John Leonard and Ruben Niesvizky at
Weill Cornell. In a Phase I single-agent study of PD 0332991 induction of pG1 in
MCL, it was found to have encouraging clinical activity and an excellent toxicity
profile. A Phase I/II clinical study in myeloma and a Phase Ib clinical study in MCL
are in progress. In addition, this therapy will be tested in aggressive acute myeloid
leukemia in the near future.
The next steps are to obtain a mechanistic understanding of cell cycle control of
cell death and to discover novel molecular targets and genome-based biomarkers
for therapy and patient stratification. Dr. Chen-Kiang hypothesizes that induction
of pG1 sensitizes cancer cells to cytotoxic killing by restricting gene expression
to those scheduled for early G1 but not other phases of the cell cycle, thereby
forcing an imbalance in gene expression which is only incompletely restored after
release of the G1 block. This hypothesis is being tested in primary tumor cells
in serial biopsies obtained from clinical trials of MCL and MM in the context of
the clinical response, by whole transcriptome sequencing in collaboration with
Dr. Chris Mason at Weill Cornell. Complementing this approach, a sensitizing
lethal suppression genome-scale pooled shRNA lentivirus screen is in progress to
identify genes that are required to mediate cell cycle control of cytotoxic killing
in collaboration with Dr. William Hahn at the Broad Institute. This integrated
approach is deeply rooted in fundamental science and propelled by real time
clinical application and the promise of advancing mechanism-based cell cycle
therapy in cancer.
RESEARCH PROFILES
David J. Christini, PhD
Professor of Biomedical Engineering in Medicine
Professor of Physiology and Biophysics
Professor of Computational Biomedicine
The laboratory of Dr. David Christini studies cardiac electrophysiological
dynamics using an integrated multiscale approach – from the subcellular level
to the organ level. Dr. Christini’s group is primarily interested in illuminating the
mechanisms underlying arrhythmia initiation and utilizing this knowledge to
develop new arrhythmia therapies. Through the use of computational modeling
and experimental approaches (primarily patch-clamping and calcium imaging of
isolated cardiac myocytes), they have provided novel insights into the ionic factors
that cause instabilities in the cardiac action potential and how these channellevel instabilities trigger cardiac arrhythmias in the whole heart. The lab’s work is
primarily focused on three NIH R01 projects:
Atrial fribrillation. Atrial fibrillation (AF) is the most common sustained cardiac
arrhythmia in the developed world. Because AF has several variants, is multifactorial, and evolves over time, it is very difficult to study comprehensively in largeanimal models. This is, in part, due to the inherent technical difficulties of imaging
whole-atria electrophysiology in vivo. Predictive multiscale computational modeling
has the potential to fill this research void. Dr. Christini and his colleagues are developing
a multiscale modeling framework using data, including human MRI structural
information and electrophysiological data, illuminating the impact of common ionchannel gene polymorphisms on drug-channel interactions. This is enabling the
evaluation of potential pharmacological and device-based atrial fibrillation therapies.
Cardiac alternans. Cardiac alternans is characterized by a beat-to-beat alternation
in membrane potential that is known to trigger cardiac reentry in experiments and
has been correlated with risk for clinical arrhythmias. Studies have suggested that
alternans may result from dynamical instabilities in either membrane voltage or
calcium cycling. For many years, the membrane voltage mechanism was thought
to explain the occurrence of alternans. More recently, evidence for the calcium
mechanism has accumulated, pushing that theory to the forefront. In recent years,
Dr. Christini’s lab has demonstrated that the two mechanisms are intertwined and
play varying, but quantifiable, roles for different cardiac cell types. These findings
have important implications for their ongoing investigations into device and drug
therapy of repolarization-triggered arrhythmias.
SELECTED Publications
Gong Y, Xie F, Stein KM, Garfinkel A, Culianu CA,
Lerman BB, Christini DJ. General mechanism
underlying initiation of paroxysmal atrial
flutter/atrial fibrillation by ectopic foci – a
simulation study. Circulation. 2007 Apr 24;
115(16):2094-102.
Gaeta SA, Bub G, Abbott GW, Christini DJ.
Dynamical mechanism for subcellular alternans
in cardiac myocytes. Circulation Research. 2009
Aug 14;105(4):335-42.
Ahrens-Nicklas RC, Christini DJ. Anthropomorphizing the mouse cardiac action potential
via a novel dynamic clamp method. Biophysical
Journal. 2009 Nov 18;97(10):2684-92.
Roberts BN, Christini DJ. NHE inhibition does
not improve Na+ or Ca2+ overload during
reperfusion: using modeling to illuminate
the mechanisms underlying a therapeutic
failure. PLoS Computational Biology. 2011
Oct;7:e1002241.
Krogh-Madsen T, Abbott GW, Christini DJ.
Effects of electrical and structural remodeling on
atrial fibrillation maintenance: a simulation study.
PLoS Computational Biology. 2012; 8:e1002390.
Real-time biological experiment contol. The ability to perturb biological systems
has traditionally been limited to rigid pre-programmed protocols. In contrast, “realtime control” allows the researcher to dynamically probe a biological system with
parameter perturbations that are calculated functions of instantaneous system
measurements (e.g., the “dynamic clamp” paradigm), thereby providing the ability
to address diverse unanswered questions that are not amenable to traditional
approaches. Unfortunately, real-time control is not possible with standard computer
operating systems and software. To circumvent these limitations, the Christini lab
develops and releases a highly versatile real-time biological experimentation system
known as Real-Time eXperiment Interface (RTXI; www.rtxi.org), helping to facilitate
new experimental paradigms. RTXI, which is open source and free, is the leading
tool of its type and has been adopted by many prominent neuroscience and cardiac
electrophysiology laboratories.
2012-2013 Research highlights
23
RESEARCH PROFILES
Ronald G. Crystal, MD
Chair and Professor of Genetic Medicine
Bruce Webster Professor of Internal Medicine
Professor of Medicine
SELECTED Publications
Hackett NR, Shaykhiev R, Walters MS, Wang R,
Zwick RK, Ferris B, Witover B, Salit J, Crystal RG.
The human airway epithelial basal cell
transcriptome. PLoS ONE. 2011 May4;6:e18378.
Tilley AE, O’Connor TP, Hackett NR, StruloviciBarel Y, Salit J, Amoroso N, Zhou XK, Raman T,
Omberg L, Clark A, Mezey J, Crystal RG. Biologic
phenotyping of the human small airway
epithelial response to cigarette smoking. PLoS
ONE. 2011;6(7):e22798.
Mao Y, Kiss S, Boyer JL, Hackett NR, Qiu J,
Carbone A, Mezey JG, Kaminsky SM, D’Amico DJ,
Crystal RG. Persistent suppression of ocular
neovascularization with intravitreal administration
of AAVrh.10 coding for bevacizumab. Human
Gene Therapy. 2011 Dec;22:1525-35.
Omberg L, Salit J, Hackett N, Fuller J, Matthew
R, Chouchane L, Rodriguez-Flores J, Bustamante
C, Crystal RG, Mezey JG. Inferring genome-wide
patterns of admixture in Qataris using fifty-fine
ancestral populations. BMC Genetics. 2012 Jun 26;
13(1):49.
Hicks MJ, Rosenberg JB, De BP, Pagovich O,
Young CN, Qiu J, Kaminsky SM, Hackett NR,
Worgall S, Janda KD, Davisson RL, Crystal RG.
AAV-directed persistent expression of an antinicotine antibody gene for smoking cessation.
Science Translational Medicine. 2012 Jun 27;
4(140):140ra87.
Dr. Ronald Crystal’s translational research program includes projects in genetic
therapies, personalized medicine, and genomic studies. In addition to gene transfer
technologies for gene therapy studies, Dr. Crystal’s laboratory utilizes microarray
and high-throughput sequencing to characterize gene expression, single-nucleotide
polymorphisms, and exome and whole genome sequences using clinical samples
to identify candidate genes associated with complex diseases such as chronic
obstructive pulmonary disease (COPD) and diabetes. The following examples of the
lab’s work have generated international public interest.
Personalized response to smoking. Microarrays of human small airway epithelium
from non-smokers, healthy smokers, and COPD smokers identified differentially
expressed genes. Individualized responsiveness to smoking was quantified with an
index score representing the percentage of smoking-responsive genes abnormally
expressed. Smokers demonstrated personalized responses to smoking, though the
transcriptome of healthy smokers with high index scores was indistinguishable from
COPD smokers, suggesting the small airway transcriptome can classify individuals
into smoking responsive subgroups in addition to using clinical criteria.
Airway basal cell transcriptome. The airway epithelium includes ciliated, secretory,
columnar, and basal cells (BC). BC function as stem/progenitor cells in the airway.
The transcriptome of purified, human airway BC was compared to the transcriptome
of complete epithelium samples that contained all four cell types. A human BC
signature was identified, providing novel insights into the biology of the human
airway epithelium stem/progenitor cells.
Vaccines for addiction. Current strategies to help smokers quit have limited success
due to the addictive properties of nicotine. Studies using an AAV gene transfer vector
expressing a high affinity anti-nicotine monoclonal antibody were carried out. Single
administration of this vector elicited persistent, high titers of an anti-nicotine antibody
that inhibited the physiologic effects of nicotine. If this degree of efficacy translates
to humans, this vector could be an effective preventative therapy for nicotine addiction.
Genetic therapy for CNS disorders. An AAV gene transfer vector was used to deliver
bevacizumab, an anti-VEGF monocolonal antibody, to mouse eyes and single
administration of this vector provided long-term suppression of neovascularization.
Dr. Crystal also has an ongoing study in children with neuronal ceroid lipofuscinosis,
a fatal childhood lysosomal storage disorder, using direct CNS infusion of a vector
expressing the CLN2 gene. This trial involves a novel surgical/vector administration
protocol that has received recognition in the neurosurgery field and by groups
wishing to do similar work.
Patterns of admixture in Qataris. A genome-wide admixture study of Qatar was
carried out in 156 individuals to develop a machine learning method that infers locispecific genomic ancestry while simultaneously analyzing many possible ancestral
populations. Simulations showed this method is more accurate than other popular
admixture discovery tools, and is the first to efficiently scale for simultaneous
analysis of 50-100 putative ancestral populations while being independent of prior
demographic information.
24
WEILL CORNELL MEDICAL COLLEGE
Research profiles
Anna Di Gregorio, PhD
Associate Professor of Cell and Developmental Biology
The notochord is the axial structure that provides support to the developing body of
all chordates, including humans, during embryogenesis. Notochord malformations
cause severe human birth defects, including spina bifida and vertebral abnormalities.
Yet, the genes controlling notochord formation and the molecular mechanisms
that turn them on at the right time during embryonic development are still
poorly characterized. To fill this gap in knowledge, the Di Gregorio lab is using an
innovative approach, by elucidating the genetic blueprint of the notochord in one of
the simplest chordates experimentally available: the ascidian Ciona, or “sea squirt.”
Why use a sea squirt to understand notochord formation? Among numerous
experimental advantages, the sea squirt embryo develops a functional notochord
within one day of fertilization, and notochord cells are easy to visualize; in
vertebrates, instead, the notochord is gradually replaced by vertebrae and its
remnants form the inner part of the intervertebral discs. Noticeably, these
notochord remnants occasionally give rise to rare but often malignant tumors,
called chordomas. Research in the Di Gregorio lab has shown that the notochord of
Ciona expresses genes that are also expressed in the mouse notochord, and most
likely in the notochord of human embryos as well.
Research in the Di Gregorio lab has shown that the
notochord of Ciona expresses genes that are also expressed
in the mouse notochord, and most likely in the notochord
of human embryos as well.
One of the genes that was conserved over half a billion years of chordate evolution is
brachyury (a Greek word for “short tail”). In all chordates, mutations in this gene locus
cause severe defects in notochord formation. However, unexpectedly, the brachyury
locus has been found to be duplicated in patients suffering from familial chordoma.
In other words, not having enough brachyury protein blocks notochord development,
while having too much of this protein in notochord cells appears to facilitate tumor
formation. Current projects in the Di Gregorio lab aim at determining the molecular
basis of this unusual mechanism of action. The experimental approach is focused on
the identification of regulatory DNAs that are bound by brachyury. A regulatory DNA is
a region of a gene that does not encode for a protein, but rather is the repository of the
information that dictates when and where the protein is going to be expressed during
development. Regulatory DNAs therefore act as “switches” for gene expression; unlike
protein-coding DNAs, they do not obey a particular genetic code and for this reason are
difficult to identify, especially in complex genomes.
In Ciona, the Di Gregorio lab has assembled the first collection of notochord
regulatory DNAs directly controlled by brachyury; these regulatory DNAs have been
analyzed in detail and the minimal sequences necessary for their activity in the
notochord have been identified. This work has led to the discovery of the different
mechanisms employed by brachyury to activate gene expression in the notochord
during different phases of its development. Their research has also begun to
shed light on the development of this structure, its evolutionary origins, and the
mechanisms that might be leading notochord remnants to give rise to tumors.
SELECTED Publications
Passamaneck YJ, Di Gregorio A. Ciona intestinalis:
chordate development made simple. Developmental Dynamics. 2005 May;233(1):1-19.
Oda-Ishii I, Di Gregorio A. Lineage-independent
mosaic expression and regulation of the Ciona
multidom gene in the ancestral notochord.
Developmental Dynamics. 2007 Jul;236(7):
1806-19.
Kugler JE, Passamaneck YJ, Feldman TG, Beh J,
Regnier TW, Di Gregorio A. Evolutionary
conservation of vertebrate notochord genes in
the ascidian Ciona intestinalis. Genesis - Special
Issue on Chordate Origins and Evolution. 2008
Nov;46(11):697-710.
Dunn MP, Di Gregorio A. The evolutionarily
conserved leprecan gene: its regulation by
Brachyury and its role in the developing Ciona
notochord. Developmental Biology. 2009 Apr 15;
328:561-74.
Passamaneck YJ, Katikala L, Perrone L, Dunn MP,
Oda-Ishii I, Di Gregorio A. Direct activation of a
notochord cis-regulatory module by Brachyury
and FoxA in the ascidian Ciona intestinalis.
Development. 2009 Nov;136(21):3679-89.
Kugler JE, Gazdoiu S, Oda-Ishii I, Passamaneck
YJ, Erives AJ, Di Gregorio A. Temporal regulation
of the muscle gene cascade by Macho1 and Tbx6
transcription factors in Ciona intestinalis. Journal
of Cell Science. 2010 Jul 15;123(Pt14):2453-63.
Kugler JE, Kerner P, Bouquet J-M, Jiang D,
Di Gregorio A. Evolutionary changes in the
notochord genetic toolkit: a comparative
analysis of notochord genes in the ascidian
Ciona and the larvacean Oikopleura. BMC
Evolutionary Biology. 2011 Jan 20;11:21.
José-Edwards DS, Kerner P, Kugler JE, Deng W,
Jiang D, Di Gregorio A. The identification of
transcription factors expressed in the notochord of Ciona intestinalis adds new potential
players to the Brachyury gene regulatory
network. Developmental Dynamics. 2011 Jul;
240(7):1793-805.
2012-2013 Research highlights
25
RESEARCH PROFILES
Sabine Ehrt, PhD
Professor of Microbiology and Immunology
Approximately eight million people develop active tuberculosis (TB) each year,
with two million dying from the disease, and it is estimated that one-third of the
world’s population is chronically infected with Mycobacterium tuberculosis (Mtb).
Most individuals respond to infection with Mtb by mounting a strong cellular
immune response that prevents active disease but does not sterilize the infection.
The pathogen has developed strategies to persist within macrophages, its primary
host cells, even in the face of fully developed T-cell immunity. Thus, there is a fine
balance between the host immune response that controls the infection and the
pathogen’s ability to evade and manipulate this response.
SELECTED Publications
Vandal O, Pierini LM, Schnappinger D, Nathan
CF, Ehrt S. A membrane protein preserves
intrabacterial pH in intraphagosomal
Mycobacterium tuberculosis. Nature Medicine.
2008 Aug;14(8):849-54.
Blumenthal A, Kobayashi T, Pierini LM, Banaiee
N, Ernst JD, Miyake K, Ehrt S. RP105 facilitates
macrophage activation by Mycobacterium
tuberculosis lipoproteins. Cell Host & Microbe.
2009 Jan 22;5(1):35-46.
Marrero J, Rhee KY, Schnappinger D, Pethe K,
Ehrt S. Gluconeogenic carbon flow of tricarboxylic acid cycle intermediates is critical for
Mycobacterium tuberculosis to establish and
maintain infection. Proceedings of the National
Academy of Sciences. 2010 May 25;107(21):
9819-24.
Gandotra S, Lebron M, Ehrt S. The Mycobacterium tuberculosis proteasome active site
threonine is essential for persistence yet
dispensable for replication and resistance to
nitric oxide. PLoS Pathogens. 2010 Aug 12;6(8):
e1001040.
Biswas T, Small J, Vandal O, Odaira T, Deng H,
Ehrt S, Tsodikov O. Structural insight into serine
protease Rv3671c that protects M. tuberculosis
from oxidative and acidic stress. Structure. 2010
Oct 13;18(10):1353-63.
Park SW, Klotzsche M, Wilson DJ, Boshoff HI,
Eoh H, Manjunatha U, Blumenthal A, Rhee K,
Barry III CE, Aldrich CC, Ehrt S, Schnappinger D.
Evaluating the sensitivity of Mycobacterium
tuberculosis to biotin deprivation using
regulated gene expression. PLoS Pathogens.
2011 Sep;7(9):e1002264.
26
WEILL CORNELL MEDICAL COLLEGE
One of the research goals of Dr. Sabine Ehrt and her colleagues is to better
understand the molecular basis for Mtb’s ability to resist host defense mechanisms.
They generate and characterize Mtb mutants that are susceptible to stresses
encountered by the bacterium during persistence within the host. In an infected
host, Mtb primarily resides within the phagosomes of macrophages. One strategy
the pathogen deploys to prevent its intracellular killing is to arrest phagosome
maturation. However, after cytokine activation the macrophage phagosome
matures resulting in fusion with lysosomes. Mtb can persist within even mature
phagosomes, indicating that the bacterium possesses resistance mechanisms
against defenses of activated macrophages, such as low pH, reactive oxygen and
nitrogen species, nutrient and co-factor limitation, and others.
One of the research goals of Dr. Sabine Ehrt and her
colleagues is to better understand the molecular basis for
Mtb’s ability to resist host defense mechanisms.
Dr. Ehrt and colleagues have identified Mtb mutants that are hypersusceptible
to such stress conditions and are also attenuated in the mouse model of TB. The
identification and characterization of the molecular mechanisms underlying the
loss of stress resistance and loss of virulence of these mutants will help to better
understand the intracellular environment encountered by Mtb and shed light on
the strategies the pathogen employs to resist host defense mechanisms.
Dr. Ehrt’s group is also interested in the metabolic environment Mtb faces within
its host. Metabolic adaptation to the host niche is a defining feature of the
pathogenicity of Mtb, yet Mtb’s central carbon metabolism and its metabolic
adaptations to the intracellular environment of a host cell remain incompletely
defined. They are investigating the metabolic pathways Mtb requires to establish
and maintain chronic infections.
In collaboration with Dr. Dirk Schnappinger’s laboratory in the Department of
Microbiology, Dr. Ehrt’s team has developed controlled expression systems that
allow silencing of mycobacterial genes in vitro and in vivo. They apply these systems
to create conditional knock-downs of mycobacterial genes that are important for
growth and persistence within the host. These conditional knock-down mutants
allow them to investigate if a mycobacterial gene is required at all or only at specific
stages of an infection. They also are used for drug target evaluation and studies of
essential mycobacterial genes.
RESEARCH PROFILES
Todd R. Evans, PhD
Professor of Cell and Developmental Biology in Surgery
Research in the laboratory of Dr. Todd Evans is focused on the molecular regulation
of organogenesis and regeneration. For this purpose, two model systems are
used in a complementary manner. Embryonic stem cells (ESCs) are used to study
pluripotency and the generation of progenitor cells and differentiated lineages in an
in vitro setting, and the zebrafish animal model is used to study organ development
and morphogenesis during embryogenesis.
The Evans laboratory was involved in the discovery and initial characterization of
the family of GATA transcription factors. These six proteins play essential roles
coordinating the development of many different organ systems. Research projects
are ongoing to understand the upstream signals that control their activity and
the downstream pathways that mediate their function. This has led to projects
in hematopoietic, cardiovascular, liver, and lung development. For example, the
group is studying the function of BMP signaling upstream of Gata2 for regulating
hematopoiesis. With respect to the cardiovascular system, they have described
functions for Gata4, Gata5, and Gata6 during embryogenesis and for homeostasis
and regeneration of the adult cardiovascular system.
The Evans laboratory was involved in the discovery and initial
characterization of the family of GATA transcription factors.
In the past year, they used deep-sequencing of RNA from embryos or embryonic
hearts depleted for specific GATA factors, and discovered new downstream target
genes that regulate cardiac cell specification and heart morphogenesis. Remarkably,
SNPs in one exciting new target gene have recently been associated with human
heart disease based on GWAS studies, demonstrating how zebrafish work can be
translated to modeling human disease. In recent collaborative work, the group also
found that Gata4 is a key target for the cardiac regenerative program in an injured
adult zebrafish heart.
In another strategy, the group is studying the directed differentiation of specific cell
types through manipulation of GATA-dependent programs in mouse and human
ESCs. These studies aim to develop cellular therapies for cardiac, liver, and lung
diseases. They also employ mouse and human induced pluripotent stem cell (iPSC)
technology, which is generating insight into how epigenetics can control regulatory
networks with relevance to cancer stem cells. Other iPSC projects are focused on
the aging process and human disease models. Chemical biology projects have
been used to identify novel small molecules that can modulate key developmental
pathways, including retinoid signaling. It is the overall goal of the group to control
with exquisite specificity regenerative pathways in the model systems, and then
translate these findings to treat organ-based disease. In addition to many strong
collaborations with laboratories at Weill Cornell Medical College (S. Chen, Y. Houvras,
T. Fahey, S. Rafii, T. Hla, M. Guzman, M. Ross, H. Stuhlmann, A. Melnick), they also
pursue projects with investigators around the country (R. Levine and J. Choudhuri at
Memorial Sloan-Kettering Cancer Center, G. Fishman at New York University, K. Poss
at Duke University, B. Das at Kansas, and many others).
SELECTED Publications
Holtzinger A, Rosenfeld G, Evans T. Gata4
directs development of cardiac-inducing
endoderm from ES cells. Developmental
Biology. 2010 Jan 1;337(1):63-73.
Kikuchi K, Holdway JE, Wedich A, Anderson
RM, Fang Y, Egnaczyk GF, Evans T, MacRae CA,
Stainier DYR, Poss K. Primary contribution to
zebrafish heart regeneration by Gata4+
cardiomyocytes. Nature. 2010 Mar 25;
464(7288):601-05.
Das BC, McCartin K, Liu T-C, Peterson RT,
Evans T. A forward chemical screen in zebrafish
identifies a retinoic acid derivative with receptor
specificity. PLoS ONE. 2010 Apr 2; 5(4):e10004.
Polo JM, Liu S, Figueroa ME, Kulalert W,
Eminli S, Tan KY, Apostolou E, Stadtfeld M, Li Y,
Natesan S, Wagers A, Melnick A, Evans T,
Hochedlinger K. Cell type of origin influences
the molecular and functional properties of
mouse induced pluripotent stem cells. Nature
Biotechnology. 2010 Aug;8(8):848-55.
Das BC, Tang X-Y, Sanyal S, Mohapatra S,
Rogler P, Nayak S, Evans T. Design and
synthesis of 3,5-disubstituted-1,2,4-oxadiazole
containing retinoids from a retinoic acid
receptor agonist. Tetrahedron Letters. 2011
May 11;52(19):2433-35.
Cook B, Liu S, Evans T. Smad1 signaling restricts
hematopoietic potential after promoting
hemangioblast expansion. Blood. 2011 Jun 16;
117(24):6489-97.
Xu C, Fan ZP, Müller P, Fogley R, DiBiase A,
Trompouki E, Unternaehrer J, Xiong F,
Torregroza I, Evans T, Megason SG, Daley GQ,
Schier AF, Young RA, Zon LI. Nanog-like
regulates endoderm formation through the
Mxtx2-Nodal pathway. Developmental Cell.
2012 Mar 13;22(3):625-38.
2012-2013 Research highlights
27
RESEARCH PROFILES
Joseph J. Fins, MD, MACP
Chief, Division of Medical Ethics
The E. William Davis, Jr., MD Professor of Medical Ethics
Professor of Medicine, Professor of Public Health
Professor of Medicine in Psychiatry
As humanist and physician-scientist, Dr. Joseph J. Fins has eloquently affirmed
society’s ethical obligation to patients with disorders of consciousness and our
responsibility to pursue knowledge that will benefit this marginalized population.
SELECTED Publications
Fins JJ. Constructing an ethical stereotaxy for
severe brain injury: balancing risks, benefits
and access. Nature Reviews Neuroscience. 2003
Apr;4(4):323-27.
Fins JJ. A Palliative Ethic of Care: Clinical Wisdom
at Life's End. Sudbury, MA: Jones and Bartlett. 2006.
Fins JJ, Schiff ND, Foley KM. Late recovery from
the minimally conscious state: ethical and policy
implications. Neurology. 2007 Jan 23;68(4):304-07.
Schiff ND, Giacino JT, Kalmar K, Victor JD, Baker
K, Gerber M, Fritz B, Eisenberg B, O’Connor J,
Kobylarz EJ, Farris S, Machado A, McCagg C,
Plum F, Fins JJ, Rezai AR. Behavioral improvements with thalamic stimulation after severe
traumatic brain injury. Nature. 2007 Aug 2;
448(7153):600-03.
Fins JJ. Minds apart: severe brain injury. Law and
Neuroscience, Current Legal Issues. 2010;13(ch18):
367-84, Freeman M, editor. Oxford University Press.
Fins JJ. Neuroethics, neuroimaging and
disorders of consciousness: promise or peril?
Transactions of the American Clinical and
Climatological Association. 2011;122:336-46.
Fins JJ, Mayberg HS, Nuttin B, Kubu CS, Galert
T, Strum V, Stoppenbrink K, Merkel R, Schlaepfer T. Neuropsychiatric deep brain stimulation
research and the misuse of the humanitarian
device exemption. Health Affairs (Millwood).
2011;30(2): 302-11.
Bardin JC, Fins JJ, Katz DI, Hersh J, Heier LA,
Tabelow K, Dyke JP, Ballon DJ, Schiff ND, Voss
HU. Dissociations between behavioural and
functional magnetic resonance imaging-based
evaluations of cognitive function. Brain. 2011
Mar;134(Pt 3):769-82.
Fins JJ. Wait, wait…Don’t tell me; tuning in
the injured brain. Archives of Neurology. 2012
Feb;69(2):158-60.
Fins JJ, Dorfman GS, Pancrazio JJ. Challenges
to deep brain stimulation: a pragmatic response
to ethical, fiscal and regulatory concerns. Annals of the New York Academy of Sciences. 2012
Aug;1265(1):80-90. [Epub ahead of print]
28
WEILL CORNELL MEDICAL COLLEGE
At a time when academic life has become increasingly fragmented, Dr. Fins has
engaged in translational work in medical ethics drawing upon the sciences and
the humanities to appreciate, and respond to, the ethical implications of medical
progress. In the 1990s, Dr. Fins developed clinical pragmatism, a method of moral
problem solving to bridge the gap between ethical theory and clinical practice.
This work, inspired by the American Pragmatic tradition, developed through his
leadership of the Ethics Consultation Service at NewYork-Presbyterian/Weill Cornell.
Clinical pragmatism was a novel formulation. Unlike the dominant bioethics
paradigm of principlism, it did not emphasize principles and moral absolutes,
but rather the importance of process, hypothesis generation, contingency, and
particularistic inductive reasoning, much like the scientific method itself. Dr. Fins’s
scholarship has brought pragmatism into mainstream bioethics, both here and
abroad, with particular relevance to ethics case consultation, palliative care, and
decision-making at life’s end.
With an ongoing commitment to interdisciplinarity, Dr. Fins’s more recent
efforts have been in the nascent field of neuroethics. He has had a pioneering
impact articulating a neuro-palliative ethic of care for patients with disorders of
consciousness, brain conditions, such as the vegetative and minimally conscious
states. Dr. Fins was the first ethicist to write on the use of neuromodulation in
disorders of consciousness and the role of neuroimaging in understanding these
conditions. Working with Weill Cornell neurologist and neuroscientist, Dr. Nicholas
D. Schiff, Dr. Fins was a co-author of their 2007 Nature paper on the use of deep
brain stimulation in the minimally conscious state. This landmark paper was the
first to demonstrate behavioral improvements with thalamic stimulation after
severe traumatic brain injury. Dr. Fins laid out the ethical and regulatory framework
for this landmark study and helped shape its scientific design. He articulated
a highly original ethical formulation that made the study possible, invoking
distributive justice claims for inclusion of subjects who could not provide informed
consent because of decisional incapacity. Using sources in the history of medicine,
he argued that the neglect of these patients was an unintended (and unrecognized)
legacy of the right-to-die movement. By deconstructing the biases distorting the
study’s risk-benefit analysis, he asserted that the minimally conscious were an
ethically proportionate subject population for this hypothesis driven research.
Dr. Fins is currently completing a book entitled, Rights Come to Mind: Severe Brain
Injury, Ethics & The Struggle for Consciousness, under contract with Cambridge
University Press. His scholarship has been supported by a Health Policy Investigator
Award from the Robert Wood Johnson Foundation, as well as funding from the Buster,
Dana, and Katz Foundations. President of the American Society for Bioethics and
Humanities, Dr. Fins is an elected Member of the Institute of Medicine of the National
Academy of Sciences and a Fellow of the American Academy of Arts and Sciences.
RESEARCH PROFILES
Daniel W. Fitzgerald, MD
Associate Professor of Medicine
Dr. Daniel Fitzgerald conducts clinical and translational research in Haiti and
Tanzania that aims to improve the survival and quality of life of people with AIDS
in resource poor settings. Research includes studies of antiretroviral therapy
(ART) and of major complications of HIV infection, including tuberculosis, tropical
diseases, and cervical cancer. The training of United States, Haitian, and Tanzanian
physician-scientists is an integral part of his research activity.
Dr. Fitzgerald conducted clinical studies in Haiti to demonstrate that ART can be
successfully administered in resource limited settings. He evaluated outcomes of
the first 1,000 AIDS patients treated with ART in Port-au-Prince, Haiti. Outcomes in
Haiti were comparable to those achieved in the United States. This study provided
critical evidence in support of international efforts to make ART available to AIDS
patients worldwide. He conducted a randomized trial of early versus deferred ART
for HIV-infected patients with a CD4 T cell count between 200 and 350 cells/mm3,
which showed that early ART decreases mortality four-fold. This study prompted the
World Health Organization to change international guidelines for the provision of
ART and affected the care of millions of people globally.
Dr. Fitzgerald’s study prompted the World Health Organization
to change international guidelines for the provision of ART
and affected the care of millions of people globally.
Studies are being conducted in Haiti and Tanzania to improve the diagnosis and
treatment of tuberculosis in HIV-infected people. Tuberculosis presents atypically
in HIV-infected people, and the standard diagnostic tests often do not detect the
disease. In collaboration with basic scientists from Weill Cornell in New York,
studies are ongoing to find metabolites of the tuberculosis bacteria in the blood or
urine that could be used as a new diagnostic biomarker. Studies are also ongoing
looking at new drug therapies to treat tuberculosis.
Studies in Tanzania are exploring the interactions between the tropical parasite
Schistosoma and HIV infection. In northern Tanzania near Lake Victoria, one-half
of the population is infected with the parasite Schistosoma. Studies suggest that
shistosomiasis may cause genital inflammation and thereby increase the risk
of HIV infection. Further, once HIV infected, shistosomiasis may accelerate HIV
disease progression.
Women with HIV are five times more likely to develop cervical cancer than other
women, and cervical cancer is now the third leading cause of death in HIV-infected
women in Haiti. In collaborations with bench-top scientists from Weill Cornell,
Dr. Fitzgerald is examining the effects of HIV infection upon the metabolism of
the inflammatory molecule Prostaglandin E2, which is a known mediator in the
development of certain cancers. This is an interesting molecule for study because
safe and inexpensive drugs like aspirin block the synthesis of Prostaglandin E2 and
could potentially be studied as cancer prevention drugs for HIV-infected women at
risk for cervical cancer.
SELECTED Publications
Severe P, Leger P, Charles M, Noel F, Bonhomme
G, Bois G, George E, Kenel-Pierr S, Wright PF,
Gulick R, Johnson WD, Pape JW, Fitzgerald DW.
Antiretroviral therapy in a thousand patients
with AIDS in Haiti. New England Journal of
Medicine. 2005 Dec 1;353(22):2325-34.
Leger P, Charles M, Severe P, Riviere C, Pape JW,
Fitzgerald DW. 5-year survival of patients with
AIDS receiving antiretroviral therapy in Haiti.
New England Journal of Medicine. 2009 Aug
20;361(8):828-29.
Pape JW, Johnson WD Jr, Fitzgerald DW. The
earthquake in Haiti – dispatch from Port-auPrince. New England Journal of Medicine. 2010
Feb 18;362(7):575-77.
Severe P, Jean Juste MA, Ambroise A, Eliacin L,
Marchand C, Apollon S, Edwards A, Bang H,
Nicotera J, Godfrey C, Gulick R, Johnson WD,
Pape JW, Fitzgerald DW. Early versus standard
antiretroviral therapy for HIV-infected adults in
Haiti. New England Journal of Medicine. 2010
Jul 15;363(3):257-65.
Fitzgerald DW, Janes H, Robertson M, Coombs R,
Frank I, Gilbert P, Loufty M, Mehrotra D, Duerr A for
the Step Study Protocol Team. An Ad5-vectored
HIV-1 vaccine elicits cell-mediated immunity
but does not affect disease progression in HIV-1
infected male subjects: results from a randomized
placebo-controlled trial (the Step study). Journal
of Infectious Diseases. 2011 Mar 15;203(6):765-72.
Downs JA, Mguta C, Kaatano GM, Mitchell KB,
Bang H, Simplice H, Kalluvya SE, Changalucha
JM, Johnson WD Jr, Fitzgerald DW. Urogenital
schistosomiasis in women of reproductive age
in Tanzania’s Lake Victoria region. American
Journal of Tropical Medicine and Hygiene. 2011
Mar;84(3):364-69.
Fitzgerald DW, Bezak K, Ocheritina O, Riviere
C, Wright TC Jr, Milne GL, Zhou XK, Du B,
Subbaramaiah K, Byrt E, Goodwin M, Rafii A,
Dannenberg AJ. The effect of HIV and HPV
co-infection on cervical COX-2 expression
and systemic prostaglandin E2 levels. Cancer
Prevention Research. 2012 Jan;5(1):34-40.
2012-2013 Research highlights
29
RESEARCH PROFILES
Paraskevi Giannakakou, PhD
Associate Professor of Pharmacology in Medicine
SELECTED Publications
Mabjeesh NJ, Escuin D, LaVallee TM, Pribluda
VS, Swartz GM, Johnson MS, Willard MT, Zhong
H, Simons J, Giannakakou P. 2ME2 inhibits
tumor growth and angiogenesis by disrupting
microtubules and dysregulating HIF. Cancer Cell.
2003 Apr;3(4): 363-75.
Marcus AI, O’Brate A, Buey R, Zhou J,
Thomas S, Khuri FR, Diaz F, Giannakakou P.
Farnesyltransferase inhibitors reverse resistance
to taxanes. Cancer Research. 2006 Sept 1;66(17):
8838-46.
Zhou J, Chanel-Vos C, Gjyrezi A, Yoshida M,
Khuri FR, Tamanoi F, Giannakakou P. The
protein farnesyltransferase regulates HDAC6
activity in a microtubule-dependent manner.
Journal of Biological Chemistry. 2009 Apr 10;
284(15):9648-55.
Chanel-Vos C, Giannakakou P. CENP-E checks
in microtubule drug resistance. Cell Cycle.
2010 Apr 15;9(8).
Darshan MS, Loftus MS, Thadani-Mulero M, Levy
BP, Escuin-Borras D, Zhou XK, Shen R, Tagawa
ST, Bander NH, Nanus DM, Giannakakou P.
Taxane-I-induced inhibition of androgen
receptor nuclear accumulation predicts clinical
response in metastatic prostate cancer. Cancer
Research. 2011 Sep 15;71(18):6019-29.
Carbonaro M, O’Brate A, Giannakakou P.
Microtubule disruption inhibits HIF-1α
translation by targeting HIF mRNA to
cytoplasmic P-bodies. (Featured on the cover)
Journal of Cell Biology. 2011 Jan 10;192(1):
83-89.
Carbonaro M, Escuin D, O’Brate A, ThadaniMulero M, Giannakakou P. Microtubules
regulate hypoxia-inducible factor-1α protein
trafficking and activity: implications for taxane
therapy. Journal of Biological Chemistry. 2012
Apr 6;287(15):11859-69.
Thadani-Mulero M, Nanus DM, Giannakakou P.
Androgen receptor on the move: boarding the
microtubule expressway to the nucleus. Cancer
Research. 2012;72(18);1-5.
30
WEILL CORNELL MEDICAL COLLEGE
Dr. Paraskevi Giannakakou’s laboratory focuses on the cellular events that depend
on the microtubule cytoskeleton, and on gaining a deeper understanding of the
mechanism of action of clinically used microtubule targeting drugs (MTDs) in
order to develop more effective and individualized therapies. Dr. Giannakakou’s
laboratory uses functional cellular and molecular biology assays coupled with highresolution microscopy and live-cell imaging to gain new information on the spatial
and temporal regulation of microtubule-cytoskeleton dynamics and its effects on
cancer-cell survival. The clinical success of taxanes, and other microtubule inhibitors,
together with their broad spectrum of antitumor activity, argue that tubulin
represents the single best target identified in clinical oncology. However, today,
15 years following the FDA approval of Taxol® for clinical oncology, there is still no
understanding of the molecular basis of clinical response to Taxol treatment.
Dr. Giannakakou believes that important, heretofore unrecognized, determinant
underlying taxane sensitivity is the involvement of the microtubule cytoskeleton
in intracellular trafficking and signaling. As such, her laboratory has identified new
roles for the microtubule cytoskeleton in the transport and activation of important
cancer transcription factors such as the tumor suppressor p53, the hypoxia-inducible
factor 1α, and most recently the androgen receptor in prostate cancer.
Dr. Giannakakou’s laboratory has previously shown that MTDs exert their antiangiogenic effects through significant down-regulation of HIF-1alpha protein levels
and transcriptional activity. More recently, her laboratory has demonstrated that the
androgen receptor, a major driver of prostate cancer that remains active even after
androgen-deprivation therapy, traffics on microtubule tracks for its translocation
from the cytoplasm to the nucleus where it activates target genes such as PSA.
Her team has also showed that MTDs, by disrupting the microtubule cytoskeleton,
sequester the androgen receptor within the cytoplasm, therefore inhibiting its
subsequent transcriptional activation. These results provide a rationale for why the
taxanes represent the sole class of chemotherapy agents that improves survival of
metastatic prostate cancer patients. However, despite their clinical success, not every
patient responds to MTD-based chemotherapy and the development of clinical drug
resistance makes patients, previously sensitive to chemotherapy, insensitive. Thus,
a better understanding of the molecular basis of clinical drug resistance to taxanes
and other widely used MTDs is imperative in order to prolong patient survival.
One of the major impediments to understanding MTD drug resistance has been
the lack of tumor tissue for molecular analyses. To overcome this, new technologies
have been developed to capture and analyze circulating tumor cells (CTCs) from the
peripheral blood of patients, which provides a readily accessible source of tumor
material. Dr. Giannakakou is collaborating with Dr. Brian Kirby from the Department
of Engineering at Cornell University and Drs. David Nanus and Linda Vahdat from the
Division of Hematology/Oncology at Weill Cornell to develop microfluidic devices
that specifically capture CTCs from metastatic prostate or breast cancer patients. The
ultimate goal is to utilize these devices to capture and molecularly analyze tumor
derived CTCs using a simple, non-invasive blood draw to determine the best treatment
for each patient based on the molecular make-up of their tumor cells. Ultimately,
Dr. Giannakakou seeks to identify new molecular targets that affect or are affected by
microtubule dynamics and can be used to develop better targeted therapies.
RESEARCH PROFILES
Laurie H. Glimcher, MD
Stephen and Suzanne Weiss Dean
Professor of Medicine
The laboratory of Dr. Laurie Glimcher pursues a cross-disciplinary understanding
of how cell biology affects the immune system. A major contributor to the field
of immunology, Dr. Glimcher has focused most of her career on understanding
how different subsets of immune cells develop and are regulated. She is known
for her discovery of XBP-1, a transcription factor important in lipogenesis and in
the endoplasmic reticulum (ER) stress and the unfolded protein response (UPR).
One component of her lab’s studies is centered on the interplay of ER stress with
immune function, with neurodegenerative diseases, and with cancer.
The complex regulatory pathways governing T helper (Th) lymphocyte responses
are critical for both the development of protective immunity and for the
pathophysiologic immune responses underlying autoimmune, infectious, and
malignant diseases. Dr. Glimcher’s laboratory uses biochemical and genetic
approaches to clarify the molecular pathways that regulate CD4 T helper cell
development and activation. While at Harvard, she and her colleagues studied
the transcriptional pathways that control this important immune checkpoint,
defining the genetic bases of both interleukin-4 (IL-4) and interferon-gamma
(IFN-γ) expression in T lymphocytes. They identified the proto-oncogene c-maf as
the transcription factor responsible for T helper type 2-specific IL-4 expression.
Subsequently, Dr. Glimcher’s lab discovered the first T helper 1-specific transcription
factor, T-bet, and demonstrated that this single factor is a master-regulator of IFN-γ
gene expression and the Th1 phenotype. Dr. Glimcher’s landmark paper in Cell on
the T-bet transcription factor has been cited more than 1,100 times.
With the knowledge that T-bet controls Type 1 immunity in cells of both the adaptive
and innate immune system, the Glimcher laboratory has been investigating the
function of T-bet in dendritic cells in mucosal immunity and tumorigenesis with an
emphasis on inflammatory bowel disease. The lab’s interest in lineage commitment
in lymphocytes has expanded to the B cell with the discovery of XBP-1. The researchers
have demonstrated a function of this factor in the generation of antibody-secreting
plasma cells, in innate immunity to pathogens, in neurodegenerative disease, and in
lipid disorders.
With evidence that a reciprocal relationship exists between cells of the immune
and skeletal systems, Dr. Glimcher’s lab has begun bridging work in both fields with
the goal of developing clinical therapeutics for diseases that share properties of
inflammation and bone remodeling. Through large scale screens, Dr. Glimcher and
her research team identified new proteins that control osteoblast and osteoclast
commitment and activation in skeletal biology. In one recent study, they found
that mice lacking the large zinc finger protein Schnurri-3 (Shn3) display increased
bone mass, in part attributable to augmented osteoblastic bone formation.
Further study elucidated that in addition to regulating bone formation, Shn3
indirectly controls bone resorption by osteoclasts in vivo. Although Shn3 plays no
cell-intrinsic role in osteoclasts, Shn3-deficient animals show decreased serum
markers of bone turnover. With significant implications for diseases of bone,
including osteoporosis, osteoarthritis, and cancer metastasis to bone, their work in
this area may provide a conceptual framework to therapeutically manipulate these
responses in the settings of human disease.
SELECTED Publications
Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman
GC, Glimcher LH. A novel transcription factor,
T-bet, directs Th1 lineage commitment. Cell.
2000 Mar 17;100(6):655-69.
Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, Szomolanyi-Tsuda E, Gravallese EM,
Friend D, Grusby MJ, Alt F, Glimcher LH. Plasma
cell differentiation requires transcription factor
XBP-1. Nature. 2001 Jul 19;412(6844):300-07.
Finotto S, Neurath MF, Glickman JN, Qin S,
Lehr HA, Green FH, Ackerman K, Haley K,
Galle PR, Szabo SJ, Drazen JM, De Sanctis GT,
Glimcher LH. Development of spontaneous
airway changes consistent with human
asthma in mice lacking T-bet. Science. 2002
Jan 11;295(5553):336-38.
Jones DC, Wein MN, Oukka M, Hofstaetter JG,
Glimcher MJ, Glimcher LH. Regulation of adult
bone mass by the zinc finger adapter protein
Schnurri-3. Science. 2006 May 26;312(5777):
1223-27.
Garrett W, Lord GM, Punit S, Lugo G, Mazmanian S, Ito S, Glickman J, Glimcher LH.
Communicable ulcerative colitis induced by
T-bet deficiency in the innate immune system.
Cell. 2007 Oct 5;131(1):33-45.
Lee A-H, Scapa EF, Cohen DE, Glimcher LH.
Regulation of hepatic lipogenesis by the
transcription factor XBP1. Science. 2008
Jun 13;320(5882):1492-96.
Kaser A, Lee A-H, Franke A, Glickman JN,
Zeissig S, Tilg H, Nieuwenhuis EES, Higgins DE,
Schreiber S, Glimcher LH, Blumberg RS.
Transcription factor XBP1 links ER stress to
intestinal inflammation and confers genetic
risk for human inflammatory bowel disease.
Cell. 2008 Sep 5;134(5):743-56.
Staton TL, Lazarevic V, Jones DC, Lanser AJ,
Takegi T, Ishii S, Glimcher LH. Dampening of
death pathways by Schnurri 2 is essential
for T cell development. Nature. 2011 Apr 7;
472(7341):105-09.
2012-2013 Research highlights
31
RESEARCH PROFILES
Lorraine J. Gudas, PhD
Chair, Pharmacology
Revlon Pharmaceutical Professor of Pharmacology and Toxicology
Professor of Pharmacology
The laboratory of Dr. Lorraine Gudas is focused on developing cancer prevention
strategies, cancer treatment therapies, and tissue regenerative therapies. Dr. Gudas
and her group are involved in the discovery of new drugs that cause normal stem
cells and cancer stem cells to change their molecular characteristics and differentiate,
i.e., to become more mature, specialized cells. Cancer cells that have “stem-like”
properties are generally more malignant and dangerous to the patient.
SELECTED Publications
Liu L, Gudas LJ. Disruption of the lecithin:
retinol acyltransferase gene makes mice more
susceptible to vitamin A deficiency. Journal of
Biological Chemistry. 2005 Dec 2;280(48):
40226-34.
Gillespie RF, Gudas LJ. Retinoic acid receptor
isotype specificity in F9 teratocarcinoma stem
cells results from the differential recruitment
of coregulators to retinoic response elements.
Journal of Biological Chemistry. 2007 Nov 16;
282(46):33421-34.
Tang XH, Albert M, Scognamiglio T, Gudas LJ. A
DNA methyltransferase inhibitor and all-trans
retinoic acid reduce oral cavity carcinogenesis
induced by the carcinogen 4-nitroquinoline
1-oxide. Cancer Prevention Research (Phila).
2009 Dec;2(12):1100-10.
Agrawal V, Johnson SA, Reing J, Zhang L,
Tottey S, Wang G, Hirschi KK, Braunhut S,
Gudas LJ, Badylak SF. Epimorphic regeneration
approach to tissue replacement in adult
mammals. Proceedings of the National
Academy of Sciences. 2010 Feb 23;107(8):
3351-55.
Kashyap V, Gudas LJ. Epigenetic regulatory
mechanisms distinguish retinoic acid-mediated
transcriptional responses in stem cells and
fibroblasts. Journal of Biological Chemistry.
2010 May 7;285(19):14534-48.
Fu L, Wang G, Shevchuck MM, Nanus DM,
Gudas LJ. Generation of a mouse model of Von
Hippel-Lindau kidney disease leading to renal
cancers by expression of a constitutively
active mutant of HIF1a. Cancer Research. 2011
Nov 1;71(21):6848-56.
One nutrient/vitamin that they have shown to cause stem cell differentiation is
the vitamin A metabolite, retinoic acid. Retinoids, which include both natural and
synthetic derivatives of vitamin A (retinol), control many aspects of normal cell
differentiation, and influence the process of carcinogenesis. While there are small
amounts of retinoic acid in our bodies from the vitamin A in the foods we eat, larger,
pharmacological doses of retinoic acid are used in treating some types of leukemia
and in reducing the occurrence of other types of human cancer. Retinoic acid works
by going into the cell, where it binds to a protein that changes the levels of mRNAs,
and subsequently, the levels of proteins in the cell.
Dr. Gudas is very excited by recent experiments from her lab showing that retinoic
acid also works by another mechanism. They have now shown that retinoic acid
changes the levels of specific mRNAs and proteins in cells in part by changing the
“epigenetic state” of the cell. This means that retinoic acid can cause alterations
in proteins, called histones, which surround DNA on the chromosome. When the
histones are altered by the addition of retinoic acid, many other proteins in the cell
are then made in greater amounts, and the cell starts producing large amounts of
the types of proteins characteristic of a more mature, specialized cell type rather
than those of a stem cell. For instance, after retinoic acid addition, normal stem cells
start making more proteins called keratins, and keratins are important for a type of
differentiated cell, called an epithelial cell, to function properly in our bodies.
Dr. Gudas and her group are involved in the discovery of new
drugs that cause normal stem cells and cancer stem cells to
change their molecular characteristics.
The lab has shown that many types of human tumors (prostate cancer, kidney cancer,
breast cancer, and others) don’t contain enough vitamin A and retinoic acid, even
though the patient is eating enough of the vitamin in his or her diet. Their experiments
suggest that during cancer development the cancer cells, by a variety of mechanisms
they are studying, reduce their levels of vitamin A and retinoic acid so that they
remain in a more “stem-like,” proliferating state. Their goal is to employ new drug
combinations to overcome this block in cell differentiation, make the cancer stem
cells become more “mature,” and thereby improve the survival of cancer patients.
They also are studying tissue regeneration after injury. Normal stem cells play an
important role in making new cells and tissues after injury, and these stem cells
also differentiate during the repair and regeneration of tissues. Their studies on the
identification of novel combinations of nutrients and drugs that can enhance and
improve regeneration should help both soldiers seriously wounded in battle and
victims of accidents with severe tissue injury.
32
WEILL CORNELL MEDICAL COLLEGE
RESEARCH PROFILES
David P. Hajjar, PhD
Dean, Weill Cornell Graduate School of Medical Sciences
Frank H.T. Rhodes Distinguished Professor of Cardiovascular Biology and Genetics
Professor of Biochemistry
Professor of Pathology and Laboratory Medicine
Atherosclerosis is an inflammatory disease characterized by the accretion
of cholesterol-laden plaque in the artery wall. During the pathogenesis of
atherosclerosis, alterations in eicosanoid biosynthesis and reactive oxygen species
production occur by mechanisms that are not well understood. The delineation of
these mechanisms is the focus of Dr. David Hajjar’s research.
Eicosanoids are a group of biologically active compounds derived from the
cyclooxygenase (COX) and lipoxygenase catalytic pathways and include the
commonly named prostaglandins. These eicosanoids play important physiological
roles in the regulation of many processes. Nitric oxide (NO), produced in blood
vessels by the nitric oxide synthases, is another critical mediator of both
physiologic and pathophysiologic processes in the regulation of vascular tone
and inflammation. Atherosclerotic lesions contain increased levels of inducible
COX (COX-2) and nitric oxide synthase (iNOS). Recent developments show that
both enzymes are bound, and the fate of eicosanoid synthesis is linked to NO and
its higher oxides (NOx) derived from iNOS. The principal aim of Dr. Hajjar’s work
is to define the mechanisms by which NO and prostaglandin synthetic pathways
interact to alter eicosanoid biosynthesis, as well as the impact of these mediators
on atherosclerosis and thrombosis. Over the years, Dr. Hajjar has defined the
roles and mechanisms of these complex signaling interactions in order to gain an
understanding of the pathophysiological processes in atherosclerosis using animal
models and the consequences of pharmacological interventions.
The principal aim of Dr. Hajjar’s work is to define the
mechanisms by which NO and prostaglandin synthetic
pathways interact to alter eicosanoid biosynthesis.
In recent work, Dr. Hajjar showed that the enzyme prostaglandin H2 synthase
(PGHS, also known as cyclooxygenase) regulates the production of eicosanoids that
modulate physiologic processes in the vessel wall, contributing to atherosclerosis
and thrombosis. He demonstrated that various forms of NOx can have different
modulatory effects on the activity of PGHS-1, the predominant isozyme in platelets.
These and other studies revealed that the active heme center of PGHS-1 regulates
peroxynitrite-induced modification and loss of enzyme reactivity, indicating that
heme may play a decisive role in catalyzing these processes in PGHS-1 when exposed
to nitrative stress in an inflammatory setting. Collectively, these studies show for
the first time that iNOS influences PGHS expression and its activity, which can
contribute to modification of an important enzyme involved in inflammation
during atherosclerosis. Since iNOS-derived species are required for robust
atherosclerosis-associated peroxynitrite production in peripheral organs, these
studies have contributed importantly to the understanding of the complex
alterations in eicosanoid metabolism that occur during the pathogenesis of heart
disease where inflammation occurs.
SELECTED Publications
Lander HM, Millbank AJ, Tauras JM, Hajjar DP.
A molecular redox switch on p21ras: structural
basis for the nitric oxide – p21ras interaction.
Nature. 1996 May 30;381(6581):380-81.
Upmacis R, Chait BT, Mirza UA, Hajjar DP. First
observation of nitrosylated heme in myoglobin
and hemoglobin by electrospray ionizationmass spectrometry. Journal of the American
Chemical Society. 1997 Oct 29;119(43):10424-29.
Upmacis RK, Deeb RS, Hajjar DP. Regulation of
prostaglandin H2 synthase activity by nitrogen oxides. Biochemistry. 1999 Sep 21;38(38):
12505-13.
Deeb RS, Shen H, Gamss C, Gavrilova T, Gross
SS, Maeda N, Hajjar DP, Upmacis RK. Inducible
nitric oxide synthase mediates prostaglandin H2
synthase nitration and suppresses eicosanoid
production. American Journal of Pathology. 2006
Jan:168(1):349-62.
Deeb RS, Cheung C, Nuriel T, Lamon BD,
Upmacis R, Gross SS, Hajjar DP. Physical
evidence for substrate binding in preventing
cyclooxygenase inactivation under nitrative
stress. Journal of the American Chemical
Society. 2010 Mar 24;132(11):3914-22.
Upmacis RK, Shen H, Lamon BD, Deeb RS,
Hajjar KA, Hajjar DP. Inducible nitric oxide
synthase provides protection against injuryinduced thrombosis. American Journal of
Physiology. 2011 Aug; 301(2)H617-24.
2012-2013 Research highlights
33
RESEARCH PROFILES
Katherine A. Hajjar, MD
Chair, Department of Cell and Developmental Biology
Brine Family Professor of Cell and Developmental Biology
Professor of Pediatrics in Medicine
In the hemostatic response to blood vessel injury, the coagulation cascade activates
thrombin, which subsequently converts soluble plasma fibrinogen into insoluble
fibrin. Fibrin, the primary protein constituent of blood clots, or thrombi, is degraded
into a defined set of peptides known as fibrin degradation products by the serine
protease plasmin, the major fibrinolytic protease in vertebrates. Both coagulation
and fibrinolysis are highly regulated biologic processes.
SELECTED Publications
Ling Q, Jacovina AT, Deora AB, Febbraio M,
Simantov R, Silverstein R, Hempstead B, Mark W,
Hajjar KA. Annexin 2 is a key regulator of fibrin
homeostasis and neoangiogenesis. Journal of
Clinical Investigation. 2004 Jan;113:38-48.
Deora AB, Kreitzer G, Jacovina AT, Hajjar KA. An
annexin 2 phosphorylation switch mediates
p11-dependent translocation of annexin 2 to
the cell surface. Journal of Biological Chemistry.
2004 Oct 15;279:43411-18.
Cesarman-Maus G, Rios-Luna NP, Deora AB,
Huang B, Villa R, del Carmen Cravioto M,
Alarcon-Segovia D, Sanchez-Guerrero J,
Hajjar KA. Autoantibodies against the fibrinolytic receptor, annexin 2, in antiphospholipid
syndrome. Blood. 2006 Jun 1;107(11): 4375-82.
He K-L, Deora AB, Xiong H, Ling Q, Weksler BB,
Niesvizky R, Hajjar KA. Annexin A2 regulates
ubiquitination and degradation of S100A10/
p11. Journal of Biological Chemistry. 2008
Jul 11;283(28):19192-200.
Jacovina AT, Deora AB, Ling Q, Broekman MJ,
Almeida D, Greenberg C, Marcus AJ, Smith JD,
Hajjar KA. Homocysteine inhibits neoangiogenesis through blockade of annexin A2dependent angiogenesis. Journal of Clinical
Investigation. 2009 Nov;119(11):3384-94.
Huang B, Deora AB, He K, Chen K, Jacovina A,
Sui G, Almeida D, Hong P, Burgman P, Hajjar KA.
Hypoxia-inducible factor-1 drives annexin A2
system-mediated perivascular fibrin clearance
in oxygen-induced retinopathy in mice. Blood.
2011 Sep 8;118:2918-29.
Scharf B, Clement CC, Wu XX, Morozova K,
Zanolini D, Follenzi A, Larocca JN, Levon K,
Sutterwala F, Rand J, Cobelli N, Purdue E, Hajjar
KA, Santambrogio L. Annexin A2 binds to endosomes following organelle destabilization by
particulate wear debris. Nature Communications.
2012 Mar 27;3:755-65.
34
WEILL CORNELL MEDICAL COLLEGE
Scientists in Dr. Katherine Hajjar’s laboratory identified the annexin A2 system as
a novel key component of the fibrinolytic system. Expressed on endothelial cells,
annexin A2 (A2) is a calcium-regulated, phospholipid-binding protein that forms a
heterotetrameric complex with protein p11 (S100A10). The Hajjar lab discovered
that the A2 complex binds two major components of the fibrinolytic system,
plasminogen and tissue plasminogen activator, and accelerates the generation of
plasmin at cell surfaces. Evidence is now emerging that the annexin A2 system
contributes to fibrin homeostasis in human health and disease.
Understanding the in vivo function of the A2 system is a major goal of the Hajjar
lab. Their development of the A2-deficient mouse uncovered two important
findings – first, the knockouts displayed the predicted accumulation of fibrin within
blood vessels, and, second, the mice exhibited unexpected defects in new blood
vessel formation (angiogenesis) – leading to the hypothesis that fibrinolysis and
angiogenesis are functionally linked. This postulate has been strengthened by the
observation that metabolic blockade of A2 function by the amino acid homocysteine
leads to fibrin accumulation and defective angiogenesis. Evidence that A2 regulates
hemostasis in humans derives from studies in patients with acute promyelocytic
leukemia in which overexpression of A2 correlates with severe, sometimes lifethreatening hemorrhage. Individuals with antiphospholipid syndrome, moreover,
often have thrombosis in association with high-titer anti-A2 antibodies that inhibit
A2 function or activate endothelial cells. High-titer anti-A2 antibodies have also been
reported in a cohort of patients with cerebral vein thrombosis.
An appreciation for the role of the A2 system in human health and disease requires
knowledge of its regulation at the molecular level. The Hajjar lab recently discovered
that synthesis of A2 is regulated by ischemia through the action of the hypoxiainducible factor-1 transcription factor, which binds directly to a hypoxia responsive
element within the A2 gene promoter. This mechanism underlies ischemic retinal
vascular disease in a mouse model that mimics retinopathy of prematurity and
diabetic retinopathy. Further work has revealed that while endothelial cell A2
stabilizes protein p11 and prevents its proteasomal degradation, p11 supports
the src kinase-stimulated, nonclassical secretion of A2 from the cytoplasm to
the cell surface. In addition, recent collaborative studies have shown that the A2
system promotes tumor cell invasion in two brain tumor models of glioblastoma
multiforme, and that annexin A2 may inhibit activation of the innate inflammatory
system in a model of joint disease by maintaining the integrity of intracellular
organelles known as lysosomes. Future studies will build upon these emerging
pathways to develop strategies aimed at understanding and manipulating the A2
system in settings of human disease.
RESEARCH PROFILES
Hugh C. Hemmings, Jr., MD, PhD
Professor of Anesthesiology
Professor of Pharmacology
There are two principal areas of research in Dr. Hugh Hemmings’ laboratory:
mechanisms of general anesthetic drugs and neuroprotective mechanisms in
global cerebral ischemia. Dr. Hemmings’ lab has demonstrated neurotransmitterand anesthetic agent-specific effects on neurotransmitter release that involve
effects on presynaptic ion channels. The specific ion channels affected and the
mechanisms of these effects are currently under investigation. Recent findings
indicate that protein phosphatase-1 is activated in global cerebral ischemia.
A combination of biochemical, genetic, and proteomic techniques are being
employed to determine the biochemical mechanisms of this pathophysiological
regulation and its potential as a therapeutic target for this devastating disease.
Mechanisms of general anesthetic. The pharmacology and toxicology of general
anesthetics are remarkably incomplete for such a widely used and clinically
important class of drugs. Despite their widespread clinical use, understanding of
the molecular and cellular mechanisms of general anesthetic action in the central
nervous system is insufficient to explain how any anesthetic produces amnesia,
unconsciousness, or immobilization (with increasing doses), the cardinal clinical
features of general anesthesia. Anesthetics have potent and specific effects on
synaptic transmission, including both presynaptic actions on the release of
neurotransmitters and postsynaptic actions on their receptors. Dr. Hemmings’ lab
aims to understand the presynaptic mechanisms of anesthetic effects on
neurotransmitter release, which is essential for developing anesthetics with
improved side-effect profiles and for optimization of current anesthetic techniques
in high-risk patients. Current focus is on the region- and transmitter-specific actions
and Na+ channel blocking mechanisms of volatile anesthetics. Such studies are
essential to understanding the balance between desirable and potentially toxic
anesthetic effects on excitatory and inhibitory synaptic transmission.
Neuroprotection and global cerebral ischemia. Global cerebral ischemia due to
cardiac arrest results in debilitating neurological impairment necessitating costly
long-term healthcare. Yet there is currently no specific medical therapy. Global
cerebral ischemia is associated with extensive cell death. These processes are tightly
regulated by several mechanisms, including a critical role for protein phosphorylation.
Protein phosphatase-1 is a serine/threonine protein phosphatase that has been
implicated in the regulation of cell death. Dr. Hemmings and his colleagues have
identified and purified a novel form of protein phosphatase-1 in mammalian brain
that is activated in vivo in animal models of global cerebral ischemia. They
hypothesize that this enzyme is a component of the signal transduction pathways
that link global cerebral ischemia to cell death. They have purified and characterized
this enzyme from control and ischemic pig brain following cardiac arrest with
resuscitation and reperfusion, and are currently studying its regulation by
reconstitution of the identified components in vitro.
These studies will elucidate physiological and pathophysiological mechanisms
that regulate protein phosphatase-1 activity in the brain and define its role in
the control of cell death in global cerebral ischemia. This approach is targeted to the
development of rational mechanism-based therapies to attenuate ischemic brain
cell death with a long-term goal of clinical translation.
SELECTED Publications
Ouyang W, Jih TY, Zhang TT, Correa AM,
Hemmings HC Jr. Isoflurane inhibits NaChBac,
a prokaryotic voltage-gated sodium channel.
Journal of Pharmacology and Experimental
Therapeutics. 2007 Sep;322(3):1076-83.
Platholi J, Heerdt PM, Lim Tung HY, Hemmings
HC Jr. Activation of brain protein phosphatase-1(I)
following cardiac arrest and resuscitation
involving an interaction with 14-3-3 gamma.
Journal of Neurochemistry. 2008 Jun;105(5):
2029-38.
Herold KF, Nau C, Ouyang W, Hemmings HC Jr.
Isoflurane inhibits the tetrodotoxin-resistant
voltage-gated sodium channel Nav1.8.
Anesthesiology. 2009 Sep;111(3):591-99.
Zhang Y, Guzinski M, Eger EI 2nd, Laster MJ,
Sharma M, Harris RA, Hemmings HC Jr.
Bidirectional modulation of isoflurane potency
by intrathecal tetrodotoxin and veratridine
in rats. British Journal of Pharmacology. 2010
Feb;159 (4):872-78.
Westphalen RI, Yu J, Krivitski M, Jih TY,
Hemmings HC Jr. Regional differences in nerve
terminal Na+ channel subtype expression and
Na+ channel-dependent glutamate and GABA
release in rat CNS. Journal of Neurochemistry.
2010 Jun;113(6):1611-20.
Westphalen RI, Kwak NB, Daniels K, Hemmings
HC Jr. Regional differences in the effects of
isoflurane on neurotransmitter release.
Neuropharmacology. 2011 Sep;61(4):699-706.
Rusinova R, Herold KF, Sanford RL, Greathouse
DV, Hemmings HC Jr, Andersen OS. Thiazolidinedione insulin sensitizers alter lipid bilayer
properties and voltage-dependent sodium
channel function: implications for drug
discovery. Journal of General Physiology. 2011
Aug;138(2):249-70.
Herold KF, Hemmings HC Jr. Sodium channels
as targets for volatile anesthetics. Frontiers in
Pharmacology. 2012 Mar 30;3:50. [Epub ahead
of print]
2012-2013 Research highlights
35
RESEARCH PROFILES
Barbara L. Hempstead, MD, PhD
O. Wayne Isom Professor of Medicine
SELECTED Publications
Kermani P, Hempstead BL. Brain-derived
neurotrophic factor: a newly described
mediator of angiogenesis. Trends in
Cardiovascular Medicine. 2007 May;17(4):
140-43.
Yang J, Siao CJ, Nagappan G, Marinic T, Jing D,
McGrath K, Chen ZY, Mark W, Tessarollo L, Lee
FS, Lu B, Hempstead BL. Neuronal release of
proBDNF. Nature Neuroscience. 2009 Feb;12(2):
113-15.
Greenberg ME, Xu B, Lu B, Hempstead BL. New
insights in the biology of BDNF synthesis and
release: implications in CNS function. Journal
of Neuroscience. 2009 Oct 14;29(41):12764-67.
Kim T, Hempstead BL. NRH2 is a trafficking
switch to regulate sortilin localization and
permit proneurotrophin-induced cell death.
EMBO Journal. 2009 Jun 3;28(11):1612-23.
Feng D, Kim T, Ozkan E, Light M, Torkin R, Teng
KK, Hempstead BL, Garcia KC. Molecular and
structural insight into proNGF engagement of
p75NTR and sortilin. Journal of Molecular
Biology. 2010 Mar 5;396(4):967-84.
Deinhardt K, Kim T, Spellman DS, Mains RE,
Eipper BA, Neubert TA, Chao MV, Hempstead
BL. Neuronal growth cone retraction relies on
proneutrotrophin receptor signaling through
Rac. Science Signaling. 2011 Dec 6;202(4):ra82.
The research in Dr. Barbara Hempstead’s laboratory focuses on the biology of
growth factors, termed neurotrophins. Dr. Hempstead was a member of the team
that identified signaling receptors for neurotrophins, the Trk receptor tyrosine
kinase, and identified proneurotrophins as independent death-promoting ligands.
Small polypeptides, neurotrophins were initially identified for their potent
biological actions in promoting the survival and function of neurons. However,
Dr. Hempstead’s laboratory identified unanticipated effects on the vasculature,
particularly the blood vessels of the heart. One member of the neurotrophin family,
brain derived neurotrophic factor or BDNF, is a required growth factor to permit
the normal development of the heart vasculature, and is further induced following
vascular injury. These results suggest that mechanisms to augment BDNF signaling
may promote angiogenesis following tissue ischemia.
In a second major line of investigation, Dr. Hempstead’s laboratory identified
precursor forms of the neurotrophins, or proneurotrophins, as independent ligands
that induce cell death. Proneurotrophins are not normally present in healthy
tissues, but are upregulated following tissue injury, where they mediate cell death
or dysfunction utilizing a distinct receptor system. Proneurotrophins are induced
following brain injury and epilepsy, and strategies to impair proneurotrophins
provide neural protection. Ongoing work is evaluating strategies to block proneurotrophin effects in a variety of injury paradigms. Thus, the long-term goals of their
research are to identify new therapeutic approaches to neurodegenerative diseases
and cardiovascular diseases.
Dr. Hempstead was a member of the team that identified
signaling receptors for neurotrophins and identified
proneurotrophins as independent death-promoting ligands.
Previous research by Dr. Hempstead and her colleagues shed light on a neural growth
factor called proBDNF, finding that it is present and potentially active during the
perinatal period when the brain’s circuitry and memory-encoding regions are being
refined. ProBDNF is the precursor form of mature BDNF, and both are active in the
hippocampus and cortex – areas key to learning, memory, and higher thinking.
Intriguingly, proBDNF and BDNF induce different actions; BDNF promotes the
differentiation of new neurons and their constituent parts and proBDNF promotes
the pruning of synapses. The results suggested that the nervous system plays an
active role in both potentiating and dampening its own activity.
The researchers developed new techniques that enabled them to observe when and
where proBDNF and mature BDNF were being made in a mouse model. They found
that proBDNF is most highly expressed in the hippocampus during the postnatal
period of the mouse at about days 3 to 21, when large numbers of axons and
synapses are being formed. They also found that p75 receptors, a class of receptors
that encode a “death domain” in which neurons are killed or pruned, are also active
during this period. Extrapolating her findings from mouse to human, this finding
provided new insight into how the brain is wired and how this wiring is refined –
particularly during the developmental stages.
36
WEILL CORNELL MEDICAL COLLEGE
RESEARCH PROFILES
Timothy Hla, PhD
Professor of Pathology and Laboratory Medicine
Dr. Timothy Hla works on cells that line the vascular tree called endothelial cells.
Two decades ago, while a postdoctoral trainee, Dr. Hla discovered a new receptor
in activated endothelial cells. He later discovered that this molecule binds to a
naturally occurring lipid molecule called sphingosine 1-phosphate (S1P). Since his
discovery of the first S1P receptor, much work has been done and it is now known
that five S1P receptors regulate vital functions in the body, such as blood vessel
function and immunity.
Serendipitously, a drug with origins in traditional Chinese medicine was discovered
to block the S1P receptor and reduce autoimmunity in the devastating disease of
multiple sclerosis (MS). It is now known that abnormal immune cells that attack
the nerve cells need S1P receptors to traffic into the central nervous system and by
targeting the receptor, nerve cell loss is reduced and patients with MS experience a
better outcome. Research in the Hla laboratory has played an important role in
understanding how this new drug, fingolimod, works. As all drugs go, efficacy is
coupled with side effects. Recent work from the Hla laboratory suggested that
interference with S1P receptors on endothelial cells may account for side effects
encountered by MS patients when taking this drug. These basic science efforts are
stimulating the search for better S1P receptor drugs, which may have utility in a wide
spectrum of autoimmune diseases, including psoriasis and rheumatoid arthritis.
Current research in the Hla laboratory is focused on better
defining S1P-related mechanisms and developing new ways
to prevent blood vessels from becoming inflamed and clot-prone.
Interestingly, S1P is carried by HDL, also referred to as the particle which carries the
“good” cholesterol. In collaboration with scientists in Europe, the Hla laboratory
discovered that an apolipoprotein M is the carrier of S1P in HDL. Since S1P in HDL
is thought to be one of the mechanisms by which HDL protects people from heart
disease and stroke, this work has tremendous potential to help people who are at
high risk for cardiovascular problems. Current research is focused on better defining
S1P-related mechanisms and developing new ways to prevent blood vessels from
becoming inflamed and clot-prone. Since the damage of the endothelial cell is
one of the most important events in heart disease and stroke, preservation of
endothelial cell function using the S1P pathway is extremely promising.
SELECTED Publications
Kohno M, Momoi M, Oo ML, Paik JH, Lee YM,
Venkataraman K, Ai Y, Ristimaki AP, Fyrst H,
Sano H, Rosenberg D, Saba JD, Proia RL, Hla T.
Intracellular role for sphingosine kinase 1 in
intestinal adenoma cell proliferation. Molecular
and Cellular Biology. 2006 Oct;26(19):7211-23.
Skoura A, Sanchez T, Claffey K, Mandala SM,
Proia RL, Hla T. Essential role of sphingosine
1-phosphate receptor 2 in pathological angiogenesis of the mouse retina. Journal of Clinical
Investigation. 2007 Sep;117(9):2506-16.
Thangada S, Khanna KM, Blaho VA, Oo ML,
Im DS, Guo C, Lefrancois L, Hla T. Cell-surface
residence of sphingosine 1-phosphate receptor 1 on lymphocytes determines lymphocyte
egress kinetics. Journal of Experimental
Medicine. 2010 Jul;207(7):1475-83.
Oo ML, Chang SH, Thangada S, Wu MT, Rezaul
K, Blaho V, Hwang SI, Han DK, Hla T. Engagement of S1P1-degradative mechanisms leads
to vascular leak in mice. Journal of Clinical
Investigation. 2011 Jun;121(6):2290-300.
Christoffersen C, Obinata H, Kumaraswamy SB,
Galvani S, Ahnström J, Sevvana M, EgererSieber C, Muller YA, Hla T, Nielsen LB, Dahlbäck
B. Endothelium-protective sphingosine-1phosphate provided by HDL-associated apolipoprotein M. Proceedings of the National Academy
of Sciences. 2011 Jun7;108(23):9613-18.
S1P and its five receptors also regulate many other processes in the body, such
as cell growth and migration. As such, it is important in cancer and angiogenesis.
Using mouse and zebrafish models in collaboration with Dr. Todd Evans in the
Department of Surgery, the Hla lab is examining how the S1P system regulates
abnormal angiogenesis and cancer. The Hla laboratory has discovered that a
simple molecule called S1P works in complex ways to regulate many essential
bodily functions and that one can control complicated diseases if one understand
the molecular details in depth. Since vascular health is essential for all organs, this
work has far-reaching implications to prevent and control human diseases.
2012-2013 Research highlights
37
RESEARCH PROFILES
Xin-Yun Huang, PhD
Professor of Physiology and Biophysics
Research in the laboratory of Dr. Xin-Yun Huang is focused on several cellular
signaling pathways, their physiological functions, and their applications in disease
treatments. Cellular signaling and cell-cell communication allow the multitude of
physiological processes in individual cells to proceed in a coordinated fashion to the
benefit of the organism. Signaling molecules are often perturbed in diseases and
are major targets for drug development.
SELECTED Publications
Yang S, Zhang JJ, Huang X-Y. Orai1 and STIM1
are critical for breast tumor cell migration and
metastasis. Cancer Cell. 2009 Feb 3;15: 124-34.
Guo D, Zhang JJ, Huang X-Y. Stimulation of
guanylyl cyclase-D by bicarbonate. Biochemistry.
2009 May 26;48: 4417-22.
Chen L, Zhang JJ, Rafii S, Huang X-Y.
Suppression of tumor angiogenesis by Gα13
haploinsufficiency. Journal of Biological
Chemistry. 2009 Oct 2;284:27409-15.
Chen L, Yang S, Jakoncic, Zhang JJ, Huang X-Y.
Migrastatin analogues target fascin to block
tumor metastasis. Nature. 2010 Apr 15;464:
1062-66.
Snyder M, Huang X-Y, Zhang JJ. STAT3 directly
controls the expression of Tbx5, Nkx2.5, and
GATA4 and is essential for cardiomyocyte
differentiation. Journal of Biological Chemistry.
2010 Jul 30;285: 23639-46.
Wang L, Guo D, Xing B, Zhang JJ, Shu HB,
Guo L, Huang X-Y. Resistance to inhibitors of
cholinesterase-8A (Ric-8A) is critical for growth
factor-receptor-induced actin cytoskeletal
reorganization. Journal of Biological Chemistry.
2011 Sep 2;286: 31055-61.
Snyder M, Huang X-Y, Zhang JJ. Stat3 directly
regulates cytokine-induced fascin expression
and is required for breast cancer cell migration.
Journal of Biological Chemistry. 2011;286:
38886-93.
38
WEILL CORNELL MEDICAL COLLEGE
One major research program is addressing the molecular signaling mechanism by
which G protein-coupled receptors and G proteins control cell functions. Dr. Huang
and his colleagues are deciphering their physiological functions in cell migration,
angiogenesis, cardiovascular diseases, and tumor metastasis using a combination
of approaches, including molecular, cellular, biochemical, genetic, structural, and
systems biological tools, as well as animal models. G protein-coupled receptors are
transmembrane proteins that act as key gatekeepers between external signals and
cellular responses. G protein-coupled receptors are the best pharmaceutical drug
targets so far. Currently Dr. Huang’s lab focuses on:
• the signaling mechanisms by which one of the G proteins, G13, controls the
migration of endothelial cells induced by G protein-coupled receptors and by
receptor tyrosine kinases
• the physiological function of this regulation in embryonic angiogenesis and adult
angiogenesis
• its implication in tumor angiogenesis
In addition, the lab has been using biochemical and biophysical techniques to investigate
the mechanism of activation of G proteins by G protein-coupled receptors.
The second major research program in Dr. Huang’s laboratory focuses on tumor
metastasis. Despite the significant improvement in both diagnostic and therapeutic
modalities for the treatment of cancer patients, metastasis remains the major cause
of mortality, being responsible for ~90 percent of all cancer deaths. Metastasis is a
multi-step process wherein a primary tumor spreads from its initial site to secondary
tissues/organs. This metastatic process is selective for cells that succeed in cell
migration/invasion, embolization, survival in the circulation, arrest in a distant
capillary bed, and extravasation into and multiplication within the organ parenchyma.
Failure at any of these steps could block the entire metastatic process. Since tumor
spreading is responsible for the majority of deaths of cancer patients, development
of therapeutic agents that inhibit tumor metastasis is essential for cancer
treatment. Tumor cell migration and invasion are critical steps in the process of tumor
metastasis. For cell migration to proceed, actin cytoskeleton must be reorganized
by forming polymers and bundles to affect the dynamic changes of cell shapes.
Individual actin filaments are flexible and elongation of individual filaments per se is
insufficient for membrane protrusion which is necessary for cell migration. Bundling
of actin filaments provides rigidity to actin filaments for protrusion against the
compressive force from the plasma membrane. Recently we have identified fascin
as a therapeutic target for blocking tumor cell migration, invasion, and metastasis.
Elevated levels of fascin have been found in metastatic tumors and are correlated
with clinically aggressive phenotypes, poor prognosis, and shorter survival. The
current objective of Dr. Huang’s research program is to develop fascin inhibitors as
therapeutics for treating and preventing tumor metastasis.
RESEARCH PROFILES
Costantino Iadecola, MD
Director, Brain and Mind Research Institute
George C. Cotzias Distinguished Professor of Neurology and Neuroscience
Research in the Division of Neurobiology, under the direction of Dr. Costantino
Iadecola, focuses on the brain dysfunction and damage that underlie two of the
most devastating brain diseases: stroke and dementia. Stroke, sometimes called
“brain attack,” is the second cause of death worldwide and the leading cause of
brain damage. It is most often caused by a blockage of the blood vessels that supply
the brain and leads to immediate paralysis, blindness, confusion, or language
problems. Dementia, such as Alzheimer’s disease, strikes an increasing number of
elderly individuals resulting in severe memory problems, disorientation, confusion,
and inability to care for oneself. The ultimate goal of Dr. Iadecola’s research is to
shed light on the causes of stroke and dementia, and to develop new therapies for
these conditions. This research flows along several interconnected lines.
Hypertension and the brain. High blood pressure, or hypertension, is a major
cause of stroke and dementia. Dr. Iadecola and his colleagues have discovered
that cerebral blood vessels are uniquely susceptible to the deleterious effects of
hypertension, and they are studying how such malfunction of blood vessels leads
to stroke and Alzheimer’s disease. Sleep apnea and aging, conditions well known to
cause stroke and dementia, also alter brain blood vessels in a similar fashion. They
have identified several therapeutic targets that would help protect the brain and its
vessels from the damaging effects of hypertension.
Why does the brain die after stroke? Dr. Iadecola’s lab group is investigating the
cellular and molecular alterations in the brain caused by blockage of the blood supply.
They found that stroke activates certain cells of the immune system and produces
brain inflammation. Blocking the action of these cells improves the brain damage
caused by the stroke. They are now looking at what triggers inflammation and finding
ways to stop it to salvage the brain. On the other hand, they also discovered that a
certain type of immune cells protect the brain after stroke. This is a new and exciting
area of investigation that may lead to developing new cell therapies for stroke.
Alzheimer’s disease and stroke. Once considered mutually exclusive, these two
highly prevalent brain diseases are now known to have much in common. The work
of Dr. Iadecola and his lab group have revealed that Alzheimer’s disease damages
blood vessels in a manner similar to hypertension and stroke. Improving the
performance of the blood vessels of the brain also improves the brain alterations
produced by Alzheimer’s disease. They have identified a “receptor” in brain vessels
that binds chemicals accumulating in Alzheimer’s disease (amyloid-β peptides)
resulting in their damage and are developing ways to block this receptor to protect
the brain from the damaging effects of amyloid-β.
Bright and dark sides of brain plasticity. The remarkable ability to learn and adapt to
a changing environment, known as neuroplasticity, is a defining characteristic of the
brain. Neuroplasticity is mediated by subtle changes in the connections through which
neurons communicate with each other and can protect the brain from the damage
associated with stroke and dementia. However, neuroplasticity also has a dark side.
Dr. Iadecola and his colleagues have discovered that the synaptic changes that underlie
learning and memory are similar to those induced by hypertension, drug addiction, and
sleep apnea. They are developing ways to harness the “good” side of neuroplasticity to
protect the brain from the damaging effects of stroke and dementia.
SELECTED Publications
Kawano T, Anrather J, Zhou P, Park L, Wang G,
Frys K, Kunz A, Cho S, Orio M, Iadecola C. Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity. Nature Medicine.
2006 Feb;12(2):225-29.
Girouard H, Park L, Anrather J, Zhou P, Iadecola
C. Cerebrovascular nitrosative stress mediates
neurovascular and endothelial dysfunction
induced by angiotensin II. Arteriosclerosis,
Thrombosis, and Vascular Biology. 2007 Feb;27(2):
303-39.
Park L, Wang G, Zhou P, Zhou J, Pistick R, Previti
ML, Younkin L, Younkin S, Van Nostrand WE,
Cho S-G, Anrather J, Carlson G, Iadecola C. The
scavenger receptor CD36 is essential for the
cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-β.
Proceedings of the National Academy of
Sciences. 2011 Mar 22;108(12):5063-68.
Iadecola C, Anrather J. The immunology of
stroke: from mechanisms to translation.
Nature Medicine. 2011 Jul 7;17(7):796-808.
Zhou P, Qian L, D’Aurelio M, Cho S, Wang G,
Manfredi G, Pickel V, Iadecola C. Prohibitin
reduces mitochondrial free radical production
and protects brain cells from different injury
modalities. Journal of Neuroscience. 2012
Jan 11;32(2):583-92.
Capone C, Faraco G, Peterson J, Coleman C,
Anrather J, Milner TM, Pickel V, Davisson RL,
Iadecola C. Central cardiovascular circuits
contribute to the neurovascular dysfunction
in angiotensin-II hypertension. Journal of
Neuroscience. 2012 Apr 4;32:4878-86.
2012-2013 Research highlights
39
RESEARCH PROFILES
Samie R. Jaffrey, MD, PhD
Associate Professor of Pharmacology
SELECTED Publications
Wu K, Hengst U, Cox LJ, Macosko EZ, Jeromin
A, Urquhart ER, Jaffrey SR. Local translation of
RhoA regulates growth cone collapse. Nature.
2005; Aug 18; 436(7053):1020-24.
Paige JS, Wu KY, Jaffrey SR. RNA mimics of
green fluorescent protein. Science. 2011 Jul 29;
333(6042):642-46.
Paige JS, Nguyen-Duc T, Song W, Jaffrey SR.
Fluorescence imaging of cellular metabolites
with RNAs. Science. 2012 Mar 9;335(6073):1194.
Ji S, Jaffrey SR. Intra-axonal translation of
SMAD1/5/8 mediates retrograde regulation
of trigeminal ganglia subtype specification.
Neuron. 2012 Apr 12;74:95-107.
Meyer KD, Saletore Y, Zumbo P, Elemento O,
Mason CE, Jaffrey SR. Comprehensive analysis
of mRNA methylation reveals pervasive
adenosine methylation in 3’ UTRs. Cell. 2012
Jun 22;149(7):1635-46.
The ability of cells to perform various functions and to respond to signaling
molecules has long been thought to be a consequence of the diversity of the
proteins encoded in the genome. However, it is now becoming clear that the cell
also contains a vast number of different types of RNAs that contribute to numerous
diverse cellular processes. Indeed, the transcriptome is no longer thought to solely
comprise tRNA, rRNA, and mRNA, but now includes microRNAs, termini-associated
RNAs, long intergenic noncoding RNAs, toxic RNAs, and many other intriguing
types of noncoding RNAs. The complexity of the noncoding RNA population points
to the existence of a parallel layer of cellular regulation beyond that provided by
proteins. Furthermore, mutations that affect these RNAs are now being recognized
as causes of various diseases. A major goal of the Jaffrey laboratory is to apply
molecular and chemical biology approaches to develop novel tools and imaging
approaches to uncover the roles of these noncoding RNAs and the mechanisms of
RNA regulation in cells.
A major impediment to studying RNA pathways is the absence of simple methods
to image RNA trafficking in living cells. To address this problem, the Jaffrey lab
has developed a novel class of RNAs that mimic GFP in cells and enable simple
and robust genetic encoding of fluorescently tagged RNAs. These RNAs bind
fluorophores resembling the fluorophore in GFP. Upon binding the fluorophores,
the RNAs “switch on” these otherwise nonfluorescent molecules, resulting
in fluorescence specifically associated with the tagged RNA. The researchers
developed a palette of RNA-fluorophore complexes that span the visible spectrum.
The Jaffrey lab has developed a novel class of RNAs that mimic
GFP in cells and enable simple and robust genetic encoding of
fluorescently tagged RNAs.
An RNA-fluorophore complex resembling enhanced GFP, termed Spinach, emits
a green fluorescence comparable in brightness to fluorescent proteins. Spinach is
markedly resistant to photobleaching, and Spinach-fusion RNAs can be imaged in
living cells. These RNA mimics of GFP provide an approach to genetically encode
fluorescent RNAs. Using Spinach, Dr. Jaffrey and his team have tagged small
non-coding RNAs to study their localization in response to cellular signaling.
Furthermore, they are currently using Spinach, as well as newer red and orange
fluorescent RNA-fluorophore tags that they have developed, Carrot and Radish,
to simultaneously image mRNAs and noncoding RNAs in living neurons. These
genetically encoded flourescent RNAs open the door to fundamentally new
approaches to explore RNA biology in cells.
The Jaffrey lab has also discovered that mRNA is subjected to a reversible
modification akin to phosphorylation in proteins. This modification, N6-methyladenosine (m6A), occurs in nearly 8,000 mRNAs and is enriched near stop codons
and at the ends of transcripts. Furthermore, this modification is regulated by
signaling pathways and during embryologic development. The Jaffrey lab also
showed that the fat mass and obesity-associated protein gene, FTO, a highly
prevalent obesity risk gene in humans, encodes an m6A demethylase, implicating
m6A as an important regulator of body mass in humans.
40
WEILL CORNELL MEDICAL COLLEGE
RESEARCH PROFILES
Rainu Kaushal, MD, MPH
Frances and John L. Loeb Professor of Medical informatics
The American healthcare system is struggling with high costs despite lower than
expected quality and safety. Dr. Rainu Kaushal and her team see great promise in
the potential of health information technology and other transformative healthcare
delivery policies to improve the value of healthcare. They conduct rigorous research
to quantify potential opportunities and actual effects of various novel technologies
and policies and then translate these findings into data-driven improvements in
healthcare.
In 2001, Dr. Kaushal published a landmark study in the Journal of the American
Medical Association showing that rates of potentially harmful medication errors were
three times higher in pediatric than adult inpatients. Dr. Kaushal then conducted a series
of inpatient and ambulatory studies further characterizing the causes of medication
errors for children and potential solutions, including new roles for clinical pharmacists,
educational material for parents, and the use of electronic prescribing. For several
years, Dr. Kaushal has translated her pediatric patient safety research directly into
quality improvement efforts as the Director of Pediatric Quality and Patient Safety at
the Komansky Center for Children’s Health at NewYork-Presbyterian Hospital.
In 2010, Dr. Kaushal published another landmark paper showing for the first
time that electronic prescribing can improve patient safety in community-based
outpatient practices. Dr. Kaushal demonstrated, in 2011, that different electronic
systems can have different effects on patient safety, depending on how they
are implemented, configured, and used. This is an important methodological
contribution, as it shows that – just like drugs and devices – healthcare delivery
interventions need to be tested and compared for their effectiveness.
Dr. Kaushal has contributed to the literature on the costs and financial returns
of implementing health information technology systems. Her work on the
costs of a national health information network and the return on investment
for a computerized order entry system have been frequently cited. Another
publication articulates which specific functions of electronic health records and
health information exchange are likely to drive financial savings. Dr. Kaushal has
also conducted research showing that community-based health information
exchange, electronic health records, and the patient-centered medical home are
associated with higher quality of care. Additional work, funded by the Agency for
Healthcare Research and Quality, developed a method for measuring quality in a
digital era and has garnered national attention. This method informed the design
of a substantial new federal investment in electronic health records.
Dr. Kaushal leads several multidisciplinary teams of investigators. The Health
Information Technology Evaluation Collaboration, an academic consortium of five
universities, is funded by New York State to conduct community-based participatory
research on the effects of health information technology. The Center for Healthcare
Informatics and Policy brings together physicians, health services researchers,
informaticists, economists, biostatisticians, and others across several departments
at Weill Cornell Medical College to create knowledge, provide education, generate
innovation, and provide service at the intersection of health information technology
and healthcare policy. Dr. Kaushal’s work continues to be timely and highly relevant
to the national discussions unfolding about innovations in healthcare delivery.
SELECTED Publications
Kaushal R, Bates DW, Landrigan C, McKenna
KJ, Clapp MD, Federico F, Goldmann DA.
Medication errors and adverse drug events in
pediatric inpatients. Journal of the American
Medical Association. 2001 Apr 23;285(16):2114-20.
Kaushal R, Blumenthal D, Poon EG, Jha AK,
Franz C, Middleton B, Glaser J, Kuperman G,
Christino M, Fernandopoulle R, Newhouse
J, Bates DW. The costs of a national health
information network. Annals of Internal
Medicine. 2005 Aug 2;143(3):165-73.
Kaushal R, Jha AK, Franz C, Glaser J, Shetty
KD, Jaggi T, Middleton B, Kuperman G,
Khorasani R, Tanasijevic M, Bates DW. Return
on investment for a computerized physician
order entry system. Journal of the American
Medical Informatics Association. 2006 May-Jun;
13(3):261-66.
Kern LM, Barron Y, Blair AJ, Salkowe J,
Chambers D, Callahan MA, Kaushal R. Electronic
result viewing and quality of care in small
group practices. Journal of General Internal
Medicine. 2008 Apr;23(4):405-10.
Kern LM, Dhopeshwarkar R, Barrón Y, Wilcox
A, Pincus H, Kaushal R. Measuring the effects
of health information technology on quality
of care: a novel set of proposed metrics for
electronic quality reporting. Joint Commission
Journal on Quality and Patient Safety. 2009 Jul;
35(7):359-69.
Kaushal R, Kern L, Barrón Y, Quaresimo J,
Abramson E. Electronic prescribing improves
medication safety in community-based office
practices. Journal of General Internal Medicine.
2010 Jun;25(6):530-36.
Kaushal R, Barrón Y, Abramson EL. The comparative
effectiveness study of 2 electronic prescribing
systems. American Journal of Managed Care.
2011 Dec;17(12 Spec No):SP88-94.
Kern LM, Wilcox A, Shapiro J, Dhopeshwarkar
R, Kaushal R. Which components of health
information technology will drive financial
value? American Journal of Managed Care.
2012;18(8):438-45.
2012-2013 Research highlights
41
RESEARCH PROFILES
Francis S. Lee, MD, PhD
Professor of Psychiatry
Professor of Pharmacology
SELECTED Publications
Chen ZY, Jing DQ, Bath KG, Ieraci A, Khan T,
Siao CJ, Herrera DG, Toth M, Yang C, McEwen
BS, Hempstead BL, Lee FS. Genetic variant
BDNF (Val66Met) polymorphism alters
anxiety-related behavior. Science. 2006 Oct 6;
314(5796):140-43.
Soliman F, Glatt CE, Bath KG, Levita L, Jones RM,
Pattwell SS, Jing DQ, Tottenham N, Amso D,
Somerville L, Voss HU, Glover G, Ballon DJ,
Liston C, Teslovich T, Van Kempen T, Lee FS*,
Casey BJ*. A genetic variant BDNF polymorphism alters extinction learning in both
mouse and human. Science. 2010 Feb 12;327
(5967):863-66. (*co-corresponding authorship)
Shmelkov SV, Hormigo A, Jing DQ, Proenca CC,
Bath KG, Tilde M, Shmelkov EV, Kushner J,
Baljevic M, Murphy AJ, Valenzuela DM, Gale NW,
Yancopoulos GD, Ninan I, Lee FS*, Rafii S*.
Slitrk5 deficiency impairs corticostriatal
circuitry and leads to obsessive-compulsive-like
behaviors in mice. Nature Medicine. 2010 May;
16(5):598-602. (*co-corresponding authorship)
Pattwell SS, Bath KG, Casey BJ, Ninan I, Lee FS*.
Selective early-acquired fear memories undergo
temporary suppression during adolescence.
Proceedings of the National Academy of
Sciences. 2011 Jan 18;108(3):1182-87.
(*co-corresponding authorship)
Proenca CC, Gao KP, Shmelkov SV, Rafii S,
Lee FS. Slitrks as emerging candidate genes
involved in neuropsychiatric disorders. Trends
in Neuroscience. 2011 Mar;34(3):143-53.
The broad goal of Dr. Francis Lee’s research program is to improve the understanding
of neuronal cell biology in order to enhance the focus of clinical studies related
to neuropsychiatric disorders. Dr. Lee’s laboratory addresses basic cell biology
questions of how a family of growth factors, neurotrophins, are sorted in and
secreted from neurons. A common single-nucleotide polymorphism (SNP) in one
of the neurotrophins, brain derived neurotrophic factor (BDNF), has been shown
by Dr. Lee to lead to defective BDNF trafficking in neurons. In humans, this genetic
alteration (BDNF Val66Met) has also been associated with alterations in brain
anatomy and memory, but its relevance to clinical disorders is unclear. Using a
novel “knock-in” mouse model of this BDNF SNP, he determined that this SNP may
lead to increased forms of anxiety that are resistant to standard drug treatments.
These findings suggest that this BDNF SNP may predict patients’ responses to
drug treatment and could lead to diagnostic testing to guide the treatment of
depression, replacing the current “trial-and-error” method.
This past year, in collaboration with Dr. B.J. Casey and Dr. John Walkup, Dr. Lee
has been studying the impact of this polymorphism in both mice and humans
on fear-based behaviors across development. In particular, his laboratory has
identified a novel form of brain plasticity in fear learning during early adolescence
that may prove informative for understanding endogenous mechanisms to
suppress unwanted fear memories. By examining fear conditioning in mice, as
they transitioned into and out of adolescence, Dr. Lee’s laboratory found that a
suppression of contextual fear occurs during adolescence. Although contextual
fear memories were not expressed during early adolescence, they could be
retrieved and expressed as the mice transitioned out of adolescence.
Dr. Lee’s findings suggest that this BDNF SNP may predict
patients’ responses to drug treatment and could lead to
diagnostic testing to guide the treatment of depression.
Dr. Lee has also expanded his efforts to study additional mouse models of anxiety
disorders. His laboratory, in collaboration with Dr. Shahin Rafii, has found that
a novel BDNF co-receptor, Slitrk5, that contributes to increased anxiety and
compulsive-like behaviors will expand the scope of his research efforts and allow
for a detailed investigation of the molecular and cell biology pathways potentially
underlying the pathogenesis of additional affective disorders such as obsessive
compulsive disorders. By establishing these animal models of anxiety-related
disorders, Dr. Lee will be able to investigate the fundamental relationship between
the trafficking fates and in vivo functional responses of these critical proteins in the
nervous system, and provide a novel research framework to study the pathophysiology
of neuropsychiatric disorders. He has started a remarkable range of collaborations to
test these ideas using animal models and clinical translational studies in humans.
In 2009, Dr. Lee received a Presidential Early Career Award for Scientists and
Engineers (PECASE), the highest honor bestowed by the White House Office of
Science and Technology Policy for outstanding scientists and engineers in the early
part of their independent research careers.
42
WEILL CORNELL MEDICAL COLLEGE
RESEARCH PROFILES
John P. Leonard, MD
Associate Dean for Clinical Research
Richard T. Silver Distinguished Professor of Hematology and Medical Oncology
Professor of Medicine
When the drug, rituximab – a monoclonal antibody directed against the CD20
molecule commonly present on the surface of lymphoma cells – was starting
to come into general use as the first of its kind for the treatment of lymphoma,
Dr. John Leonard was drawn to the opportunity to work on these exciting new
targeted treatment options to potentially improve outcomes for patients with
lymphoma, while minimizing treatment-related toxicity to improve quality of life. When
administered to patients, these molecules can specifically target tumor cells, while
relatively sparing normal cells, and can kill them via both direct and indirect mechanisms,
including activation of the immune system. In the past few years, this type of treatment
has made a major impact on the lives of patients with lymphoma, causing tumor
shrinkage, improvement in symptoms, and in some cases, improved survival.
Today, Dr. Leonard and his research team have established one of the leading centers
in the world for monoclonal antibody-based therapies and other novel therapeutics
for lymphoma. Much of this work has involved the development of radiolabeled
and unlabeled monoclonal antibody-based therapies for lymphoma, and other
immune-based strategies for the treatment of lymphoma and related hematologic
malignancies. They conducted the first major clinical trial of epratuzumab, a
monoclonal antibody against the CD22 molecule on lymphoma cells, and have
led other trials exploring its role as lymphoma therapy, including the first trial of
combination antibody therapy (epratuzumab and rituximab), which could allow patients
to delay or avoid chemotherapy. This work has led to involvement in the development
of other classes of targeted agents, including proteosome inhibitors, histone
deacetylase inhibitors, other epigenetic therapeutics, cell cycle inhibitors, and
immunomodulatory and various kinase inhibitors. Several of these compounds that
the group has evaluated have subsequently been approved by the FDA.
Dr. Leonard is currently collaborating with Dr. Ari Melnick in the Department of
Medicine, Hematology, and Medical Oncology and the Department of
Pharmacology, and Dr. Selina Chen-Kiang, Department of Pathology and Laboratory
Medicine, exploring important aspects of lymphoma biology and new treatments
for diffuse large cell, follicular, and mantle cell lymphomas.
Other efforts by the group include assessment of intensive versus non-intensive
treatment strategies in various settings, studies of the utility of various imaging
approaches in lymphoma, and issues relating to survivorship concerns of lymphoma
patients in remission. Dr. Leonard is Vice Chair of the Lymphoma Committee for the
Alliance for Clinical Trials in Oncology (formerly Cancer and Leukemia Group B), a
cooperative group of the National Cancer Institute that helps to develop new
standards of care for cancer treatment. Additionally, he recently became the Chair
of the Scientific Advisory Board of the Lymphoma Research Foundation and the
Leukemia and Lymphoma Society, where he contributes to advancing the research
agenda and patient services missions of these organizations.
Recently, Dr. Leonard was named Associate Dean for Clinical Research at Weill
Cornell, where he is leading the effort to improve and expand high-impact clinical
research that synergizes with the clinical, laboratory, and educational missions of
the Medical College.
SELECTED Publications
Furman RR, Martin P, Ruan J, Cheung YK, Vose
JM, LaCasce AS, Elstrom R, Coleman M, Leonard
JP. Phase I trial of bortezomib plus R-CHOP in
previously untreated patients with aggressive
non-Hodgkin lymphoma. Cancer. 2010 Dec 1;
116(23):5432-39.
Wilson WH, O’Connor OA, Czuczman MS,
LaCasce AS, Gerecitano JF, Leonard JP, et al.
Navitoclax, a targeted high-affinity inhibitor of
BCL-2, in lymphoid malignancies: a Phase I doseescalation study of safety, pharmacokinetics,
pharmacodynamics, and antitumour activity.
The Lancet Oncology. 2010 Dec;11(12):1149-59.
Ruan J, Martin P, Furman RR, Lee SM, Cheung
K, Vose JM, Lacasce A, Morrison J, Elstrom R,
Ely S, Chadburn A, Cesarman E, Coleman M,
Leonard JP. Bortezomib plus CHOP-rituximab
for previously untreated diffuse large B-cell
lymphoma and mantle cell lymphoma. Journal
of Clinical Oncology. 2011 Feb 20;29(6):690-97.
Czuczman MS, Leonard JP, et al. Phase II
trial of galiximab (anti-CD80 monoclonal
antibody) plus rituximab (CALGB 50402):
follicular lymphoma international prognostic
index (FLIPI) score is predictive of upfront
immunotherapy responsiveness. Annals of
Oncology. 2012 Apr; 87(4):433-35.
Elstrom RL, Martin P, Rua SH, Shore TB, Furman
RR, Ruan J, Pearse RN, Coleman M, Mark T,
Leonard JP, Gergis U. Autologous stem cell
transplant is feasible in very elderly patients
with lymphoma and limited comorbidity.
American Journal of Hematology. 2012
Apr;87(4):433-35.
Leonard JP, et al. Selective CDK4/6 inhibition
with tumor responses by PD0332991 in
patients with mantle cell lymphoma. Blood.
2012 May 17;119(20):4597-607.
Elstrom RL, Andemariam B, Martin P, Ruan J,
Shore TB, Coleman M, Leonard JP, Furman RR.
Bortezomib in combination with R-DICE chemoimmunotherapy (VIPER) in patients with relapsed
and primary refractory diffuse large B cell
lymphoma. Leukemia and Lymphoma. 2012
Aug;53(8):1469-73.
2012-2013 Research highlights
43
RESEARCH PROFILES
Steven M. Lipkin, MD, PhD
Associate Professor of Genetic Medicine
SELECTED Publications
Lipkin SM, Chao EC, Moreno V, Rozek LS,
Rennert H, Pinchev M, Dizon D, Rennert G,
Kopelovich L, Gruber SB. Genetic variation in
3-hydroxy-3-methylglutaryl CoA reductase
modifies the chemopreventive activity of
statins for colorectal cancer. Cancer Prevention
Research. 2010 May;3(5):597-603.
Wang X, Wei X, Thijssen B, Das J, Lipkin SM, Yu
H. Three-dimensional reconstruction of protein
networks provides insight into human genetic
disease. Nature Biotechnology. 2012 Jan 15;
30(2):159-64.
Jahid S, Sun J, Edwards RA, Dizon D, Panarelli NC,
Milsom JW, Sikandar SS, Gümüș ZH, Lipkin SM.
miR-23a and miR-27a promote the transition
from indolent to invasive and metastatic
colorectal cancer. Cancer Discovery. 2012
Jun;2(6):540-53.
Crous-Bou M, Rennert G, Salazar R, RodriguezMoranta F, Rennert HS, Lejbkowicz F, Kopelovich
L, Lipkin SM, Gruber SB, Moreno V. Genetic
polymorphisms in fatty acid metabolism genes
and colorectal cancer. Mutagenesis. 2012
Mar;27(2):169-76.
Stadler ZK, Esposito D, Shah S, Vijai J, Yamrom
B, Levy D, Lee Y, Kendall J, Leotta A, Ronemus M,
Hansen N, Sarrel K, Rau-Murthy R, Schrader K,
Kauff N, Klein RJ, Lipkin SM, Murali R, Robson M,
Sheinfeld J, Feldman D, Bosl G, Norton L, Wigler
M, Offit K. Rare de novo germline copy-number
variation in testicular cancer. American Journal
of Human Genetics. 2012 Aug 10;91(2):379-83.
Verma S, Salmans M, Geyfman M, Wang H,
Yu Z, Lu Z, Zhao F, Lipkin SM, Andersen BA.
Estrogen-responsive Agr2 gene regulates
mammary epithelial proliferation and facilitates
lobuloalveolar development. Developmental
Biology. 2012 Sep 15;369(2):249-60.
Chen J, Edwards J, Tucci S, Bu P, Milsom JW,
Lee J, Edelmann W, Gümüș ZH, Shen X, Lipkin
SM. The chemokine 25/chemokine receptor
9 axis suppresses colon cancer invasion and
metastasis. Journal of Clinical Investigation.
2012. [in press]
44
WEILL CORNELL MEDICAL COLLEGE
Most cancers are curable when detected early, before they have spread. Identifying
individuals who are at higher risk of developing cancer so that cancer surveillance
can be optimized for them is an important goal. Most of the patients with hereditary
breast, colon, hematologic, or multiple primary cancers do not have mutations in
the known risk genes. The laboratory of Dr. Steven Lipkin is using an innovative
tiered, resource-conscious strategy incorporating whole exome, full genome
sequencing, and previously untapped computational resources to discover,
prioritize, and rigorously validate new constitutional risk genes. Dr. Lipkin and
his colleagues have identified several candidate genes that they are investigating
further. Such an approach can help build a research paradigm for other as-yetuncharacterized cancer syndromes, and will identify individuals who will benefit
from increased cancer surveillance, early detection, and targeted cancer prevention.
The laboratory of Dr. Steven Lipkin is using an innovative
tiered, resource-conscious strategy to discover, prioritize, and
rigorously validate new constitutional risk genes.
A Weill Cornell principal investigator in the Starr Cancer Consortium, Dr. Lipkin
has a particular interest in colorectal cancer. In one study, Dr. Lipkin and his team
discovered why statins appear to protect against colorectal cancer development
in some individuals taking statins, but not all. They found that about 44 percent
of Caucasians taking statins likely are not protected against cancer as well as
others because they have inherited a particular gene variant. In a subsequent
study, they genotyped 40 candidate genes known to be important for synthesis
and metabolism of cholesterol through a population case-control study of
colorectal cancer in northern Israel. Included in the 40 genes were six SNPs, or DNA
sequences, within the HMGCR gene, which produces a critical enzyme involved
in the formation of cholesterol. They found one SNP within HMGCR that was
associated with statin protection against colorectal cancer.
The protective association was significantly stronger among individuals with what
they dubbed the “A” SNP allele, or variant, compared with people who had a “T”
variant. The researchers concluded that carriers of the A allele express more of the
full-length protein that binds statins, and are therefore more sensitive to statins
and more likely to experience the colorectal cancer risk reduction associated with
long-term use – especially if a person has two A alleles. Carriers of the T allele are
less sensitive to statins because they are missing part of the protein that binds
to statins. A protective effect against colorectal cancer development is largely
absent from people who have two T alleles. A test for this genetic variant has been
incorporated into the National Cancer Institute-sponsored P5 clinical trial, which is
evaluating the role of statins and aspirin to reduce colorectal cancer risk.
Dr. Lipkin has recently begun focusing efforts on identifying new gene mutations
that increase an individual’s risk of developing colon and breast cancers and
leukemias so that people carrying these mutations can be targeted for early
detection and cancer prevention. This new project was ranked in the top 1 percent
of National Cancer Institute-sponsored new projects in mid-2012.
RESEARCH PROFILES
David C. Lyden, PhD, MD
Stavros S. Niarchos Associate Professor in Pediatric Cardiology
Associate Professor in Pediatrics and Cell and Developmental Biology
Dr. David Lyden and colleagues have examined the earliest steps prior to influx
of metastatic tumor cells in distant organs. They have defined the cellular and
molecular events leading to the formation of the “pre-metastatic niche” that
identifies the receptive microenvironment at designated sites prior to the influx of
metastatic tumor cells in distant organs known as “metastatic niches” following
tumor cell engraftment. They uncovered a crucial role for specific bone marrowderived cells of myeloid lineage in priming distant tissues for tumor cell metastasis.
Dr. Lyden showed that factors released by the primary tumor drive the recruitment
of bone marrow-derived cells to fibronectin-enriched sites in the vicinity of the
future metastatic niche. These bone marrow cells express vascular endothelial
receptor 1 (VEGFR1), as well as integrins that allow binding to fibronectin-produced
sites. Together, these cells provide a platform of chemokines, growth factors,
matrix-degrading enzymes, and adhesion molecules, accelerating assembly of the
metastatic lesion.
Since this newly recognized field in cancer biology has been described by Dr. Lyden
and colleagues, an intense research focus related to mechanisms at the premetastatic niche, and to the metastatic niche, have been ongoing. One component
that remains particularly perplexing is the tissue-specific pattern of metastatic
progression in cancer. Unraveling an explanation for preferential metastasis to
specific organs known as organotropism has been challenging. To date, little is
known about the tumor-derived secreted factors that mediate the formation of the
pre-metastatic niche and hence organotropism of metastatic disease.
Recently, Dr. Lyden and colleagues (H. Peinado et al) have identified tumor-secreted
microparticles known as exosomes, which carry tumor information such as mRNAs,
microRNAs, DNA, and proteins, as new factors in the crosstalk between tumor
cells and cells in the tumor microenvironment. Tumor-derived exosomes circulate
in the bloodstream and fuse with cells in distant organ sites, mediating vascular
leakiness, inflammation, extracellular matrix remodeling, and the formation of
pre-metastatic niches that enhance metastatic burden and the number of sites
of metastatic disease, explaining the organotropic specificity of cancer. Exosomes
are also preferentially fused with bone marrow-derived cells, promoting their
“education” to a pro-vasculogenic, pro-migratory, and pro-metastatic phenotype
and enhancing their mobilization to pre-metastatic niche sites. Proteomic profiling
revealed that highly metastatic melanoma exosomes expressed high levels of the
MET oncoprotein as compared to non-metastatic exosomes. Moreover, exosomal
transfer and delivery of an oncogenic cargo to bone marrow-derived cells resulted
in the increase of MET-positive bone marrow-derived cells in melanoma models.
Consistent with these findings, higher amounts of MET were found in circulating
tumor-derived exosomes and bone marrow cells in patients with widespread
metastasis. In addition, an exosome protein signature could be used to identify
patients who are more likely to develop distant metastatic disease.
These insights are integral steps towards identifying molecular and cellular targets
for therapeutic development in the metastatic process. Interventions to prevent
or reduce the metastatic burden by targeting exosome production, transfer, and
education of bone marrow cells are hoped to significantly improve survival in
patients with cancer and metastatic disease.
SELECTED Publications
Lyden D, Young AZ, Zagzag D, Yan W, Gerald
W, O’Reilly R, Bader BL, Hynes RO, Zhuang Y,
Manova K, Benezra R. Id1 and Id3 are required
for neurogenesis, angiogenesis, and vascularization of tumour xenografts. Nature (article),
(News and Views). 1999 Oct 14;401:670-77.
Lyden D, Hattori K, Dias S, Blaikie P, Butros L,
Chadburn A, Heissig B, Marks W, Hackett NR,
Crystal RG, Moore MAS, Hajjar KA, Manova
K, Benezra R, Rafii R. Impaired recruitment of
marrow-derived VEGRF1+ hematopoietic and
VEGRF2+ endothelial precursor cells block tumor
angiogenesis and growth. Nature Medicine.
2001 Nov;7(11):1194-201.
Kaplan RN, Riba RD, Zacharoulis S, Bramley
AH, Vincent L, Costa C, MacDonald DD, Jin DK,
Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port
JL, Altorki N, Port ER, Ruggero D, Shmelkov SV,
Jensen KK, Rafii S, Lyden D. VEGFR1-positive
haematopoietic bone marrow progenitors
initiate the pre-metastatic niche. Nature
(article) (Nature Milestones Cancer; News and
Views, p.750). 2005 Dec 8;438(7069): 820-27.
Psaila B, Lyden D. The metastatic niche: adapting
the foreign soil. Nature Reviews Cancer. 2009
Apr;9:285-93.
Matei I, Ghajar CM, Lyden D. A TeNaCious
foundation for the metastatic niche. Cancer
Cell. 2011 Aug 16;20(2):139-41.
Peinado H, Aleckovic M, Lavothskin S, Costa da
Silva B, Moreno-Bueno G, Hergueta-Redondo
M, Williams C, Matei I, Garcia-Santos G, Nitadori-Hoshino A, Hoffman C, Garcia BA, Callahan
MK, Yuan J, Martins VR, Kaplan R, Brady MS,
Wolchok JD, Chapman PB, Kang Y, Bromberg JF,
Lyden D. Melanoma-derived exosomes educate
bone marrow progenitor cells toward a prometastatic phenotype through upregulation of
the MET oncoprotein. Nature Medicine (article),
(News and Views; Nature Reviews Cancer
‘Highlight’; Cancer Discovery, Science Signaling).
2012 Jun;18(6):833-94.
2012-2013 Research highlights
45
RESEARCH PROFILES
Khaled Machaca, PhD
Associate Dean for Research
Weill Cornell Medical College in Qatar
Professor of Physiology and Biophysics
SELECTED Publications
Machaca K, Haun S. Induction of maturationpromoting factor during Xenopus oocyte
maturation uncouples Ca2+ store depletion
from store-operated Ca2+ entry. Journal of Cell
Biology. 2002 Jan 7;156(1):75-85.
Sun L, Machaca K. Ca2+cyt negatively regulates
the initiation of oocyte maturation. Journal of
Cell Biology. 2004 Apr;165(1):63-75.
Machaca K. Increased sensitivity and clustering
of elementary Ca2+ release events during oocyte
maturation. Developmental Biology. 2004 Nov 1;
275(1):170-82.
El-Jouni W, Haun S, Hodeify R, Walker AH,
Machaca K. Vesicular traffic at the cell
membrane regulates oocyte meiotic arrest.
Development. 2007 Sep;134(18):3307-15.
Sun L, Haun S, Jones RC, Edmondson RD,
Machaca K. Kinase-dependent regulation of IP3dependent Ca2+ release during oocyte maturation. Journal of Biological Chemistry. 2009 Jul 24;
284(30):20184-96.
Yu F, Sun L, Machaca K. Orai1 internalization
and STIM1 clustering inhibition modulate SOCE
inactivation during meiosis. Proceedings of the
National Academy of Sciences. 2009 Oct 13;
106(41):17401-06.
Yu F, Sun L, Machaca K. Constitutive recycling of
the store-operated Ca2+ channel Orai1, and its
internalization during meiosis. Journal of Cell
Biology. 2010 Nov 1;191(3):523-35.
Sun L, Yu F, Ullah A, Hubrack S, Daalis A, Jung P,
Machaca K. Endoplasmic reticulum remodeling
tunes IP3-dependent Ca2+ release sensitivity.
PLoS One. 2011;6(11):e27928
Ca2+ is a ubiquitous intracellular messenger that mediates various physiological
processes including fertilization, muscle contraction, neurostransmitter release,
and the regulation of gene expression. As such Ca2+ plays fundamental roles
in regulating intracellular signaling. The specificity of the cellular response
downstream of the intracellular Ca2+ signal is encoded in its spatial and temporal
properties. Hence different cell types and even the same cell type during its
development and differentiation handle Ca2+ signals differentially. However, the
molecular mechanisms mediating the remodeling of the Ca2+ signaling machinery
during cellular development remain poorly understood.
Dr. Khaled Machaca and his colleagues have made significant contributions to
the understanding of the regulation of Ca2+ signaling pathways during cellular
development and division using oocyte maturation as their preferred model system.
Ca2+ is the universal signal for egg activation at fertilization and for mediating the
critical egg to embryo transition. Ca2+ signals remodel during oocyte maturation
to endow the egg with the capacity to activate at fertilization and transition to
embryogenesis. The Machaca lab has shown over the year that this remodeling
involves some of the key channels and transporters that underlie Ca2+ signaling.
The plasma membrane Ca2+ ATPase is removed from the cell membrane into an
intracellular vesicular pool and the IP3 receptor forms large patches in the context
of the remodeling of the endoplasmic reticulum during meiosis. Furthermore, the
predominant Ca2+ entry pathway in the oocyte, store-operated Ca2+ entry (SOCE),
inactivates completely during oocyte maturation. SOCE inactivation has been
shown by the Machaca lab to be due to modulation of the two molecules mediating
SOCE, STIM1, and Orai1. STIM1 clustering is inhibited and Orai1 is internalized
during oocyte maturation.
Dr. Khaled Machaca and his colleagues have made significant
contributions to the understanding of the regulation of Ca2+
signaling pathways during cellular development and division
using oocyte maturation as their preferred model system.
Because oocyte maturation is a contributing limiting factor in infertility treatments,
this line of investigations has the potential to improve human infertility treatments.
Furthermore, given the ubiquitous role that Ca2+ signals play in a variety of cellular
signaling pathways, these studies are likely to have wide-ranging implications to
a variety of human diseases, including hypertension. In fact, current studies in the
Machaca lab focus on the regulation of the IP3 receptor in hypertension.
Dr. Machaca’s group is also interested in elucidating the signaling and cellular
mechanisms regulating the arrest and resumption of the meiotic cell cycle during
oocyte maturation. These studies have implicated a role for Zn2+ in resumption of
the meiotic division at ovulation.
46
WEILL CORNELL MEDICAL COLLEGE
RESEARCH PROFILES
Frederick R. Maxfield, PhD
Vladimir Horowitz and Wanda Toscanini Horowitz
Distinguished Professor of Neuroscience
Professor of Biochemistry
Research in Dr. Fred Maxfield’s laboratory uses sophisticated microscopy imaging
to gain insight into basic processes in cell biology and to understand how these
processes are associated with disease. Because many fundamental processes are
similar in cells from various tissues, this approach leads Dr. Maxfield’s research
into several different diseases, which might seem to be unrelated until one
sees similarity in the underlying cellular mechanisms. One example is a process
called endocytosis, which is used by cells to take in nutrients and also to remove
unwanted materials from the extracellular environment. Normally, such materials
are taken into a digestive organelle called the lysosome, where the ingested
molecules are broken down and reutilized by the cell to make membranes and
proteins. A well-characterized example is the uptake of lipoproteins by cells. This
process evolved to deliver cholesterol that is obtained from the diet or made in the
liver to be distributed to cells throughout the body, where the cholesterol is used as
an essential component of cell membranes. The process leads to atherosclerosis and
heart disease when there is excess cholesterol.
Recently, Dr. Maxfield’s group used careful high resolution microscopy imaging to
see how specialized cells, called macrophages, interact with cholesterol deposits
from lipoproteins similar to those found in the walls of blood vessels. Surprisingly,
they found that rather than taking in the lipoproteins and digesting them inside
the cells (as had been presumed for many years), the cells actually create a digestive
organelle, a lysosomal synapse, outside the cell. This releases cholesterol outside
the cells and may lead to abnormal deposition of cholesterol crystals, a hallmark of
advanced atherosclerosis.
Several years ago, Dr. Maxfield became interested in the similarity between uptake
of lipoproteins by macrophages and the interaction of macrophage-like cells in the
brain, called microglia, with Alzheimer’s amyloid deposits. His laboratory showed
that a cell-surface receptor, called a scavenger receptor, which had been shown to
be involved in uptake of some lipoproteins by macrophages, was also able to lead
to internalization of Alzheimer’s amyloid fibrils by microglia. Unexpectedly, the
microglia were unable to digest the amyloid even though they delivered it to their
lysosomes, the digestive organelle of the cell. In recent studies, Dr. Maxfield’s group
showed that this was due to poor acidification of the lysosomes. They also recently
identified the molecular mechanism for this weak acidification in microglia and
indicated ways in which this might be corrected to allow for better clearance of
amyloid deposits.
SELECTED Publications
Grosheva I, Haka AS, Qin C, Pierini LM, Maxfield
FR. Aggregated LDL in contact with macrophages induces local increases in free
cholesterol levels that regulate local actin
polymerization. Arteriosclerosis, Thrombosis,
and Vascular Biology. 2009 Oct;29(10):1615-21.
Haka AS, Grosheva I, Chaing E, Buxbaum AR,
Baird BA, Pierini LM, Maxfield FR. Macrophages
create an acidic extracellular hydrolytic
compartment to digest aggregated lipoproteins. Molecular Biology of the Cell. 2009
Dec;20(23):4932-40. (selected as Paper of the
Year)
Rosenbaum AI, Zhang G, Warren JD, Maxfield
FR. Endocytosis of beta-cyclodextrins is responsible for cholesterol reduction in Niemann-Pick
type C mutant cells. Proceedings of the National
Academy of Sciences. 2010 Mar 23;107(12):
5477-82.
Pipalia NH, Cosner CC, Huang A, Chatterjee A,
Bourbon P, Farley N, Helquist P, Wiest O,
Maxfield FR. Histone deacetylase inhibitor
treatment dramatically reduces cholesterol
accumulation in Niemann-Pick type C1 mutant
human fibroblasts. Proceedings of the National
Academy of Sciences. 2011 Apr 5;108(14):
5620-25.
Majumdar A, Capetillo-Zarate E, Cruz D, Gouras
GK, Maxfield FR. Degradation of Alzheimer’s
amyloid fibrils by microglia requires delivery
of ClC-7 to lysosomes. Molecular Biology of the
Cell. 2011 May 15;22(10):1664-76.
In some inherited disorders, the lysosomes fail to function properly because of a
missing or defective protein. One such disorder is Niemann-Pick type C disease, which
leads to cholesterol accumulation in lysosomes and is usually fatal before age 20.
Dr. Maxfield’s laboratory carried out a microscopy-based screen for compounds
that might ameliorate the cholesterol accumulation. A recent study showed that
a class of drugs called HDAC inhibitors were very effective in cells from patients.
Some of these drugs are FDA approved for other diseases, and Dr. Maxfield and
his collaborators at the NIH and Notre Dame are arranging for clinical trials in
Niemann-Pick type C disease.
2012-2013 Research highlights
47
RESEARCH PROFILES
Ari M. Melnick, MD
Associate Professor of Medicine
SELECTED Publications
Cerchietti LC, Lopes EC, Yang SN, Hatzi K, Bunting
KL, Tsikitas LA, Mallik A, Robles AI, Walling J,
Varticovski L, Shaknovich R, Bhalla KN, Chiosis G,
Melnick AM. A purine scaffold Hsp90 inhibitor
destabilizes BCL6 and has specific anti-tumor
activity in BCL6 dependent DLBCLs in vitro and
in vivo. Nature Medicine. 2009 Dec;15(12):1369-76.
Figueroa ME, Lugthart S, Li Y, ErpelinckVerschueren C, Deng X, Christos PJ, Schifano E,
Booth J, van Putten W, Skrabanek L, Campagne F,
Mazumdar M, Greally JM, Valk PJ, Löwenberg B,
Delwel R, Melnick AM. DNA methylation
signatures identify biologically distinct
subtypes in acute myeloid leukemia. Cancer Cell.
2010 Jan 19;17(1):13-27. Cited by Faculty of 1000
Medicine and Faculty of 1000 Biology.
Cerchietti LC, Ghetu AF, Zhu X, Da Silva GF,
Zhong S, Matthews M, Bunting KL, Polo JM,
Farès C, Arrowsmith CH, Yang SN, Garcia M,
Coop A, Mackerell AD Jr, Privé GG, Melnick AM.
A small molecule inhibitor of BCL6 kills DLBCL
cells in vitro and in vivo. Cancer Cell. 2010
Apr 13;17(4):400-11. Cited by Faculty of 1000.
Figueroa ME, Abdel-Wahab O, Lu C, Ward PS,
Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar
A, Fernandez HF, Tallman MS, Sun Z, Wolniak
K, Peeters JK, Liu W, Choe SE, Fantin VR, Paietta
E, Löwenberg B, Licht JD, Godley LA, Delwel R,
Valk PJ, Thompson CB, Levine RL, Melnick AM.
Leukemic IDH1 and IDH2 mutations result in
a hypermethylation phenotype, disrupt TET2
function, and impair hematopoietic differentiation. Cancer Cell. 2010 Dec 14;18(6):553-67.
Cited by Faculty of 1000.
Duy C, Hurtz C, Shojaee S, Cerchietti L, Geng H,
Swaminathan S, Klemm L, Kweon SM, Nahar R,
Braig M, Park E, Kim YM, Hofmann WK, Herzog
S, Jumaa H, Koeffler HP, Yu JJ, Heisterkamp N,
Graeber TG, Wu H, Ye BH, Melnick AM, Müschen
M. BCL6 enables Ph1 acute lymphoblastic leukaemia cells to survive BCR–ABL1 kinase inhibition. Nature. 2011 May 19;473(7347):384-88.
Cited by Faculty of 1000.
48
WEILL CORNELL MEDICAL COLLEGE
A majority of tumors are caused by mutations or inappropriate expression of
master regulatory factors that can “reprogram” normal cells into cancerous tissue.
Under the direction of Dr. Ari Melnick, researchers are developing ways to identify
these master regulatory proteins and to dissect out their molecular mechanisms of
action. By combining sophisticated gene mapping tools that can track the location
of these factors throughout the genome, together with advanced structural biology
and biochemistry methods, Dr. Melnick’s team has discovered how several of these
cancer-causing factors work at the most basic level, by hijacking and taking control
of thousands of different genes using a variety of biochemical mechanisms. These
findings are leading directly to novel forms of treatments for patients with B-cell
lymphomas, leukemias, and other tumors.
Dr. Melnick’s team discovered that a master regulatory protein, called BCL6, causes
aberrant growth and survival of lymphoma cells through a specific “intermolecular
bridge.” BCL6 mediates its cancer-causing actions by attaching to other proteins.
Traditionally, protein-protein interactions have been viewed as being too difficult
to block with small-molecule drugs. By observing the atomic scale structure of BCL6
attached to its partner proteins, Dr. Melnick and colleagues identified a critical “hot
spot” that appeared to be amenable to designing a drug. Using this information,
his lab generated a peptidomimetic drug, called RIBPI, that destroys this bridge,
which restored lymphoma cells back to their normal programming. Dr. Melnick and
his colleagues used structure-based advanced computational modeling to design
small molecule inhibitor drugs that work similarly to RIBPI. The BCL6 inhibitors are
highly effective in killing lymphoma cells and were non-toxic to normal tissues.
They discovered that the molecular chaperone Hsp90 plays a central role in diffuse
large B-cell lymphomas and that a newly developed inhibitor of Hsp90, called
PUH71, has potent anti-lymphoma effects. Based on these data, the National
Cancer Institute is supporting translation of PUH71 to clinical trials.
Dr. Melnick’s group discovered that the molecular chaperone
Hsp90 plays a central role in diffuse large B-cell lymphomas
and that a newly developed inhibitor of Hsp90 called PUH71
has potent anti-lymphoma effects.
In other research, Dr. Melnick and his colleagues recently established a technology
platform for deciphering how genes are controlled in cancer cells. The technique
combines biochemistry, mathematics, and computational biology to capture at a
holistic level the molecular instructions that control cancer cells and can even
decode those epigenetic instructions that control gene expression independently of
DNA sequence. Using this approach in large cohorts of patients with acute myeloid
leukemia (AML), they were able to show for the first time that profound disruption
of epigenetic gene regulation is a universal feature of tumors, identified new
biologically and clinically distinct forms of AML, discovered a common epigenetic
signature that underlies almost all AML (thus showing that epigenetic lesions occur
more frequently and universally than genetic lesions), and identified a predictive
DNA methylation-based biomarker for patient survival that outperforms the
traditional currently available biomarkers.
RESEARCH PROFILES
Anant K. Menon, PhD
Professor of Biochemistry
The laboratory of Dr. Anant Menon is interested in membrane biogenesis, a critical
activity required for cell growth, differentiation, and maintenance. It is a particularly
complex process in eukaryotic cells as these cells have a characteristically diverse set
of membranes with unique compositional and functional identities. Dr. Menon and
his colleagues consider a number of questions. How are the components of biological
membranes synthesized? How are they inserted and assembled into a pre-existing
membrane template? How are molecules transported across membranes and
exchanged between different membrane-bound compartments? Their current focus
is on the molecular mechanisms of intracellular lipid transport. Lipids are generally
amphipathic – they have a polar head and a hydrophobic tail. These features pose
a challenge: The polar headgroup makes it next to impossible for lipids to move
spontaneously across cellular membranes on a reasonable timescale, whereas the
apolar nature of the tail prevents fast lipid movement from one membrane to another,
via the aqueous cytoplasm. Nevertheless, cell growth and homeostasis demand that
lipids move rapidly across and between membranes in cells, and for this specialized
machinery must exist. Dr. Menon’s research team is interested in identifying the molecular
components of this machinery and understanding lipid transport mechanisms.
Cholesterol is an important constituent of biological membranes. Cells make
cholesterol in the endoplasmic reticulum, a biosynthetically active intracellular
compartment, or import it by receptor-mediated endocytosis of lipoproteins.
Regardless of its source, cholesterol is mainly found in the plasma membrane where
it represents 40 percent of the lipids. Cellular cholesterol levels are tightly controlled
by acute responses as well as by transcriptional programming, both of which require
sterol exchange between membranes. By analyzing sterol transport in baker’s yeast, the
Menon lab discovered that it occurs largely by non-vesicular mechanisms requiring
cytoplasmic transport proteins. The researchers recently developed methods to visualize
sterol transport in living yeast cells, and they are now combining this technology with
genetic and biochemical approaches to identify the enigmatic sterol carriers.
Lipid movement across membranes (lipid flip-flop) is required at many biological levels.
For example, it is needed for protein N-glycosylation and the clearance of apoptotic
cells; in bacteria, it is needed for cell wall assembly. Activity assays reveal that unique
membrane-embedded transport proteins facilitate flip-flop whereas others act as
lipid pumps. A number of lipid pumps have been identified, but facilitators of lipid
flip-flop have eluded researchers for decades. Dr. Menon and his colleagues recently
reported that the visual receptor rhodopsin facilitates phospholipid flip-flop at a
rapid rate. This activity is important for clearance of by-products of the visual cycle
whose accumulation contributes to the progression of macular degeneration. They
are now analyzing how rhodopsin carries out this remarkable transport function. In
collaboration with Dr. Alessio Accardi at Weill Cornell, they identified proteins that
facilitate calcium ion-dependent lipid scrambling at the plasma membrane. This is a
key event that enables activated platelets to facilitate coagulation at sites of blood
vessel injury and signals macrophages to engulf cells undergoing programmed cell
death. In a parallel effort with Dr. Johannes Graumann of Weill Cornell Medical
College-Qatar, Dr. Menon’s lab is using quantitative proteomics to identify facilitators
that flip lipids needed for protein N-glycosylation in the endoplasmic reticulum.
Through these efforts the Menon laboratory hopes to reveal basic mechanisms of cell
biology, as well as identify new targets for therapeutic intervention.
SELECTED Publications
Frank CG, Sanyal S, Rush JS, Waechter CJ,
Menon AK. Does Rft1 flip an N-glycan lipid
precursor? Nature. 2008 Jul 31;454(7204):E3-4;
discussion E4-5.
Sanyal S, Menon AK. Specific transbilayer
translocation of dolichol-linked
oligosaccharides by an endoplasmic reticulum
flippase. Proceedings of the National Academy
of Sciences. 2009 Jan 20;106(3):767-72.
Sanyal S, Menon AK. Stereoselective
transbilayer translocation of mannosyl
phosphoryl dolichol by an endoplasmic
reticulum flippase. Proceedings of the National
Academy of Sciences. 2010 107, 11289-94.
Menon I, Huber T, Sanyal S, Banerjee S, Barré P,
Canis S, Warren JD, Hwa J, Sakmar TP, Menon
AK. Opsin is a phospholipid flippase. Current
Biology. 2011 Jan 25;21(2):149-53.
Georgiev A, Sullivan DP, Kersting MC, Dittman
JS, Beh CT, Menon AK. Osh proteins regulate
membrane sterol organization but are not
required for sterol movement between the ER
and PM. Traffic. 2011 Oct;12(10):1341-55.
Beh CT, McMaster CR, Kozminski KG, Menon
AK. A detour for yeast oxysterol-binding protein
homologues and nonvesicular trafficking. The
Journal of Biological Chemistry. 2012 Mar 30;
287(14):11481-88.
2012-2013 Research highlights
49
RESEARCH PROFILES
Teresa A. Milner, PhD
Professor of Neuroscience
Throughout the life cycle, estrogens and other gonadal steroids can influence
many brain functions. In addition to regulating reproductive functions and
homeostasis, estrogens can affect cognitive and emotional processes, as well as
autonomic functions. Dr. Teresa Milner’s research focuses on delineating the
mechanisms by which estrogens influence cognition, particularly those related to
drug abuse and to cardiovascular functions during menopause.
SELECTED Publications
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tincidunt
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magna aliquam
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2011 Mar
16;1379:86-97.
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Williams TJ, Akama KT, Knudsen MG, McEwen
BS, Milner TA. Ovarian hormones influence
corticotropin releasing factor receptor
colocalization with delta opioid receptors in
CA1 pyramidal cell dendrites. Experimental
Neurology. 2011 Aug;230:186-96.
50
WEILL CORNELL MEDICAL COLLEGE
Women are more susceptible to several aspects of drug addiction than men,
including relapse following stressful events. The hippocampus is a brain region
that is critically involved in learning relevant to drug abuse. Moreover, estrogens
and opioid peptides, by binding to select receptors, can modulate learning
processes in the hippocampus. Over the years, Dr. Milner’s research has localized
both estrogen and opioid receptors in rodents using electron microscopic
immunocytochemical methods to help elucidate the mechanisms by which
estrogens and opioids interact to impact learning relevant to drug abuse. In
particular, her lab has found that estrogen receptors (ERs) are not only found in
nuclei where they can influence genomic events, but also are located in synapses
where they can influence rapid communication between nerve cells.
Dr. Milner’s research has localized both estrogen and opioid
receptors in rodents to help elucidate the mechanisms by
which estrogens and opioids interact to impact learning
relevant to drug abuse.
Dr. Milner also has demonstrated that the mu- and delta-opioid receptors (MOR
and DORs, respectively) are present on select subtypes of hippocampal neurons
where they can influence the balance of excitation and inhibition. Her most
recent studies indicate that estrogens regulate endogenous hippocampal opioid
peptides and MORs and DORs in a manner that could promote learning processes
relevant to drug abuse and relapse after chronic stress.
After menopause, hypertension and stress reactivity increases in women.
Dr. Milner’s research investigates the central mechanisms by which estrogens
regulate blood pressure in rodents to help understand the development of
hypertension and stress reactivity in menopause. Her research has shown that
receptors for estrogens and other ovarian steroids have a regionally selective
location relative to cardiovascular brain circuits.
Using combined neuroanatomical and physiological approaches, Dr. Milner’s lab
has shown that estrogens, primarily via ER beta, regulate angiotensin-signaling in
the rostral ventrolateral medulla, a brain region crucial for the regulation of blood
pressure. Her most recent research utilizes a new “accelerated ovarian failure”
model of menopause to study the mechanisms by which changes in estrogen
levels during menopause influence cells in the hypothalamic paraventricular
nucleus, a brain region critical for integrating and coordinating neurohumoral
responses involved in blood pressure regulation. These studies have contributed
importantly to understanding changes in the brain during menopause that
contribute to the increased susceptibility to hypertension.
RESEARCH PROFILES
John P. Moore, PhD
Professor of Microbiology and Immunology
The laboratory of Dr. John Moore is focused on contributing to international efforts
to prevent and treat HIV-1 infection. This virus has already infected and killed tens of
millions of people, particularly in the developing world, and it continues to spread.
While nowadays excellent drug therapies are available to treat infected people,
provided they have access, prevention successes have been partial and patchy.
Dr. Moore’s laboratory has several different, but interrelated, basic science research
programs that are based on understanding how the virus enters the cells it infects,
and on finding ways to prevent that process from happening. Specific inhibitors of
virus entry are now available, including licensed drugs. Working within a research
consortium, Dr. Moore and his colleagues are studying how some of these inhibitors
can be used to prevent virus transmission, not just treat it. More specifically, they
are evaluating the protective potential of compounds that block access to the
CCR5 receptor for HIV-1 on the surface of target cells. These inhibitors, alone and
in combination with other types, are being tested in the rhesus macaque model of
vaginal HIV-1 transmission. To help improve the chances that inhibitors like these
would actually be used by women, they are studying ways to deliver them in a userfriendly, minimally inconvenient manner. One such approach is to formulate the
inhibitors in plastic rings that can be inserted vaginally and left in place for up to a
month, gradually releasing the active compound where it is needed. Another is to
use silicone gel formulations similar to personal lubricants that can be applied only
once a day. In a related study, scientists in the lab are testing whether this kind of
approach to prevention can be combined with vaccination. Do two partially effective
intervention approaches work better together than apart?
The laboratory of Dr. John Moore is focused on contributing to
international efforts to prevent and treat HIV-1 infection.
Dr. Moore’s laboratory is also involved in vaccine-related research, particularly
work on the viral envelope glycoproteins that are involved in virus entry. These
proteins are the targets for antibodies that neutralize virus infection. In principle,
this kind of antibody could protect people from HIV-1, if ways to induce them
consistently by vaccination could be devised. To gain more information on how to
do this, Dr. Moore and his researchers are working with colleagues elsewhere to
obtain detailed structural information on the envelope glycoproteins in a trimeric
configuration that mimics how they appear on the virus surface. They hope that
this kind of information could help them and others design improved versions of
the envelope glycoproteins for use as vaccine components. They are also testing
how to make the envelope glycoproteins more immunogenic by studying how
they interact with cells of the immune system and learning how to overcome
limitations on how the body raises antibodies to them.
SELECTED Publications
Anastassopoulou CG, Ketas TJ, Klasse PJ, Moore
JP. Resistance to CCR5 inhibitors caused by
sequence changes in the fusion peptide of
HIV-1 gp41. Proceedings of the National
Academy of Sciences. 2009 Mar 31;106(13):
5318-23.
Berro R, Sanders RW, Lu M, Klasse PJ, Moore JP.
Two HIV-1 variants resistant to small molecule
CCR5 inhibitors differ in how they use CCR5 for
entry. PLoS Pathogens. 2009 Aug;5(8):e1000548.
Veazey RS, Ketas TJ, Dufour J, MoroneyRasmussen T, Green LC, Klasse PJ, Moore JP.
Protection of rhesus macaques from vaginal
infection by vaginally delivered Maraviroc, an
inhibitor of HIV-1 entry via the CCR5 co-receptor.
Journal of Infectious Diseases. 2010 Sep 1;202(5):
739-44.
Burton DR, Hessell AJ, Keele BF, Klasse PJ, Ketas
TA, Moldt B, Dunlop CC, Poignard P, Doyle LA,
Cavacini L, Veazey RS, Moore JP. Limited or no
protection by weakly or non-neutralizing antibodies against SHIV challenge compared to a
strongly neutralizing antibody. Proceedings of
the National Academy of Sciences USA. 2011 Jul 5;
108(27):11181-86.
Barouch DH, Klasse PJ, Dufour J, Veazey RS,
Moore JP. Macaque studies of vaccine and
microbicide combinations for preventing HIV-1
sexual transmission. Proceedings of the
National Academy of Sciences USA. 2012
May 29; 109(22):8694-98.
A third project involves understanding how HIV-1 becomes resistant to the
inhibitors that prevent virus binding to the CCR5 receptor. Dr. Moore’s lab found that
the resistant viruses still use CCR5, but do so differently. They now seek to obtain
fundamental information on the way the virus interacts with CCR5, and how, by
doing so, it enters cells both when the inhibitors are present and when they are not.
2012-2013 Research highlights
51
RESEARCH PROFILES
Anne Moscona, MD
Vice Chair, Research, Department of Pediatrics
Professor of Pediatrics
Professor of Microbiology and Immunology
SELECTED Publications
Palermo L, Porotto M, Yokoyama C, Palmer S,
Mungall B, Greengard O, Niewiesk S, Moscona A.
Human parainfluenza virus infection of the
airway epithelium: the viral hemagglutininneuraminidase regulates fusion protein
activation and modulates infectivity. Journal of
Virology. 2009 Jul;83(13):6900-08.
Porotto M, Rockx B, Yokoyama CC, Talekar A,
DeVito I, Palermo LM, Cortese R, Lu M, Feldmann
H, Pessi A, Moscona A. Inhibition of Nipah virus
infection in vivo: targeting an early stage of
paramyxovirus fusion activation during viral
entry. PLoS Pathogens. 2010 Oct 28; 6(10).
Farzan S, Palermo LM, Yokoyama CC, Orefice G,
Fornabaio M, Sarkar A, Kellogg GE, Greengard O,
Porotto M, Moscona A. Premature activation of
the paramyxovirus fusion protein before target
cell attachment: corruption of the viral fusion
machinery. Journal of Biological Chemistry.
2011 Nov 4;286(44):37945-54.
Porotto M, DeVito I, Palmer SG, Jurgens EM, Yee JL,
Yokoyama CC, Pessi A, Moscona A. Spring-loaded
model revisited: paramyxovirus fusion requires
engagement of a receptor binding protein beyond
initial triggering of the fusion protein. Journal of
Virology. 2011 Dec;85(24):12867-80.
Porotto M, Palmer S, Palermo L, Moscona A.
Mechanism of fusion triggering by
paramyxoviruses: dommunication between
viral glycoproteins during entry. Journal of
Biological Chemistry. 2012 Jan 2;287(1):778-93.
Porotto M, Salah Z, Devito I, Talekar A,
Palmer SG, Xu R, Wilson IA, Moscona A. The
second receptor binding site of the globular
head of the Newcastle disease virus (NDV)
hemagglutinin-neuraminidase activates the
stalk of multiple paramyxovirus receptor
binding proteins to trigger fusion. Journal of
Virology. 2012 May;86(10):5730-41.
Moscona A, Porotto M, Palmer S, Tai C,
Aschenbrenner L, Triana-Baltzer G, Li H, Wurtman
D, Niewiesk S, Fang F. A recombinant sialidase
fusion protein effectively inhibits human parainfluenza viral infection in vitro and in vivo. Journal
of Infectious Diseases. 2012 Jul 15;202(2):234-41.
52
WEILL CORNELL MEDICAL COLLEGE
Dr. Anne Moscona is widely recognized as one of the world’s leading experts in
viral pathogenesis and treatment. The overall goal of Dr. Moscona’s research is
to understand the steps in the entry of enveloped viruses into their target cells,
as the first step in infection. The focus is on a group of paramyxoviruses that
includes pediatric respiratory pathogens, as well as emerging lethal viruses. The
fundamental aspects of this research have identified key roles of viral glycoproteins
during the receptor binding and entry process, and most recently have elucidated
some of the interactions between the two surface glycoproteins during the process
of virus-induced membrane fusion.
Dr. Moscona identified critical roles of the viral receptor binding protein in activating
the viral fusion/entry process during infection, proving that the binding protein
actively triggers its partner fusion protein to mediate entry. She has identified
essential contributions of the host tissue to pathogenesis, and the interplay
between host and viral factors during viral entry and infection. These fundamental
findings have led, in the last five years, to the design of novel antiviral strategies
that target each of the steps in entry. The novel antiviral approaches, in turn, have
yielded valuable tools and reagents for study of basic mechanisms.
Dr. Moscona has identified essential contributions of the host
tissue to pathogenesis, and the interplay between host and
viral factors during viral entry and infection.
Dr. Moscona’s investigations into the human parainfluenza viruses are of critical
importance because these respiratory viruses cause croup, bronchiolitis, and
pneumonia, leading global causes of disease and death in infants and children
under five years of age. In revealing specific mechanisms of the two viral surface
proteins during entry, Dr. Moscona identified new potential targets for entry
inhibitors for pediatric respiratory viruses.
Dr. Moscona is also a prominent investigator in the field of emerging lethal
pathogens, known for her work on the Nipah and Hendra viruses, paramyoviruses
that are causing outbreaks with recent evolution of human-to-human transmission.
In addition to acute infection, these viruses may lead to late-onset disease or
relapse of encephalitis years after initial infection, as well as persistent or delayed
neurological sequelae. For these viruses she has elucidated entry mechanisms and
identified new antiviral targets and is developing candidate therapeutics.
Dr. Moscona has tackled the problems of antiviral resistance, and based upon her
fundamental studies of resistance mechanisms, has contributed to the discussion
of antiviral development and resistance for influenza.
Current projects in Dr. Moscona’s group include basic studies on the mechanisms
of virus-induced membrane fusion, centered on parainfluenza virus for the most
fundamental research, with Nipah virus as a contrasting mechanism, along with
applications of the findings to preventing infection by parainfluenza virus, Nipah
virus, and other pediatric respiratory pathogens (respiratory syncytial virus, measles
virus, influenza) and emerging lethal viruses.
RESEARCH PROFILES
Carl Nathan, MD
Chair, Microbiology and Immunology
R.A. Rees Pritchett Professor of Microbiology
Professor of Medicine
Professor of Microbiology and Immunology
In work spanning four decades, Dr. Carl Nathan established that lymphocyte
products activate macrophages, that interferon-gamma is a major macrophage
activating factor in mice and humans, and that mechanisms of macrophage
antimicrobial activity include induction of the respiratory burst and inducible nitric
oxide synthase (iNOS), which he and his colleagues purified, cloned, knocked out,
and characterized biochemically and functionally.
Although iNOS helps the host control Mycobacterium tuberculosis, Mtb resists
sterilization by host immunity. Non-replicating Mtb exhibits relative resistance
to conventional anti-infectives, resulting in the need to treat tuberculosis longer
than almost any other infectious disease and the emergence of hereditable drug
resistance. One goal of Dr. Nathan’s lab is to identify new anti-infectives that
aim to shorten the course of treatment and provide effective therapies against
drug-susceptible and drug-resistant strains of TB. The biochemical basis of Mtb’s
persistence is the present focus of Dr. Nathan’s laboratory. Genetic and chemical
screens have identified enzymes that Mtb requires to survive during non-replicative
persistence, including the proteasome, a serine protease that controls intrabacterial
pH, and components of pyruvate dehydrogenase and nucleotide excision repair,
along with inhibitors of each.
Under Dr. Nathan’s leadership, the faculty within the Department of Microbiology
and Immunology pursue diverse projects, but share the concern of how genomes
regulate themselves and each other. Their interest in genetic information spans the
spectrum from how information can be extracted, understood, and applied at the
genomic level to how gene products interact at the atomic level.
SELECTED Publications
Xie Q-W, Cho H, Calaycay J, Mumford RA,
Swiderek KM, Lee TD, Ding A, Troso T, Nathan C.
Cloning and characterization of inducible nitric
oxide synthase from mouse macrophages.
Science. 1992 Apr 10;256:225-28.
Bryk R, Lima C, Erdjument-Bromage H, Tempst
P, Nathan C. Metabolic enzymes of mycobacteria linked to antioxidant defense by a
thioredoxin-like protein. Science. 2002 Feb 8;
295:1073-77.
Darwin KH, Ehrt S, Gutierrez-Ramos J-C, Weich N,
Nathan C. The proteasome of Mycobacterium
tuberculosis is required for resistance to nitric
oxide. Science. 2003 Dec 12;302:1963-66.
Vandal OH, Pierini LM, Schnappinger D, Nathan C*,
Ehrt SE.* A membrane protein preserves intrabacterial pH in intraphagosomal Mycobacterium
tuberculosis. Nature Medicine. 2008 Aug 8;14:
849-54. (*co-senior authorships)
After graduation from Harvard College and Harvard Medical School, Dr. Nathan
trained in internal medicine and oncology at Massachusetts General Hospital, the
National Cancer Institute, and Yale before joining the faculty of The Rockefeller
University from 1977 to 1986.
Lin G, Li D, Sorio de Carvalho LP, Deng H, Tao H,
Vogt G, Wu K, Schneider J, Chidawanyika T,
Warren JD, Li H, Nathan C. Inhibitors selective
for mycobacterial versus human proteasomes.
Nature. 2009 Oct 1;461:621-26.
Since 1986, Dr. Nathan has been at Weill Cornell Medical College, where he has
served as Founding Director of the Tri-Institutional MD-PhD Program, Senior
Associate Dean for Research, and Acting Dean. A member of the National Academy
of Sciences, the Institute of Medicine of the National Academies, and a Fellow of
the American Academy of Microbiology, Dr. Nathan serves as Associate Scientific
Director of the Cancer Research Institute; on the scientific advisory boards of the
American Asthma Foundation and the Rita Allen Foundation; as a member of the
Board of Governors of the Tres Cantos Open Lab Foundation; and on the juries for
the Paul Marks Prize at Memorial Sloan-Kettering Cancer Center and the Lurie
Prize of the Foundation for NIH.
Nathan C, Ding A. Non-resolving inflammation.
Cell. 2010 Mar 19;140(6):871-82.
Nathan C. Bacterial pathogenesis: fresh approaches to anti-infective therapies. Science
Translational Medicine. 2012 Jun 27;
4(140):140sr2.
He recently stepped down from 10 years of service as a Trustee of Hospital for
Special Surgery and Chair of the Board of Trustees’ Research Committee, and from
the Scientific Advisory Committee of the Cambridge Institute for Medical Research
at Cambridge University, United Kingdom. Since 1981, Dr. Nathan has served as an
editor of the Journal of Experimental Medicine. In 2009, he received the Robert Koch
Prize for his work on host defense against infection.
2012-2013 Research highlights
53
RESEARCH PROFILES
Steven M. Paul, MD
Professor of Neuroscience, Psychiatry and Pharmacology
The research laboratory of Dr. Steven Paul, who is also the Director of the Helen &
Robert Appel Alzheimer’s Disease Research Institute, seeks to better define the
underlying pathogenesis of Alzheimer’s disease (AD). How do the genes known to
greatly influence the risk of developing the most common form of late-onset AD
(and the proteins they encode) actually contribute to the subsequent molecular and
cellular events leading to the neuropathological signatures of the disease, namely
amyloid plaques and neurofibrillary tangles? The latter subsequently leads to the
neurodegeneration that typifies the disease and ultimately the dementia and other
signs and symptoms of AD.
SELECTED Publications
Bales KR, Verina T, Dodel RC, Du Y, Altstiel L,
Bender M, Hyslop P, Johnstone EM, Little SP,
Cummins DJ, Piccardo P, Ghetti B, Paul SM.
Lack of apolipoprotein E dramatically reduces
amyloid b-peptide deposition. Nature Genetics.
1997;17,263-64.
Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathis C, Delong CA, Wu S, Wu X,
Holtzman DH, Paul SM. Immunization reverses
memory deficits without reducing brain Aβ
burden in Alzheimer’s disease model. Nature
Neuroscience. 2002;5/5;452-7.
Dodart J-C, Marr RA, Koistinaho M, Gregersen
BM, Malkani S, Verma IM, Paul SM. Gene
delivery of human apolipoprotein E alters brain
Aβ burden in a mouse model of Alzheimer’s
disease. Proceedings of the National Academy
of Sciences. 2005 Jan 25;102(4):1211-16.
Zhao L-Z, Lin S-Z, Bales KR, Gelfanova V, Koger
D, DeLong C, Hale J, Liu F, Hunter JM, Paul SM.
Macrophage-mediated degradation of βamyloid via an apolipoprotein E isoformdependent mechanism. Journal of Neuroscience.
2009 Mar 18;29(11):3603-12.
Bales KR, Liu F, Wu S, Koger D, DeLong C,
Sullivan PM, Paul SM. Human APOE isoformdependent effects on brain β-amyloid levels
in PDAPP transgenic mice. Journal of
Neuroscience. 2009 May 27;29(21):6771-79.
Kim J, Castellano J, Jiang H, Basak JM,
Parsadanian M, Pham V, Mason SM, Paul SM,
Holtzman DM. Overexpression of low density
lipoprotein receptor in the brain markedly
inhibits amyloid deposition and increases
extracellular Aβ clearance. Neuron. 2009 Dec 10;
64:632-644.
Castellano JM, Kim J, Stewart FR, Jiang H,
DeMattos RB, Patterson BW, Fagan AM, Morris
JC, Mawuenyega KG, Cruchaga C, Goate AM,
Bales KR, Paul SM, Bateman RJ, Holtzman DM.
Human apoE isoforms differentially regulate
brain amyloid beta peptide clearance. Science
Translational Medicine. 2011 Jun 29;3:89ra57.
54
WEILL CORNELL MEDICAL COLLEGE
Dr. Paul’s research has helped shed light on genetic factors that dramatically
increase risk for Alzheimer’s and actually cause the brain abnormalities that lead
to the loss of neurons and the symptoms of the disease. The work of Dr. Paul and
his laboratory team has focused on the most common genetic risk factors for late
onset AD, the apolipoprotein E (apoE) alleles. ApoE4 carriers have a 3-15 fold greater
risk for developing AD (heterozygotes and homozygotes respectively) and apoE2 is
a known protective allele, reducing risk by approximately 50 percent. How do these
two apoE alleles, which differ by only two codons/amino acids, so dramatically alter
the risk to develop AD?
Over the past 15 years, Dr. Paul’s laboratory, in collaboration with several other
laboratories, has shown that apoE4 is a major determinant of brain-amyloid burden
in vivo. Using a series of transgenic mouse models, the researchers have shown agedependent and apoE isoform-dependent (E4>E3>E2) increases in brain amyloid
burden that closely recapitulates what is observed in AD patients. More recent work
in the Paul laboratory has shown that the brain levels of amyloid-β-peptides (Aβ),
which form amyloid plaques, are greatly influenced by the apoE isoform expressed
(E4>E3>E2) and that soluble brain levels of Aβ are already increased at a very early
age and then continue to increase in an apoE isoform- and age-dependent manner.
The apoE isoform-dependent changes in brain Aβ levels are due to apoE isoform
dependent-alterations in local Aβ metabolism and clearance (E4>E3>E2) and
appear to involve differential metabolism of Aβ by microglia and astrocytes.
Using a series of transgenic mouse models, the researchers
have shown age-dependent and apoE isoform-dependent
(E4>E3>E2) increases in brain amyloid burden that closely
recapitulates what is observed in AD patients.
In related work, Dr. Paul and his research team have shown that microglia and
macrophages metabolize Aβ in an apoE isoform-dependent manner via a novel
C-terminal peptidase among other proteases. Their data help to explain recent PET
neuroimaging findings in elderly patients at high genetic risk for AD which show
early apoE isoform-dependent accrual of Aβ in brain and the formation of amyloid
plaques many years before the onset of AD. Finally, their most recent data suggest
an important role of apoE4 in the formation of tau aggregates and neurofibrillary
tangles, the other major neuropathological hallmark of AD. Their findings have both
diagnostic and therapeutic implications and both are being actively pursued.
RESEARCH PROFILES
Gregory A. Petsko, DPhil
Mahon Professor of Neurology and Neuroscience
For over 30 years Dr. Gregory Petsko and his colleague, Prof. Dagmar Ringe,
have used protein crystallography, molecular biology, and genetics to probe the
relationship between protein structure and function. Their research has been
concerned with the three-dimensional structures and dynamics of proteins and
their biochemical functions, with a particular focus on the structural basis for
efficient enzymic catalysis; direct visualization of proteins in action by timeresolved protein crystallography; the evolution of new enzyme activities; and the
biology of the quiescent state in eukaryotic cells.
During the past 10 years, Drs. Petsko and Ringe have pursued groundbreaking
research not only on how proteins work, but how they are related to the causes
of neurodegenerative diseases. They use the techniques of genetics, structural
biology, and structure-guided drug discovery to identify, validate, and exploit
novel targets for the treatment of age-related neurodegenerative disorders such
as Alzheimer’s, Parkinson’s, and Lou Gehrig’s diseases.
During the past 10 years, Drs. Petsko and Ringe have pursued
groundbreaking research not only on how proteins work, but how
they are related to the causes of neurodegenerative diseases.
Alzheimer’s disease starts when a protein that should be folded up properly for
normal brain functioning instead misfolds and then aggregates. Interestingly,
diseases that affect other parts of the brain also show similar aggregates of
misfolded proteins. This suggests that a therapeutic approach developed for
Alzheimer’s might also be used to treat many neurological diseases. With this in
mind, they have been collaborating with Dr. Scott Small of Columbia University on
the development of drugs that will route the Alzheimer’s protein away from the
subcellular compartments where misprocessing and aggregation begin. Two of
their compounds have shown good results in neurons in cell culture, and are now
being tested in mouse models of Alzheimer’s disease.
The pathological hallmark of Parkinson’s is the accumulation in nerve cells of dense
clumps of another aggregated protein, called alpha-synuclein. Alpha-synuclein does
not normally form such aggregates in healthy brain cells, so identifying the process
that triggers its aggregation in the early stages of Parkinson’s disease may provide
a therapeutic opportunity. Focusing on what might be nucleating the formation of
the synuclein aggregates, they identified an enzyme that clipped synuclein, forming
rapidly aggregating fragments, and showed that inhibiting it with a specific drug
blocked the formation of the synuclein fragments, thereby preventing or delaying
the formation of the aggregates that these fragments promote. Two such inhibitors
are now being tested in several rodent models of Parkinson’s disease.
Finally, they have been developing a novel gene therapy for amyotrophic lateral
sclerosis (Lou Gehrig’s disease or ALS). By overexpressing the human UPF1 gene,
which codes for a protein that is involved in a cellular pathway called nonsensemediated decay, they have succeeded in completely blocking the death of motor
neurons in cell culture models of ALS. With the help of several collaborators,
they have been able to engineer a virus to carry this gene into the spinal motor
neurons, and are now testing the therapy on rat and mouse models of ALS to see if
it can either retard or halt the progression of the disease.
SELECTED Publications
Henzler-Wildman KA, Thai V, Lei M, Ott M, WolfWatz M, Fenn T, Pozharski E, Wilson MA, Petsko
GA, Karplus M, Hübner CG, Kern D. Intrinsic motions along an enzymatic reaction trajectory.
Nature. 2007 Dec 6;450(7171):838-44.
Landon MR, Lieberman RL, Hoang QQ, Ju S,
Caaveiro JM, Orwig SD, Kozakov D, Brenke R,
Chuang GY, Beglov D, Vajda S, Petsko GA, Ringe
D. Detection of ligand binding hot spots on
protein surfaces via fragment-based methods:
application to DJ-1 and glucocerebrosidase.
Journal of Computer-Aided Molecular Design.
2009 Aug;23(8):491-500.
Auclair JR, Boggio KJ, Petsko GA, Ringe D,
Agar JN. Strategies for stabilizing superoxide
dismutase (SOD1), the protein destabilized in
the most common form of familial amyotrophic
lateral sclerosis. Proceedings of the National
Academy of Sciences USA. 2010 Dec 14;107(50):
21394-99.
Ju S, Tardiff DF, Han H, Divya K, Zhong Q,
Maquat LE, Bosco DA, Hayward LJ, Brown RH Jr,
Lindquist S, Ringe D, Petsko GA. A yeast model of
FUS/TLS-dependent cytotoxicity. PLoS Biology.
2011 Apr;9(4):e1001052.
Bosco DA, LaVoie MJ, Petsko GA, Ringe D. Proteostasis and movement disorders: Parkinson's
disease and amyotrophic lateral sclerosis. Cold
Spring Harbor Perspectives in Biology. 2011
Oct 1;3(10):a007500.
Wang W, Perovic I, Chittuluru J, Kaganovich A,
Nguyen LT, Liao J, Auclair JR, Johnson D, Landeru
A, Simorellis AK, Ju S, Cookson MR, Asturias FJ,
Agar JN, Webb BN, Kang C, Ringe D, Petsko GA,
Pochapsky TC, Hoang QQ. A soluble α-synuclein
construct forms a dynamic tetramer. Proceedings
of the National Academy of Sciences USA. 2011
Oct 25;108(43):17797-802.
Bharadwaj PR, Verdile G, Barr RK, Gupta V, Steele
JW, Lachenmayer ML, Yue Z, Ehrlich ME, Petsko GA,
Ju S, Ringe D, Sankovich SE, Caine JM, Macreadie IG,
Gandy S, Martins RN. Latrepirdine (Dimebon™)
enhances autophagy and reduces intracellular
GFP-Aβ42 levels in yeast. Journal of Alzheimer’s
Disease. 2012 Aug 17. [Epub ahead of print]
2012-2013 Research highlights
55
RESEARCH PROFILES
Shahin Rafii, MD
Arthur B. Belfer Professor in Genetic Medicine
Professor of Medicine
A pioneer in the fields of vascular biology and stem cell research, Dr. Shahin Rafii
has established novel preclinical models to target vascular cells for the treatment of
stem cell-related disorders by paving the way to exploit the potential of pluripotent
stem cells for therapeutic organ revascularization and cancer targeting. He has made
the following seminal discoveries.
SELECTED Publications
Seandel M, Rafii S. Reproductive biology:
in vitro sperm maturation. Nature. 2011
Mar 24;471(7339):453-55.
Henderson PW, Singh SP, Krijgh DD, Yamamoto
M, Rafii DC, Sung JJ, Rafii S, Rabbany SY, Spector
JA. Stromal-derived factor-1 delivered via
hydrogel drug-delivery vehicle accelerates
wound healing in vivo. Wound Repair and
Regeneration. 2011 May-Jun;19(3):420-25.
Kimura Y, Ding B, Imai N, Nolan DJ, Butler JM,
Rafii S. c-Kit-mediated functional positioning of
stem cells to their niches is essential for maintenance and regeneration of adult hematopoiesis. PLoS One. 2011 Oct 26;6(10):e26918.
Ding BS, Nolan DJ, Guo P, Babazadeh AO, Cao Z,
Rosenwaks Z, Crystal RG, Simons M, Sato TN,
Worgall S, Shido K, Rabbany SY, Rafii S. Endothelial-derived angiocrine signals induce and
sustain regenerative lung alveolarization. Cell.
2011 Oct 28;147(3):539-53.
Jain S, Ward MM, O'Loughlin J, Boeck M, Wiener
N, Chuang E, Cigler T, Moore A, Donovan D,
Lam C, Cobham MV, Schneider S, Christos P,
Baergen RN, Swistel A, Lane ME, Mittal V, Rafii
S, Vahdat LT. Incremental increase in VEGFR1+
hematopoietic progenitor cells and VEGFR2+
endothelial progenitor cells predicts relapse
and lack of tumor response in breast cancer
patients. Breast Cancer Research and Treatment.
2012 Feb;132(1):235-42.
Gao D, Joshi N, Choi H, Ryu S, Hahn M, Catena
R, Sadik H, Argani P, Wagner P, Vahdat LT, Port
JL, Stiles B, Sukumar S, Altorki NK, Rafii S, Mittal
V. Myeloid progenitor cells in the premetastatic
lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Research.
2012 Mar 15;72(6):1384-94.
Curradi G, Walters MS, Ding BS, Rafii S,
Hackett NR, Crystal RG. Airway basal cell
vascular endothelial growth factor-mediated
cross-talk regulates endothelial cell-dependent
growth support of human airway basal cells.
Cellular and Molecular Life Sciences. 2012
Jul;69(13):2217-31.
56
WEILL CORNELL MEDICAL COLLEGE
Bone marrow-derived endothelial precursors are required for tumor angiogenesis.
This discovery was hailed by the journal Nature as revolutionary for blood vessel
formation. Dr. Rafii introduced the concept that tumors and regenerating organs rely
on stem cells from the bone marrow to help build new blood vessels. Both tumor
cells and injured tissue, such as that at the site of a heart attack, stroke, or organ
transplant, can recruit stem cells from the bone marrow. He discovered mobilizing
factors that activate the stem cells in bone marrow that form new blood vessels
destroyed by chemotherapy or radiation.
Adult testes can be turned into stem cells. Dr. Rafii described how cells from the
testes of adult male mice can be turned into stem cells, thereby opening the way
to therapeutic use of spermatogonial stem cells (SSC) for regenerative medicine.
He demonstrated that reprogrammed SSC could develop into working blood-vessel
tissue, as well as contractile cardiac tissue and brain cells, and others. He isolated
SSC and showed a conversion of SSC into multipotent stem cells, indicating the
pluripotency of adult germline stem cells. Since the donor and recipient are identical,
use of SSC for cell transplantation will allow establishment of individual cell-based
therapy avoiding many of the ethical issues associated with embryonic stem cells.
Signaling pathways and transcriptional networks promote endothelial differentiation.
Dr. Rafii identified signaling pathways and transcriptional networks that promote
and augment endothelial differentiation in human embryonic stem cell (hESC)
culture, with more than 80 percent of the population differentiating to cardiovascular
derivatives. He established a method for vascular differentiation from hESC to scale
up the serum-free humanized feeder-based differentiation platform to test the ability
of discreet vascular subpopulations to restore vascular perfusion in model left
descending coronary artery ligation induced ischemia. This presents an unprecedented
resource for pre-clinical study of cell-based therapies of cardiovascular disease.
Organ specific blood vessels produce a specific set of growth factors that support
expansion of organ specific progenitor cells and augment organ regeneration.
Dr. Rafii identified the molecular and cellular pathways that allow expansion and
engraftment of hepatocytes and augment liver regeneration, showing that after
70 percent partial hepatectomy, activation of liver sinusoidal endothelial cells
(LSECs) by production of paracrine factors – defined as angiocrine factors – induce
liver regeneration. He defined the phenotype of LSECs and has shown that LSECs
are composed of a specialized vascular network that is in direct cellular contact
with hepatocytes and sustains the regeneration of remaining lobes of the liver.
Hepatocyte transplantation provides for a clinically plausible approach to improve
liver function. Therefore, identification of the molecular and cellular pathways
that allow expansion and long-term engraftment of hepatocyte or augment liver
regeneration will have significant therapeutic impact.
RESEARCH PROFILES
M. Cary Reid, MD, PhD
Associate Professor of Medicine
The work of Dr. Cary Reid over the past decade has focused on the epidemiology
and treatment of common pain disorders (e.g., back pain, osteoarthritis,
neuropathic pain) in older adults. Dr. Reid’s research is informed by training in both
geriatric medicine and clinical epidemiology. His work has involved elucidating risk
factors for pain onset and adverse outcomes (e.g., disability) after development of
various pain disorders.
Dr. Reid has conducted epidemiologic analyses focusing on the prevalence and
strategies employed by older adults to self-manage pain, as well as outcomes
associated with these strategies, to include activity restriction, exercise, use of
relaxation techniques, and religiosity. His work has also involved developing,
testing, and implementing various non-pharmacologic interventions for older
adults with non-cancer pain disorders such as back pain and osteoarthritis.
Examples include implementation and evaluation of specific exercise protocols,
cognitive-behavioral interventions, as well as combined exercise and cognitivebehavioral programs for seniors with pain. Given established disparities in the
management of pain as a function of race/ethnicity, much of this work has focused
on the development and testing of pain programs in minority communities.
Dr. Reid has conducted epidemiologic analyses focusing on the
prevalence and strategies employed by older adults to self-manage
pain, as well as outcomes associated with these strategies.
Dr. Reid’s recent work has also been directed towards identifying research gaps
in knowledge regarding the pharmacologic management of pain among older
adults and examining the role of specific analgesic agents as treatment for
diverse pain disorders. These gaps include uncertainties regarding the longterm safety and efficacy of commonly employed analgesic medications, lack
of knowledge regarding factors that predict positive (or negative) treatment
outcomes associated with specific analgesic medications, as well as limited
knowledge regarding optimal approaches to prevent or minimize side effects,
which increase as a function of age. His work also involves identifying strategies to
extend the reach of evidence-based pain programs for use by older minority adults,
particularly those living in underserved neighborhoods.
SELECTED Publications
Reid MC. What can population-based studies tell
us about pain in the last years of life? Annals of
Internal Medicine. 2010 Nov 2;153:612-13.
Reid MC, Bennett DA, Chen WG, Eldadah BA, Farrar
JT, Ferrell B, Gallagher RM, Hanlon JT, Herr K, Horn
SD, Inturrisi CE, Lemtouni S, Lin YW, Michaud K,
Morrison RS, Neogi T, Porter LL, Solomon DH, Von
Korff M, Weiss K, Witter J, Zacharoff KL. Improving
the pharmacologic management of pain in
older adults: identifying the research gaps and
methods to address them. Pain Medicine. 2011
Sep;12(9):1336-57.
Beissner K, Parker S, Henderson CR, Reid MC.
Implementing a self-management program
for back pain in New York City senior centers:
evidence for a possible race/ethnicity effect.
Journal of Aging and Physical Activity. 2012
Apr;20(2):246-65.
Thielke S, Sale J, Reid MC. A critical examination of
stereotypes about pain and aging. The Journal of
Family Practice. 2012. [in press]
Dr. Reid serves as the Director of Cornell University’s Edward R. Roybal Center for
Translational Research on Aging, an NIH-funded center that focuses on pain in
later life. The goals of the Roybal Center include translating the findings of basic
behavioral, medical, public health, and social science research into treatments,
intervention programs, and policies that improve the health and well-being of
older adults who suffer from or are at increased risk for pain; promoting translation
of evidence-based practices, treatments, and interventions across diverse venues
to improve management of pain; and developing and testing innovative methods,
tools, and strategies that facilitate successful translation of evidence into practice.
Dr. Reid also directs Weill Cornell’s Center of Excellence in Geriatric Medicine. This
John A. Hartford sponsored grant seeks to train the next generation of leaders in
geriatric medicine.
2012-2013 Research highlights
57
RESEARCH PROFILES
Enrique J. Rodriguez-Boulan, MD
Charles and Margaret Dyson Professor of Ophthalmic Research
Professor of Cell and Developmental Biology
Professor of Physiology and Biophysics
Professor of Neurosciences
SELECTED Publications
Gravotta D, Deora A, Perret E, Oyanedel C, Soza
A, Schreiner RA, Gonzalez A, Rodriguez-Boulan E.
The AP1B adaptor sorts basolateral proteins in
the biosynthetic and recycling routes of MDCK
cells. Proceedings of the National Academy of
Sciences USA. 2007 Jan 30;104(5):1564-69.
Faculty of 1000 selection.
Lakkaraju A, Finnemann SC, Rodriguez-Boulan E.
The lipofuscin fluorophore A2E perturbs cholesterol
metabolism in retinal pigment epithelial cells.
Proceedings of the National Academy of Sciences
USA. 2007 Jun 26;104(26):11026-31.
Deborde S, Gravotta D, Perret E, Deora A,
Rodriguez-Boulan E. Clathrin is a key regulator
of epithelial polarity. Nature. 2008 Apr 10;452(7188):
719-23. Faculty of 1000 selection.
Tanos B, Rodriguez-Boulan E. The epithelial
polarity program: machineries involved and
their hijacking by cancer. Oncogene. 2008
Nov 24;27(55):6939-57.
Diaz F, Gravotta D, Deora A, Schreiner R,
Schoggins J, Falck-Pedersen E, Rodriguez-Boulan
E. Clathrin adaptor AP1B controls adenovirus
infectivity of epithelial cells. Proceedings of the
National Academy of Sciences USA. 2009 Jul 7;
106(27):11143-48. Faculty of 1000 selection.
Schreiner R, Frindt G, Diaz F, Carvajal-Gonzalez
JM, Perez-Bay A, Palmer LG, Marshansky V,
Brown D, Philp NJ, Rodriguez-Boulan E. Missing
clathrin adaptor AP1B confers unique polarity
essential to proximal tubule function. Kidney
International. 2010 Aug;78(4):382-88. Cover article.
Carvajal-Gonzalez JM, Gravotta D, Mattera R,
Diaz F, Perez-Bay A, Roman AC, Schreiner R,
Thuenauer R, Bonifacino JS, Rodriguez-Boulan E.
Basolateral sorting of CAR through interaction
of a canonical YXXF motif with the clathrin
adaptors AP-1A and AP-1B. Proceedings from the
National Academy of Sciences USA. 2012 Mar 6;
109(10):3820-25.
Gravotta D, Carvajal-Gonzalez JM, Mattera R,
Deborde S, Banfelder J, Bonifacino J, RodriguezBoulan E. AP-1A mediates basolateral protein
sorting in the biosynthetic route. Developmental
Cell. 2012 Apr 17;22(4):811-23. Cover article.
58
WEILL CORNELL MEDICAL COLLEGE
The human body has 150 to 200 different types of epithelial cells, which are
responsible for the performance of vital functions for the organism. Examples
of organs or systems that are based on epithelial cells are the skin, the
gastrointestinal, respiratory, urinary, and reproductive tracts, the kidney, the
liver, exocrine and endocrine glands, eye and brain neuroepithelia, and so on.
Epithelial cells form the main barrier between the organism and its environment
and are therefore exposed to many disease agents (bacteria, viruses, toxins). Not
surprisingly, epithelial cells constitute the source of 90 percent of human cancers.
Epithelial cells perform a variety of vectorial functions (absorption, secretion,
polarized transport) that require a highly polarized organization. Elucidating the
cellular and molecular bases of epithelial polarity is a major focus of Dr. Enrique
Rodriguez-Boulan’s research.
Dr. Rodriguez-Boulan’s landmark papers in 1978 and 1980 that demonstrated
the polarized budding of enveloped RNA viruses from cultured canine kidney
cells (PNAS, 1978; Cell, 1980) introduced the MDCK model (in collaboration
with Cereijido and Sabatini) which quickly became the paradigmatic model to
study the generation and maintenance of epithelial cell polarity. Over 6,000
publications have used this model, as indicated by a recent PubMed search. Using
a combination of various biochemical, molecular, structural, and live imaging
approaches, his laboratory has contributed over 150 publications using this model
that elucidate sorting signals, sorting compartments, and trafficking routes of
apical and basolateral proteins, as well as various components of the polarized
trafficking machinery of epithelial cells (e.g. clathrin and clathrin adaptors).
Dr. Rodriguez-Boulan has discovered a variety of mechanisms responsible for
epithelial cell polarity using the MDCK model system that he co-introduced in
1978. His research also focuses on the interaction between the two major cells in
the outer retina, the retinal pigment epithelium, and the retinal photoreceptors,
which are essential for normal vision.
A second major focus of Dr. Rodriguez-Boulan’s laboratory is the interaction
between the retinal pigment epithelium (RPE) and the photoreceptors, respectively,
the first and second layers of the retina, which is key for normal vision. His laboratory
has made major contributions in this area, including the discovery of a major RPE
receptor (the integrin αvβ5) for phagocytosis of rod outer segments, a circadian
process that occurs every day and is essential for retinal health. His group recently
reported that the RPE belongs to a small group of epithelia (also including the liver
and the kidney proximal tubule) that lacks the major basolateral sorting adaptor
AP-1B and therefore expresses various basolateral proteins at the apical plasma
membrane, with profound consequences for the physiology of the host epithelia.
Finally, his group has discovered a group of small drugs (cyclodextrins) that efficiently
remove lipofuscin from RPE. These drugs may turn out to be useful therapeutic
agents for genetic and age-related retinal diseases that accumulate lipofuscin, such
as Stargardt disease and age-related macular degeneration (AMD), a major cause of
blindness among the senior population, for which there is no cure yet.
RESEARCH PROFILES
M. Elizabeth Ross, MD, PhD
Professor of Neurology and Neuroscience
The laboratory of Dr. Elizabeth Ross studies how genes direct brain construction,
combining basic science and clinical genetic components in three major projects:
Neural tube formation – spina bifida. Neural tube defects (NTDs), principally
spina bifida and anencephaly, affect one to two per 2,000 pregnancies or more
worldwide. Using both animal models and human populations, Dr. Ross and
her research team investigate the complex genetic and gene-environment
interactions that predispose to NTDs. They showed that prenatal folic acid (FA)
supplementation could prevent NTD in the Crooked tail (Cd) mouse strain in a
manner that closely paralleled human clinical experience. They identified the Cd
gene defect in the Lrp6 co-receptor that is required for Wnt signaling, a pathway
essential for early brain development. Illuminating a previously unrecognized
interaction between FA supplementation and Wnt signaling, they showed that
both low and high FA levels attenuate responses to Wnt. This was the first
demonstration that FA supplementation could have harmful effects on neural
tube closure, depending on individual genetic background. They are leading
a multicenter clinical effort to discover complex genetic and epigenetic traits
causing NTDs, using genome-wide, massively parallel sequencing to identify
human polymorphisms and DNA and chromatin methylation marks associated
with increased NTD risk.
Role of cell cycle regulation in patterning brain – microcephaly. The many genetic
and environmental factors leading to microcephaly (small brain) together affect
2 percent of the population worldwide. Most of these disorders arise from failure
of cell division to generate sufficient neurons and glia during embryonic and early
postnatal development. Studies by the Ross lab in neurogenesis were the first
to recognize that the cell cycle protein, G1-phase active cyclin D2 (cD2), has an
important role in brain formation. Loss of cD2 leads to microcephaly with selective
interneuron deficits in both cerebellum and forebrain. This is due to the differential
use of cD2 and cyclin D1 (cD1) in precursors of the subventricular zone (SVZ) vs.
the ventricular zone (VZ), respectively, of developing forebrain. These interneuron
deficits lead to behavioral abnormalities and seizures due to inhibitory GABA
deficits. Their research showed that cD2 expression is critical for intermediate
progenitor proliferation in the mouse SVZ and that cD2 is the predominant cyclin
expressed in the human fetal SVZ at 19 gestational weeks, suggesting particular
importance of cD2 for human brain development.
Cytoskeletal regulation in motile neurons required for migration and synaptogenesis – autism spectrum disorders and epilepsy. Dr. Ross’ laboratory discovered
the unexpected role of a gene associated with lissencephaly (smooth brain), Lis1,
in signal transduction through small GTPases to the actin-based cytoskeleton of
motile neurons. Lis1 participates in the dynein protein motor complex component
of intracellular transport, and many consider Lis1 synonymous with dynein
function. However, their studies indicate Lis1 is also required for signalling that
modulates actin rich structures like growth cones and filopodia. They investigate
the ability of Lis1 to regulate plasticity of neural networks relevant to autism and
epilepsy. They also seek additional neuronal migration genes through investigation
of patients with brain malformations and their families.
SELECTED Publications
Carter M, Chen X, Slowinska B, Minnerath S,
Glickstein S, Shi L, Campagne F, Weinstein H,
Ross ME. Crooked tail (Cd) model of human
folate-responsive neural tube defects is
mutated in Wnt coreceptor lipoprotein
receptor-related protein 6. Proceedings of the
National Academy of Sciences. 2005 Sep 6;
102:12843-48.
Kholmanskikh SS, Koeller HB, Wynshaw-Boris
A, Gomez T, Letourneau PC, Ross ME. Calciumdependent interaction of Lis1 with IQGAP1
and Cdc42 promotes neuronal motility. Nature
Neuroscience. 2006 Jan;9(1):50-57.
Glickstein SB, Moore M, Slowinska B, Racchumi
J, Suh M, Chuma N, Ross ME. Selective cortical
interneuron and GABA deficits in cyclin D2 null
mice. Development. 2007 Nov;134(22):4083-93.
Glickstein SB, Monaghan JA, Koeller HB, Jones TK,
Ross ME. Cyclin D2 is critical for intermediate
progenitor cell proliferation in the embryonic
cortex. Journal of Neuroscience. 2009 Jul 29;
29(30):9614-24.
Gray JD, Nakouzi G, Slowinska-Castaldo B,
Dazard JE, Sunil Rao J, Nadeau JH, Ross ME.
Functional interactions between the LRP6
WNT co-receptor and folate supplementation.
Human Molecular Genetics. 2010 Dec 1;19(23):
4560-72.
Riviere JB, van Bon BW, Hoischen A,
Kholmanskikh SS, Ross ME, Pilz DT, Dobyns WB.
De novo mutations in the actin genes ACTB
and ACTG1 cause Baraitser-Winter syndrome.
Nature Genetics. 2012 Feb 26;44(4):440-44.
2012-2013 Research highlights
59
RESEARCH PROFILES
Mark A. Rubin, MD
Homer T. Hirst, III, Professor of Oncology in Pathology
Professor of Pathology and Laboratory Medicine
Professor of Pathology in Urology
SELECTED Publications
Berger MF*, Lawrence MS*, Demichelis F*, Drier
Y*, Cibulskis K, Sivachenko AY, Sboner A, Esgueva
R, Pflueger D, Sougnez C, Onofrio R, Carter
SL, Park K, Habegger L, Ambrogio L, Fennell T,
Parkin M, Saksena G, Voet D, Ramos AH, Pugh
TJ, Wilkinson J, Fisher S, Winckler W, Mahan S,
Ardlie K, Baldwin J, Simons JW, Kitabayashi N,
MacDonald TY, Kantoff PW, Chin L, Gabriel SB,
Gerstein MB, Golub TR, Meyerson M, Tewari A,
Lander ES*, Getz G*, Rubin MA*, Garraway LA*.
The genomic complexity of primary human
prostate cancer. Nature. 2011 Feb;470(7333):
214-20. (*co-corresponding authorship)
Demichelis F, Setlur SR, Banerjee S, Chakravarty
D, Chen JY, Chen CX, Huang J, Beltran H,
Oldridge DA, Kitabayashi N, Stenzel B, Schaefer
G, Horninger W, Bektic J, Chinnaiyan AM,
Goldenberg S, Siddiqui J, Regan MM, Kearney
M, Soong TD, Rickman DS, Elemento O, Wei JT,
Scherr DS, Sanda MA, Bartsch G, Lee C, Klocker
H, Rubin MA. Identification of functionally
active, low frequency copy number variants at
15q21.3 and 12q21.31 associated with prostate
cancer risk. Proceedings of the National Academy
of Sciences USA. 2012 Apr 24;109(17):6686-91.
Barbieri CE, Baca SC, Lawrence MS, Demichelis
F, Blattner M, Theurillat JP, White TA, Stojanov
P, Van Allen E, Stransky N, Nickerson E, Chae SS,
Boysen G, Auclair D, Onofrio RC, Park K, Kitabayashi
N, MacDonald TY, Sheikh K, Vuong T, Guiducci
C, Cibulskis K, Sivachenko A, Carter SL, Saksena
G, Voet D, Hussain WM, Ramos AH, Winckler W,
Redman MC, Ardlie K, Tewari AK, Mosquera JM,
Rupp N, Wild PJ, Moch H, Morrissey C, Nelson PS,
Kantoff PW, Gabriel SB, Golub TR, Meyerson M,
Lander ES, Getz G, Rubin MA, Garraway LA. Exome
sequencing identifies recurrent SPOP, FOXA1
and MED12 mutations in prostate cancer. Nature
Genetics. 2012 May 20;44(6):685-89.
Rickman DS, Soong TD, Moss B, Mosquera JM,
Dlabal J, Terry S, Macdonald TY, Tripodi J,
Bunting K, Najfeld V, Demichelis F, Melnick AM,
Elemento O, Rubin MA. Oncogene-mediated
alterations in chromatin conformation.
Proceedings of the National Academy of Sciences
USA. 2012 Jun 5;109(23):9083-88.
60
WEILL CORNELL MEDICAL COLLEGE
Dr. Mark Rubin has made significant contributions to the field of prostate cancer
research in the area of genomics and biomarker development, including the publication
of the first expression profiling study in prostate cancer and the identification
of important prostate cancer biomarkers (e.g., AMACR, Hepsin, EZH2, PIM1, and
JAGGED1). In 2005, the team made a landmark discovery with the indentification and
characterization of recurrent ETS rearrangements in prostate cancer involving TMPRSS2ERG and TMPRSS2-ETV1. This paradigm-shifting work demonstrated that over 50
percent of prostate cancers harbor recurrent gene fusions involving an androgen driven
promoter, TMPRSS2, and an ETS family member transcription factor, and invigorated
a new line of research trying to establish a molecular classification of prostate cancer
similar to AML. These fusions are virtually 100 percent prostate cancer specific and are
being developed into diagnostic and prognostic clinical tests to supplement PSA testing.
Extending this genomic work to other types of mutations, Drs. Rubin and Levi
Garraway (Broad Institute of MIT and Harvard) conducted a first-in-class study
demonstrating novel mutations involving the PI3K/PTEN/AKT pathway through
inactivating mutations of MAGI2, a PTEN scaffolding protein. The Rubin lab has
also demonstrated recurrent functionally active mutations occurring in around
10 percent of ETS rearrangement negative prostate cancers. Dr. Rubin continues to
develop novel approaches for genomic discovery. His group was one of the first to use
laser capture microdissection, tissue microarrays, oligonucleotide arrays, and Next
Generation Sequencing technology for translational research. He has also been at
the cutting edge of helping develop computational approaches to analyze emerging
data from expression profiling and oligonucleotide arrays and Next Generation
Sequencing. His collaborative role in team science was recognized by the inaugural
AACR Team Science Award in 2007 for the discovery and characterization of recurrent
gene fusions in prostate cancer.
In further research, Dr. Rubin and his colleagues are investigating chromatin
conformation changes in diseases such as cancer and how oncogenic transcription
factors, which bind to thousands of sites across the genome, influence gene regulation
by globally altering the topology of chromatin. Using unbiased high-resolution
mapping of intra- and interchromosome interactions upon overexpression of ERG,
an oncogenic transcription factor frequently overexpressed in prostate cancer as
a result of a gene fusion, they demonstrated that oncogenic transcription factor
overexpression is associated with global, reproducible, and functionally coherent
changes in chromatin organization. These results have broader implications,
as genomic alterations in other cancer types frequently give rise to aberrant
transcription factor expression.
In other recent work, the Rubin lab sequenced the exomes of 112 prostate tumor
and normal tissue pairs to determine if recurrent somatic base-pair substitutions
are less contributory in prostate tumorigenesis. Identifying new recurrent
mutations in multiple genes, with SPOP the most frequently mutated gene, the
researchers determined that prostate cancers with mutant SPOP lacked ETS family
gene rearrangements and showed a distinct pattern of genomic alterations, and
therefore, may define a new molecular subtype of prostate cancer.
RESEARCH PROFILES
Timothy A. Ryan, PhD
Professor of Biochemistry
Dr. Timothy Ryan’s laboratory studies the molecular basis of how neurons in the brain
communicate. Neurons make use of two main forms of communication: an electrical
signal that carries information within a given cell and chemical communication that
carries information from one cell to another at specialized junctions called synapses.
Diseases of the brain, such as neurodegenerative disorders or psychiatric disorders,
are all thought to be manifest at synapses and lead to changes in the ability of brain
cells to efficiently communicate. In the last decade, neuroscientists have tracked
down many genetic associations between these diseases and synaptic function.
The challenge is to understand how synapses work at a molecular level to devise
a scheme to repair synaptic lesions. Dr. Ryan’s lab devises new methodologies that
allow them to study living synapses at work in great detail by labeling individual
protein molecules that form part of the synaptic machinery with a fluorescent
molecule. This enables them to see what the function of that molecule is in a
synapse as it does its work, which is to communicate with another neuron.
The Ryan lab focuses on two key aspects of synaptic function. Chemical message
synapses used to communicate are stored in specialized compartments called
synaptic vesicles that reside within the synapse. Each synapse only contains ~100
of these synaptic vesicles. When an electrical stimulus travels down a neuron to the
synapse, it triggers one of the synaptic vesicles to release its content into the tiny
space between neurons. Electrical signals, however, often arrive at a furious pace,
often as high as 50 times per second.
The Ryan lab is dissecting how the efficiency of the process that causes vesicles
to release their content is controlled. The lab recently discovered that a protein
known to play an important role in pain sensitivity and the target of one of the
most widely prescribed medications for neuropathic pain, Neurontin, is critical in
controlling how many calcium channels are at synapses. Electrical signals, when
they arrive at the nerve terminal, open a gate that allows calcium to flow into the
synapse through calcium channels. This entry of calcium is the “trigger” that causes
the chemical message to be sent. Dr. Ryan’s lab discovered that a protein called
“alpha2delta” controls how many of these gates are present at synapses. This
suggests that a mechanism by which Neurontin functions to limit pain is reducing
the number of these gates. In another study they showed that in a certain type
of dopamine neuron, a protein named calbindin controls how much calcium is
available to trigger the sending of the message once calcium flows in. Dopamine,
one type of chemical message that neurons can send, is especially important in
controlling many behaviors.
SELECTED Publications
Kim SH, Ryan TA. CDK5 serves as a major
control point in neurotransmitter release.
Neuron. 2010 Sep 9;67(5):797-809.
Armbruster M, Ryan TA. Synaptic vesicle
retrieval time is a cell-wide rather than
an individual synapse property. Nature
Neuroscience. 2011 May 29;14(7):824-26.
Raimondi S, Ferguson X, Lou M, Armbruster S,
Paradise S, Giovedi M, Messa N, Kono J, Takasaki
V, Capello E, O’Toole T, Ryan TA, De Camilli
P. Overlapping roles of dynamin isoforms in
synaptic vesicle endocytosis. Neuron. 2011
Jun 23;70(6):1100-14.
Hoppa M, Lana B, Margas W, Dolphin AC, Ryan
TA. α2δ expression sets presynaptic calcium
channel abundance and release probability.
Nature. 2012 May 13;486(7401):122-25.
Pan PY, Ryan TA. Calbindin controls erlease
probability in ventral legmental area
dopamine neurons. Nature Neuroscience. 2012
Jun;15(16):813-15.
Once a vesicle releases its chemical message, the entire vesicle must be remade
locally and refilled with message. This process of vesicle recycling is of particular
interest to Dr. Ryan’s lab. Studies have uncovered how this process is controlled and
what gene products are critical. A certain portion of these vesicles are always held
in reserve and did not seem to normally participate in the process of delivering the
chemical message. Recently the lab showed that the reserve vesicles are held in
check by a particular enzyme called CDK5. Blocking this enzyme allows synapses to
make use of the full complement of synaptic vesicles. Through these approaches,
Dr. Ryan and his research team hope to eventually be able to write repair manuals
for synapses that don’t work properly.
2012-2013 Research highlights
61
RESEARCH PROFILES
Bruce R. Schackman, PhD
Associate Professor of Public Health
Dr. Bruce Schackman is Chief of the Division of Health Policy in the Department
of Public Health at Weill Cornell. His research includes cost and cost-effectiveness
analyses conducted alongside clinical trials and cohort studies; simulation modeling
of comparative effectiveness and cost-effectiveness outcomes; and implementation
science. His current projects focus on economic evaluations of screening, prevention,
and treatment for HIV and hepatitis C, and the cost-effectiveness and comparative
effectiveness of opioid dependence treatment as it affects quality of life.
SELECTED Publications
Schackman BR, Neukermans CP, Fontain SN,
Nolte C, Joseph P, Pape JW, Fitzgerald DW.
Cost-effectiveness of rapid syphilis screening
in prenatal HIV testing programs in Haiti. PLoS
Medicine. 2007 May;4:e183.
Schackman BR, Ribaudo HJ, Krambrink A,
Hughes V, Kuritzkes DR, Gulick RM. Racial
differences in virologic failure associated with
adherence and quality of life on efavirenzcontaining regimens for initial HIV therapy:
results of ACTG A5095. Journal of Acquired
Immune Deficiency Syndromes. 2007 Dec 15;
46:547-54.
Schackman BR, Scott CA, Walensky RP, Losina E,
Freedberg KA, Sax PE. The cost-effectiveness of
HLA-B*5701 genetic screening to guide initial
antiretroviral therapy for HIV. AIDS. 2008 Oct 1;
22:2025-33.
Schackman BR, Teixeira PA, Weitzman G, Mushlin
AI, Jacobson IM. Quality-of-life tradeoffs for
hepatitis C treatment: do patients and providers
agree? Medical Decision Making. 2008 Mar-Apr;28:
233-42.
Martin EG, Paltiel AD, Walensky RP, Schackman
BR. Expanded HIV screening in the United States:
what will it cost government discretionary
and entitlement programs? A budget impact
analysis. Value in Health. 2010 Dec;13:893-902.
Schackman BR. Implementation science for the
prevention and treatment of HIV/AIDS. Journal
of Acquired Immune Deficiency Syndromes. 2010
Dec;55 Suppl 1:S27-31.
Koenig SP, Bang H, Severe P, Jean Juste MA,
Ambroise A, Edwards A, Hippolyte J, Fitzgerald
DW, McGreevy J, Riviere C, Marcelin S, Secours R,
Johnson WD, Pape JW, Schackman BR. Costeffectiveness of early versus standard antiretroviral therapy in HIV-infected adults in Haiti. PLoS
Medicine. 2011 Sep;8:e1001095.
Schackman BR, Leff JA, Polsky D, Moore BA,
Fiellin DA. Cost-effectiveness of long-term
outpatient buprenorphine-naloxone treatment
for opioid dependence in primary care. Journal of
General Internal Medicine. 2012 Jun;27:669-76.
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WEILL CORNELL MEDICAL COLLEGE
Dr. Schackman has an ongoing collaboration with the Cost-Effectiveness of
Preventing AIDS Complications (CEPAC) modeling group based at Massachusetts
General Hospital in Boston. Working with this group, he has co-authored studies
of the lifetime cost of HIV care in the United States, the cost-effectiveness of
earlier treatment and expanded HIV screening, and the economic value of
pharmacogenomics testing for HIV care. Results of these studies have been widely
cited, including in the President’s National HIV/AIDS Strategy for the United States.
Dr. Schackman also collaborates with clinical trial teams as a member of the NIHsupported AIDS Clinical Trials Group and the National Institute on Drug Abuse Clinical
Trials Network (CTN). With funding from the National Institute on Drug Abuse (NIDA)
he recently led an economic sub-study of a CTN trial of on-site rapid HIV testing in
drug treatment programs. Using cost and outcomes results from the CTN trial and
the CEPAC model, he found that on-site rapid HIV testing met commonly accepted
cost-effectiveness thresholds. His team also produced an HIV testing budgeting tool
for drug abuse treatment programs and collaborated in describing implementation
challenges. He is now using trial results and simulation modeling to evaluate the cost
and cost-effectiveness of on-site rapid hepatitis C testing in drug treatment programs,
in combination with rapid HIV testing and on its own.
In a recent study funded in part by the Robert Wood Johnson Foundation,
Dr. Schackman and his colleagues found that treating opioid dependence with
long-term outpatient buprenorphine-naloxone in primary care settings may be
cost-effective, but that results are highly dependent on quality of life on and off
treatment for which data are limited. To address this evidence gap, he has recently
been funded by NIDA to develop with colleagues a set of “off the shelf” quality-oflife weights that can be used in future economic evaluations of new pharmacologic
interventions to treat the growing problem of opioid dependence, particularly
dependence resulting from misuse of prescription opioid drugs. Dr. Schackman and
Ann B. Beeder, MD, Associate Professor of Public Health and Psychiatry, have begun
a new collaborative research and training initiative called the Program in Addiction
Treatment Effectiveness and Economics.
Dr. Schackman has a longstanding collaboration with the investigators at the
Groupe Haitien d’Etude du Sarcome de Kaposi et des Infections Opportunistes
(GHESKIO) in Haiti and the Weill Cornell Center for Global Health, and he is actively
involved in research training programs in support of Haiti’s national scale-up of HIV
treatment. In conjunction with a GHESKIO randomized trial of earlier HIV treatment
that led to the World Health Organization revising their HIV treatment guidelines,
Dr. Schackman and colleagues found that earlier initiation of treatment is indeed
cost-effective if toxicity monitoring tests that have low value in resource-limited
settings are eliminated.
RESEARCH PROFILES
Nicholas D. Schiff, MD
Professor of Neurology and Neuroscience
Professor of Public Health
Dr. Nicholas Schiff directs an integrative translational research program with
a primary focus on understanding the process of recovery of consciousness
following brain injuries. This research program links basic systems and clinical
neuroscience with the goal of developing novel neurophysiologic and neuroimaging
diagnostics applied to human subjects and therapeutic strategies. Dr. Schiff and
his research group have contributed several landmark advances, including the first
demonstrations of brain structural alterations occurring in the setting of very late
recovery from severe brain injury.
More recently, Dr. Schiff and his colleagues have taken insights into the
neurophysiological mechanisms of arousal regulation and of deep brain electrical
stimulation techniques to demonstrate evidence that long-lasting, severe
cognitive disability may be influenced by electrical stimulation of the human
central thalamus. Dr. Schiff received the 2007 Research Award for Innovation
in Neuroscience from the Society for Neuroscience for this research. This work
provides an important foundation for developing further understanding of both
the mechanisms of recovery of consciousness and basic mechanisms underlying
consciousness in the human brain.
Dr. Schiff and his colleagues demonstrated that long-lasting,
severe cognitive disability may be influenced by electrical
stimulation of the human central thalamus.
Dr. Schiff’s research involves close collaboration with investigators at the Citigroup
Biomedical Imaging Center and with long-standing colleagues Drs. Keith Purpura
and Jonathan Victor in the Systems Neuroscience group. In collaborative studies
with Dr. Purpura, animal models of central thalamic deep brain stimulation are
providing fundamental understanding of the circuit mechanisms underlying
this novel therapeutic method and insight into the thalamocortical mechanisms
underlying arousal regulation and conscious behavior. In collaboration with
Dr. Victor, methods of advanced signal processing are being developed and applied
to the study of human brain electrical signals obtained from normal subjects and
patients recovering from severe brain injuries.
SELECTED Publications
Voss HU, Ulug AM, Watts R, Heier LA,
McCandliss B, Kobylarz E, Giacino J, Ballon D,
Schiff ND. Possible axonal regrowth in late
recovery from minimally conscious state.
Journal of Clinical Investigation. 2006 Jul;116
(7):2005-11.
Schiff ND, Giacino JT, Kalmar K, Victor JD,
Baker K, Gerber M, Fritz B, Eisenberg B,
O’Connor J, Kobylarz EJ, Farris S, Machado A,
McCagg C, Plum F, Fins JJ, Rezai AR. Behavioral
improvements with thalamic stimulation after
severe traumatic brain injury. Nature. 2007 Aug
2;448(7153):600-03.
Schiff, ND. Recovery of consciousness after
brain injury: a mesocircuit hypothesis. Trends in
Neuroscience. 2010 Jan;33(1):1-9.
Brown EN, Lydic R, Schiff ND. General anesthesia,
sleep and coma. New England Journal of
Medicine. 2010 Dec 30;363(27): 2638-50.
Bardin JC, Fins JJ, Katz DI, Hersh J, Heier LA,
Tabelow K, Dyke JP, Ballon DJ, Schiff ND, Voss
HU. Dissociations between behavioural and
functional magnetic resonance imaging-based
evaluations of cognitive function after brain
injury. Brain. 2011 Mar;134(Pt 3):769-82.
The clinical and scientific program is paralleled by collaborative studies directed
by Dr. Joseph Fins in the Departments of Public Health, Medicine, and Psychiatry.
Dr. Fins’ studies are aimed at the ethical and policy dimensions of this research field,
which has a unique and strong impact on medical practice. Dr. Schiff and Dr. Fins
co-direct the CASBI (Consortium for the Advanced Study of Brain Injury) program.
Dr. Schiff’s research program has a strong international reach through his leadership
of a large consortium grant from the James S. McDonnell Foundation, which links
his research team with groups at Cambridge University, University of Liege, Belgium,
Harvard University, and Hebrew University, Israel. This international collective is
focused on developing a large database to assess the specificity and sensitivity of
novel diagnostic methods and to deepen clinical-pathologic correlations underlying
recovery from severe brain injuries.
2012-2013 Research highlights
63
RESEARCH PROFILES
Dirk Schnappinger, PhD
Associate Professor of Microbiology and Immunology
The number of new tuberculosis cases is still rising and reached almost 10 million
in 2010. The extraordinary impact of this infectious disease on public health is in
part due to drug-resistant strains of Mycobacterium tuberculosis, which in some
cases have acquired resistance to four or more drugs. These extensively drugresistant strains continue to emerge and spread. Success rates for treating drugresistant tuberculosis are generally low and mortality can reach 100 percent for
outbreaks in patients co-infected with HIV. New drugs are thus needed to limit the
impact of tuberculosis on global health.
SELECTED Publications
Blumenthal A, Trujillo C, Ehrt S, Schnappinger D.
Simultaneous analysis of multiple Mycobacterium
tuberculosis knockdown mutants in vitro and
in vivo. PLoS One. 2010 Dec 22;5(12):e15667.
Kim JH, Wei JR, Wallach JB, Robbins RS, Rubin
EJ, Schnappinger D. Protein inactivation in
myco-bacteria by controlled proteolysis and its
application to deplete the beta subunit of RNA
polymerase. Nucleic Acids Research. 2011 Mar;
39(6):2210-20.
Wei JR, Krishnamoorthy V, Murphy K, Kim JH,
Schnappinger D, Alber T, Sassetti CM, Rhee KY,
Rubin EJ. Depletion of antibiotic targets has
widely varying effects on growth. Proceedings
of the National Academy of Sciences. 2011 Mar 8;
108(10):4176-81.
Woong Park S, Klotzsche M, Wilson DJ, Boshoff
HI, Eoh H, Manjunatha U, Blumenthal A, Rhee
K, Barry CE 3rd, Aldrich CC, Ehrt S, Schnappinger
D. Evaluating the sensitivity of Mycobacterium
tuberculosis to biotin deprivation using regulated
gene expression. PLoS Pathogy. 2011 Sep;7(9):
e1002264.
Duckworth BP, Geders TW, Tiwari D, Boshoff
HI, Sibbald PA, Barry CE 3rd, Schnappinger D,
Finzel BC, Aldrich CC. Bisubstrate adenylation
inhibitors of biotin protein ligase from
Mycobacterium tuberculosis. Chemistry &
Biology. 2011 Nov 23;18(11):1432-41.
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WEILL CORNELL MEDICAL COLLEGE
Significant progress has recently been made in the identification and characterization
of new small molecule compounds that can kill M. tuberculosis. However, the
attrition rate in drug discovery is high and it is unlikely that the number of
current lead compounds is sufficient to solve the global health problems caused
by tuberculosis. The paucity of validated targets and new lead compounds are
therefore significant bottlenecks in the search for new drugs against tuberculosis.
Dr. Dirk Schnappinger and his colleagues have developed
genetic approaches for the conditional inactivation of
M. tuberculosis genes.
Dr. Dirk Schnappinger and his colleagues have developed genetic approaches for
the conditional inactivation of M. tuberculosis genes. In one of these approaches,
the native promoter of a gene of interest is replaced with a synthetic “tet promoter”
that contains binding sites for a tetracycline repressor, TetR. TetRs are bacterial
transcription factors that can prevent binding of RNA polymerase and silence a
promoter.
By codon variation and site directed mutagenesis, they adapted two forms of TetR
for use in mycobacteria, which can silence tet promoters either in the presence
or absence of a tetracycline. These two types of TetRs allow the construction of
mutants in which a single mycobacterial gene is specifically silenced by the addition
(TetOFF) or removal (TetON) of a tetracycline. More recently, they also developed a
complementary approach in which tetracycline-inducible proteolytic degradation is
employed to conditionally inactivate a target protein.
As tetracyclines can penetrate eukaryotic cells and tissue, as well as bacterial cells,
either of these approaches can be used to inactivate an M. tuberculosis gene or
gene product not only in vitro but also during mouse infections. In ongoing work,
the researchers are applying these new genetic approaches to further elucidate
how M. tuberculosis adapts to the hostile and changing environments it encounters
during an infection, to rank potential drug targets according to their suitability
for the development of new drugs, to study the mechanism of action of new drug
candidate molecules, and to characterize essential genes of unknown function.
RESEARCH PROFILES
Heidi Stuhlmann, PhD
Harvey Klein Professor of Biomedical Sciences
Professor of Cell and Developmental Biology
Professor of Cell and Developmental Biology in Pediatrics
Development of a functional circulatory system in the vertebrate embryo is crucial
for delivery of nutrients and oxygen to the embryo. Defects in the development
of blood vessels result in death before birth or in congenital cardiovascular
abnormalities. Vascular development involves two basic processes: vasculogenesis
and angiogenesis. In vasculogenesis, blood vessels form de novo from endothelial
progenitors. In angiogenesis, new blood vessels form from preexisting ones
by proliferation and sprouting, differentiation, migration, extracellular matrix
formation, and pericyte recruitment. Central to these processes are the endothelial
cells that form a continuous layer lining the blood vessels.
In the adult, endothelial cells become quiescent but can respond to angiogenic
signals to form new vessels. During physiological angiogenesis in the adult
organism, such as wound healing and during pregnancy, endothelial cells are
stimulated to form new vessels, a process termed neo-angiogenesis. Similarly,
during pathological processes such as ischemia, myocardial infarct, repair of injured
tissue, and tumor growth, endothelial cells become activated to sprout, migrate,
and undergo remodeling. Thus, endothelial cells constitute a dynamic system that
changes in response to environmental stimuli. Research in Dr. Heidi Stuhlmann’s
laboratory focuses on understanding the molecular mechanisms that orchestrate
these processes, using the mouse as a model system.
In a genetic screen for early developmental genes, Dr. Stuhlmann and her colleagues
identified two novel genes that play important roles in vascular development and
homeostasis. One of these, vascular endothelial zinc finger 1 (VEZF1), encodes an
endothelial transcription factor that plays essential, dosage-dependent roles in
vascular system development. Unexpectedly, they found that heterozygous embryos
display lymphatic vessel abnormalities that are reminiscent of the human congenital
malformation syndrome, nuchal edema. They are collaborating with Maternal-Fetal
Medicine to investigate if human fetuses with nuchal edemas carry mutations
in the VEZF1 gene, or show dysregulation of VEZF1 expression. Another exciting
finding is that VEZF1 is involved in the epigenetic regulation of gene expression
through the DNA methyltransferase DNMT3b.
SELECTED Publications
Gowher H, Stuhlmann H, Felsenfeld G. Vezf1
regulates genomic DNA methylation through its
effect on expression of DNA methyltransferase
Dnmt3b. Genes & Development. 2008 Aug 1;
22(15):2075-84.
Durrans A, Stuhlmann H. A role for Egfl7 during
endothelial organization in the embryoid body
model system. Journal of Angiogenesis Research.
2010 Feb 19;2(4):1-12.
Zou Z, Ocaya PA, Sun H, Kuhnert F, Stuhlmann H.
Targeted Vezf1-null mutation impairs vascular
structure formation during embryonic stem cell
differentiation. Arteriosclerosis, Thrombosis, and
Vascular Biology. 2010 Jul;30(7):1378-88.
Nichol D, Shawber CJ, Fitch MJ, Bambino K,
Sharma A, Kitajewski J, Stuhlmann H. Impaired
angiogenesis and altered Notch signaling in
mice overexpressing Egfl7. Blood. 2010 Dec 23*;
116(26):6133-43. *Commentary: Davis GE.
Vascular balancing act: Egfl7 and Notch. Blood.
2010 Dec 23; 116 (26):5791-93.
Nichol D, Stuhlmann H. EGFL7: a unique
angiogenic signaling factor in vascular
development and disease. Blood. 2012 Feb 9;
119(6):1345-52.
A second gene identified in their screen, EGF-like domain 7 (EGFL7), is an early embryonic
marker for endothelial cells and their progenitors. EGFL7 is a unique angiogenic
factor: It is secreted specifically by endothelial cells, acts as a chemoattractant, and
binds to the extracellular matrix. Importantly, Dr. Stuhlmann’s lab showed that
EGFL7 interacts with and antagonizes endothelial Notch, a key vascular signaling
pathway component. Ongoing studies indicate that EGFL7 expression is induced by
hypoxia and vascular endothelial growth factor, VEGF, and that it plays an important
role in physiological angiogenesis during pregnancy, in the bone marrow vascular
niche, and in pathological angiogenesis in response to hypoxia and vascular injury.
In collaboration with Dr. Robin Davisson’s group they are also investigating its
role during placental development and placentopathies such as preeclampsia, a
pregnancy-specific disease that is defined by sudden onset of hypertension and
proteinuria in the last trimester.
2012-2013 Research highlights
65
RESEARCH PROFILES
Tao Sun, PhD
Associate Professor of Cell and Developmental Biology
The human brain is organized into distinct functional regions controlling complex
behaviors. Accurate structural formation and precise function of the central
nervous system rely on the production of multipotent and self-renewing neural
stem cells (or progenitors) and the interconnection of specific cell types derived
from them during development. Gene mutations and environmental factors can
alter gene regulation during the development of the central nervous system and
result in neurological disorders.
SELECTED Publications
Sun T, Patoine C, Visvader J, Sum E, Cherry TJ,
Orkin SH, Geschwind DH, Walsh CA. Early
asymmetry of gene transcription in embryonic
human left and right cerebral cortex. Science.
2005 Jun 17;308(5729):1794-98.
Sun T, Walsh CA. Molecular approaches to brain
asymmetry and handedness. Nature Review
Neuroscience. 2006 Aug;7(8):655-62.
Huang Z, Kawase-Koga Y, Zhang S, Visvader J,
Toth M, Walsh CA, Sun T. Transcription factor
Lmo4 defines the shape of functional areas in
developing cortices and regulates sensorimotor
control. Developmental Biology. 2009 Mar 1;
327(1):132-42.
Kawase-Koga Y, Low R, Otaegi G, Pollock A,
Deng H, Eisenhaber F, Maurer-Stroh S, Sun T.
RNAase III enzyme dicer maintains signaling
pathways for differentiation and survival in
mouse cortical neural stem cells. Journal of
Cell Science. 2010 Feb 15;123(Pt 4):586-94.
Otaegi G, Pollock A, Hong J, Sun T. MicroRNA
miR-9 modifies motor neuron columns by a
tuning regulation of FoxP1 levels in developing
spinal cords. Journal of Neuroscience. 2011
Jan 19;31(3):809-18.
Bian S, Sun T. Functions of noncoding RNAs in
neural development and neurological diseases.
Molecular Neurobiology. 2011 Dec;44(3):359-73.
Otaegi G, Pollock A, Sun T. An optimized sponge
for microRNA miR-9 affects spinal motor neuron
development in vivo. Frontiers in Neurogenesis.
2011 Jan;5:146.
The research in Dr. Tao Sun’s laboratory seeks to reveal gene regulation mechanisms
in normal and disease conditions. The goals are to address three broad and essential
questions:
• What is the genetic regulation of brain asymmetry and handedness?
• How do neural stem cells self-renew and then differentiate into distinct cell types
to establish complex brain anatomy and function?
• What are the molecular mechanisms regulating normal neural development and
under human neurological disease conditions?
In Dr. Sun’s lab, researchers are using mouse genetic tools, mouse behavioral tests,
neural stem cell cultures, and various molecular and cell biology approaches. They
are investigating how gene alterations and mutations at developmental stages can
affect behaviors in the adult using mouse models; how coding genes and noncoding RNAs such as microRNAs control neural development; and how they may be
associated with neurological disorders.
The Sun lab has investigated microRNA functions in the
developing central nervous system and found that microRNAs
are important to control brain size.
Using a genetic screening approach, the lab has identified asymmetrically
expressed genes in human fetal brains. Dr. Sun and his research team are
now examining their functions in brain asymmetry and functional laterality
using mouse models. The Sun lab has investigated microRNA functions in the
developing central nervous system and found that microRNAs are important to
control brain size. Ablation of microRNA function in developing brains can cause
neurodegeneration defects. They have identified a group of microRNAs that play a
role in promoting proliferation of neural stem cells in embryonic and adult brains.
They have also discovered that a microRNA miR-9 is essential for motor neuron
development in the spinal cord and axonal projections to target muscles.
Dr. Sun’s research has revealed a novel mechanism of gene regulation that is
mediated by non-coding RNAs in neural development. Because of the technical
advance of microRNA in vitro synthesis and delivery, microRNAs have become a
promising means for gene therapies. Thus, the research of Dr. Sun’s lab of revealing
functions of microRNAs in brain development and in motor neuron specification
may provide new methods of stem cell based therapies for neurodegeneration
diseases and spinal cord injuries.
66
WEILL CORNELL MEDICAL COLLEGE
RESEARCH PROFILES
Manikkam Suthanthiran, MB, BS
Stanton Griffis Distinguished Professor of Medicine
Professor of Medicine in Surgery and Professor of Biochemistry
The Founding Chairman of the Department of Transplantation Medicine and
Chief of Nephrology and Hypertension at NewYork-Presbyterian/Weill Cornell,
Dr. Manikkam Suthanthiran pursues research in transplantation immunology
and molecular biology to improve outcomes following organ transplantation.
Molecular Medicine. Dr. Suthanthiran’s laboratory has pioneered the development
of noninvasive gene-based assays to ascertain kidney transplant status, which had
previously required an invasive kidney biopsy procedure. The original study, first
conducted at Weill Cornell, led to an NIH-sponsored multicenter Cooperative Clinical
Trial in Transplantation comprised of 500 subjects from major transplant centers in
the United States. Results of the molecular studies of transplant recipients were
presented at the plenary sessions of the 2011 American Transplant Congress Annual
Meeting and the 2011 International Transplantation Society Meeting. Based on the
bench-to-bedside approach, this study has led to state-of-the-art, individualized care
(personalized medicine) of kidney transplant recipients. Recently, Dr. Suthanthiran
and his research team have determined the expression profiles of small RNAs are
considered as master regulators of immunity in kidney transplants.
Human Pancreatic Islet Cell Transplantation. The first successful human islet
cell transplantation in the tri-state area for the treatment of Type 1 diabetes
mellitus was carried out at Weill Cornell by an interdisciplinary team led by Dr.
Suthanthiran. His laboratory established a human islet cell isolation facility
and successfully transplanted Type 1 diabetic recipients. In a bedside-to-bench
approach, the laboratory has developed approaches to meet the twin challenges of
limited islet supply and their tendency toward early loss of function and successful
transplantation without any immunosuppressive drugs.
Transplantation without Immunosuppressive Therapy. The ultimate goal in organ
transplantation is transplant tolerance, that is, transplantation of organs without
any drug therapy. Dr. Suthanthiran’s laboratory contributed to the first ever report
on tolerance of mismatched kidney transplants, which was published in the New
England Journal of Medicine. The ability to transplant a human organ without drug
therapy is of exceptional significance. In recognition of their contribution, NewYorkPresbyterian/Weill Cornell was selected by the Immune Tolerance Network, NIH,
to conduct the innovative transplant tolerance trials. Recently, Dr. Suthanthiran
and his colleagues identified a molecular signature in the urine of patients who are
tolerant of kidney transplants. Their research findings were published in 2010 in a
premier journal, The Journal of Clinical Investigation.
Personalized Medicine. In 2009, Dr. Suthanthiran and his team initiated the first ever
study of immunosuppressive drug, tacrolimus, under the guidance of urinary cell
gene expression patterns. This NIH-sponsored molecular monitoring study was also
recognized by the awarding of the NIH MERIT Award in 2009 to Dr. Suthanthiran.
Outstanding Clinical Outcomes. The advances made in the laboratory have been
translated to make organ transplants safer, offer personalized therapy, and
move from a reactive treatment strategy to a preventive and predictive approach.
This is reflected in part by kidney transplant patient and graft survival rates at
Weill Cornell being significantly higher than expected survival rates.
SELECTED Publications
Li B, Hartono C, Ding R, Sharma VK, Ramaswamy
R, Qian B, Serur D, Mouradian J, Schwartz JE,
Suthanthiran M. Noninvasive diagnosis of renalallograft rejection by measurement of messenger
RNA for perforin and granzyme B in urine.
New England Journal of Medicine. 2001 Mar
29;344(13): 947-54.
Muthukumar T, Dadhania D, Ding R,
Snopkowski C, Naqvi R, Lee JB, Hartono C, Li
B, Sharma VK, Seshan SV, Kapur S, Hancock
WW, Schwartz JE, Suthanthiran M. Messenger
RNA for FOXP3 in the urine of renal-allograft
recipients. New England Journal of Medicine.
2005 Dec 1;353(22):2342-51.
Luo X, Tarbell KV, Yang H, Pothoven K, Bailey SL,
Ding R, Steinman RM, Suthanthiran M. Dendritic
cells with TGF-beta1 differentiate naive CD4+CD25T cells into islet-protective Foxp3+ regulatory
T cells. Proceedings of the National Academy of
Sciences USA. 2007 Feb 20;104(8):2821-26.
Anglicheau D, Sharma VK, Ding R, Hummel
A, Snopkowski C, Dadhania D, Seshan SV,
Suthanthiran M. MicroRNA expression profiles
predictive of human renal allograft status.
Proceedings of the National Academy of Sciences
USA. 2009 Mar 31;106(13):5330-35.
Newell KA, Asare A, Kirk AD, Gisler TD, Bourcier
K, Suthanthiran M, et al; Immune Tolerance
Network ST507 Study Group. Identification of
a B cell signature associated with renal transplant
tolerance in humans. Journal of Clinical
Investigation. 2010 Jun 1;120(6):1836-47.
Cheng EY, Sharma VK, Chang C, Ding R,
Allison AC, Leeser DB, Suthanthiran M, Yang H.
Diannexin decreases inflammatory cell
infiltration into the islet graft, reduces B cell
apoptosis, and improves early graft function.
Transplantation. 2010 Oct 15;90(7):709-16.
Yang H, Cheng EY, Sharma VK, Lagman M,
Chang C, Song P, Ding R, Muthukumar T,
Suthanthiran M. Dendritic cells with TGF-β1
and IL-2 differentiate naive CD4+ T cells into
alloantigen-specific and allograft protective
Foxp3+ regulatory T cells. Transplantation.
2012 Mar 27;93(6):580-88.
2012-2013 Research highlights
67
RESEARCH PROFILES
Jonathan D. Victor, MD, PhD
Fred Plum Professor of Neurology
Professor of Neurology and Neuroscience
SELECTED Publications
Victor JD, Mechler F, Ohiorhenuan IE, Schmid A,
Purpura KP. Laminar and orientation-dependent
characteristics of spatial non-linearities:
implications for the computational architecture
of visual cortex. Journal of Neurophysiology.
2009 Dec;102(6):3414-32.
Tkacik G, Prentice J, Victor JD, Balasubramanian
V. Local statistics in natural scenes predict the
saliency of synthetic textures. Proceedings of the
National Academy of Sciences. 2010 Jul 28;107
(42):18149-54.
Ohiorhenuan IE, Mechler F, Purpura KP, Schmid
AM, Victor JD. Sparse coding and high-order
correlations in fine-scale cortical networks.
Nature. 2010 Jul 29;466(7306):617-21.
Victor JD, Drover JD, Conte MM, Schiff ND.
Mean-field modeling of thalamocortical
dynamics, and a model-driven approach to
EEG analysis. Proceedings of the National
Academy of Sciences. 2011 Feb 28; (108 supp. 3):
15631-38.
Kuang X, Poletti M, Victor JD, Rucci M. Temporal
encoding of spatial information during active
visual fixation. Current Biology. 2012 Mar 20;22(6):
510-14.
Roussin AT, D’Agostino AE, Fooden AM, Victor
JD, Di Lorenzo PM. Taste coding in the nucleus
of the solitary tract of the awake, freely licking
rat. Journal of Neuroscience. 2012 Aug 1;32(31):
10494-506.
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WEILL CORNELL MEDICAL COLLEGE
Dr. Jonathan Victor’s research combines mathematical, computational, and
experimental approaches to address fundamental problems in basic and clinical
systems neuroscience. His laboratory’s basic research focuses on the design principles
of sensory processing, both in the sensory periphery and in the brain, and how these
design principles are implemented in neural circuits. Using the visual system as a
model, the research seeks to determine the aspects of sensory information that are
represented in the brain, the features of the activity of individual neurons and neural
populations that support these representations, and realistic models for how these
representations are transformed. Experimental approaches include psychophysical
studies in man and multineuronal recordings in the primate brain.
The psychophysical studies have delineated a specific set of computations
that characterize the statistics of the sensory input, and have shown that these
computations are closely matched to the informative aspects of our visual
environment. The neurophysiological studies have shown that these computations
take place in primary visual cortex, arising from feedback interactions between
cortical layers and dynamic reconfiguration of local networks by the incoming
visual stimulus.
Basic research in Dr. Victor’s laboratory focuses on the design
principles of sensory processing, both in the sensory periphery and
in the brain, and how they are implemented in neural circuits.
Neurophysiological and psychophysical studies are complemented by theoretical
work. One aspect of this work is the development of mathematical techniques to
bridge the gap between traditional systems-identification methods (such as the
“white noise” approach), and methods based on ethologically relevant stimuli,
such as natural scenes. A second aspect is the development of strategies to analyze
neural coding by individual neurons and neural populations, with a particular focus
on information-theoretic tools. Dr. Victor is applying these techniques to the visual
system and, in collaboration with Dr. Patricia Di Lorenzo of SUNY Binghamton, to
the gustatory system.
Clinically oriented work is directed at understanding thalamocortical dynamics, and
the role that alterations in these dynamics may play in the pathogenesis and/or
symptomatology of neurologic diseases, including epilepsy and chronic brain injury.
In collaboration with Dr. Nicholas Schiff and colleagues at Weill Cornell, Dr. Victor’s
laboratory is analyzing EEG, functional imaging, and anatomical imaging in brain
injury patients to probe these dynamics and their relationship to spontaneous and
induced fluctuations in cognitive ability and behavior. A central aspect of the work
is the development of mathematical models of thalamocortical interactions. These
modeling studies support the notion that thalamic interactions may control cortical
functional connectivity, and also inspire novel approaches to the analysis of the
EEG. It is anticipated that both the investigational methods developed and the
insights gained will generalize to other conditions, such as autism and Alzheimer’s
disease, in which rapid fluctuations in level of function are a prominent feature.
RESEARCH PROFILES
Yi Wang, PhD
Faculty Distinguished Professor in Radiology
Professor of Biomedical Engineering
Dr. Yi Wang’s research interest is to develop magnetic resonance imaging (MRI)
methods using mathematics, physics, electronic engineering, and computer
science tools, and to work with clinicians and scientists to apply these developed
imaging methods to improve basic scientific understanding, diagnose disease more
accurately, and treat patients better.
Recently, Dr. Wang’s group has introduced a fundamentally new concept to MRI:
quantitative susceptibility mapping (QSM) by inverting the magnetic field to define
the local magnetization source for tissue characterization. So far, MRI practice
primarily utilizes information from magnitude images and mostly discards phase
images. Phase image allows detection of the local magnetic field. The inversion from
magnetic field to magnetization source (tissue magnetic susceptibility in MRI)
would generate a new contrast mechanism that may be a valuable addition to
the traditional contrast mechanisms. Dr. Wang and his colleagues have developed
effective conditioning and regularization approaches for an accurate and robust
solution to this inverse problem. This novel QSM magnetic source MRI approach
may for the first time provide an accurate and practical solution to the fundamental
problem of contrast agent quantification in molecular MRI and contrast enhanced
MRI, as well as quantification of endogenous contrast agents, including iron and
calcium depositions and deoxyhemoglobin that are fundamental for investigating
organ functions.
Dr. Wang is working with neurological clinicians to develop research projects on clinical
applications of QSM. Potential clinical applications include mapping iron deposition in
neurodegenerative diseases, including Parkinson’s and Alzheimer’s diseases, evaluating
and measuring blood products in cerebral microhemorrhage and hemorrhagic stroke,
evaluating hypoxia in ischemic stroke and tumor, and investigating myelin of unique
negative susceptibility. Dr. Wang will work with neuroscientists, neurologists, and
neuroradiologists to develop and apply QSM techniques.
Dr. Wang is also interested in working with scientists and clinicians to investigate
other important QSM applications, including:
Mapping bone mineralization in vivo. While traditional water-based tissue contrasts
in MRI cannot detect calcium, QSM allows mapping of calcium components due to
their unique negative magnetic susceptibilities and may enable a powerful in vivo
assessment of bone vulnerability.
Selected publications
Liu T, Spincemaille P, de Rochefort L, Kressler
B, Wang Yi. Multiple angle acquisitions
for conditioning the inverse problem from
magnetic field to magnetic source. Magnetic
Resonance in Medicine. 2009 Jan;61(1):196-204.
de Rochefort L, Liu T, Kressler B, Liu J,
Spincemaille P, Lebon V, Wu J, Wang Yi.
Quantitative susceptibility map reconstruction
from MR phase data using bayesian regularization:
validation and application to brain imaging.
Magnetic Resonance in Medicine. 2010 Jan;
63(1):194-206.
Liu T, Khalidov I, de Rochefort L, Spincemaille
P, Liu J, Wang Yi. A novel background field
removal method for MRI using projection onto
dipole fields (PDF). NMR in Biomedicine. 2011
Nov;24(9):1129-36.
Liu T, Surapaneni K, Lou M, Cheng L, Spincemaille
P, Wang Yi. Cerebral microbleeds: burden
assessment by using quantitative susceptibility
mapping. Radiology. 2012 Jan;262(1):269-78.
Liu J, Liu T, de Rochefort L, Ledoux J, Khalidov I,
Chen W, Tsiouris AJ, Wisnieff C, Spincemaille
P, Prince MR, Wang Yi. Morphology enabled
dipole inversion for quantitative susceptibility
mapping using structural consistency between
the magnitude image and the susceptibility
map. NeuroImage. 2012 Feb 1;59(3):2560-68.
Mapping iron depositions in liver and heart. While MRI is very sensitive to iron
depositions, absolute iron quantification has not been possible so far. QSM can
overcome this problem, enabling absolute iron quantification for accurate diagnosis
and effective treatment of diseases involving iron overloading.
Quantification of contrast agents in routine contrast enhanced MRI and in
molecular MRI. Currently, in vivo estimation of gadolinium concentration [Gd]
in contrast-enhanced MRI is based on the assumption that [Gd] is linearly
proportional to MRI intensity, which breaks down when [Gd] is high, such as
in tumor imaging. This results in poor specificity in cancer diagnosis. QSM can
overcome these limitations in contrast-enhanced MRI, which is promising for
resolving pseudoresponse and pseudoprogression in cancer MRI.
2012-2013 Research highlights
69
RESEARCH PROFILES
Harel Weinstein, MSc, DSc
Chairman, Department of Physiology and Biophysics
Maxwell M. Upson Professor of Physiology and Biophysics
SELECTED Publications
Zhao Y, Terry D, Shi L, Weinstein H, Blanchard,
SC, Javitch JA. Substrate-modulated gating
dynamics in a Na+-coupled neurotransmitter
transporter homolog. Nature. 2011 Jun 2;474
(7349):109-13.
Mondal S, Khelashvili G, Shan J, Andersen OS,
Weinstein H. Quantitative modeling of
membrane deformations by multihelical
membrane proteins: application to GPCRs.
Biophysical Journal. 2011 Nov 2;101(9)2092-101.
Weinstein H, Scarlata S. The correlation between
multidomain enzymes and mutiple activation
mechanisms: the case of phospholipase Cbeta
and its membrane interactions. Biochimica et
Biophysica Acta. 2011 Dec;1808(12):2940-47.
Quick M, Shi L, Zehnpfennig B, Weinstein H,
Javitch JA. Experimental conditions can obscure
the second high-affinity site in LeuT. Nature
Structural & Molecular Biology. 2012 Jan 15;
19(2):207-11.
Shan J, Khelashvili G, Mondal S, Mehler EL,
Weinstein H. Ligand-dependent conformations
and dynamics of the serotonin 5-HT2A receptor
determine its activation and membrane-driven
oligomerization properties. PLoS Computational
Biology. 2012 Apr;8(4):e1002473.
Stolzenberg S, Khelashvili G, Weinstein H.
Structural intermediates in a model of the
substrate translocation path of the bacterial
glutamate transporter homologue GltPh.
The Journal of Physical Chemisty B. 2012
May 10;116(18):5372-83.
Weinstein H, Editor, Comprehensive Biophysics,
Volume 9: Simulation and Modeling, Oxford:
Academic Press, 2012.
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WEILL CORNELL MEDICAL COLLEGE
Dr. Harel Weinstein’s laboratory is devoted to studies of complex molecular systems
in the cell, and of their function in mechanisms of cell-to-cell communication in
physiological systems under normal conditions and in disease. The studies aim to
gain quantitative insight into the gene and protein structure of molecular machines
that carry out processes of a cell’s life and communication, such as receptors and
transporters, the minute but powerful molecular machines responsible for neuronal
signaling, and the regulation/deregulation of cell growth. Their malfunction or
misdirection underlies a wide spectrum of disease, from neurological dysfunctions
to drug abuse, and from cancer to diabetes. The studies in the Weinstein lab aim to
uncover how disease sets in, how it evolves, and how to design therapies.
The lab’s work on receptors for the neurotransmitters serotonin and dopamine,
and the proteins that transport them, illustrates how such studies have
pioneered a quantitative understanding of molecular processes in key aspects of
neurotransmission and cell signaling. Documented in the scientific literature
over the last two years, these studies employed the strategy established in
Dr. Weinstein’s lab of combining computational and experimental methodologies.
The quantitative models used in the computational studies are based on
mathematical modeling, molecular biophysics, and bioinformatics and
engineering approaches in systems biology. Information and data are obtained
from collaborative experiments in laboratories studying molecular structure and
dynamics, and cell and organ physiology.
Combining these advanced tools, Dr. Weinstein’s lab was able to track for the
first time how, and why, the transporter molecules change their shape to enable
various substances to travel across the cell membrane and regulate transmission
of the brain’s messages, and the manner in which drugs such as antidepressants,
modify these actions. This was done with computational simulations using rules
based on fundamental laws of physics, in computational “what if” studies able to
interpret the observations from experiments in the lab, as well as from patients,
at unprecedented atomic detail to produce structure-based information about
mechanisms. These studies enabled the first detailed description of the molecular
sites of action of antidepressant drugs, which are the transporters that normally
remove neurotransmitters from the synapse.
The research led Dr. Weinstein and his collaborators to recognize for the first
time in the computer simulations the manner in which the movements of the
transporter proteins determine the binding and permeation of the transported
molecule in the normal state of neuronal transmission. The new findings help
explain not only how known antidepressant medications, such as Prozac and
Zoloft (the selective serotonin reuptake inhibitors – SSRIs), produce their effects,
but also highlight the way in which stimulants like cocaine and amphetamine
act in altering the normal exchange process between cells in a variety of excited
states. The new level of understanding of the key molecular mechanisms in
neuronal signaling in the brain should also prove useful in the development of
more targeted medication therapies for anxiety, depression, schizophrenia, and
substance abuse.
Research PROFILES
Pengbo Zhou, PhD
Professor of Pathology and Laboratory Medicine
The focus of Dr. Pengbo Zhou’s laboratory is to understand the molecular mechanisms
by which ubiquitin-dependent proteolysis operates under physiological and
pathological conditions. Using a combination of biochemical, cell, and molecular
biological and mouse genetic approaches, Dr. Zhou has carried out studies in many
aspects of biology and regulation of the cullin ubiquitin ligases, including:
• initial discovery of the auto-ubiquitination mechanism by which cullin 1(Cul1)
dynamically assembles with distinct substrate receptors for targeting a wide range
of substrates
• engineering of Cul1-based ubiquitin ligase for the development of the “protein
knockout” technology that directs destruction of cellular proteins at will
• discovery of the cullin 4a (Cul4a) ubiquitin ligase in governing DNA repair/DNA
damage checkpoint response and genomic integrity, normal and malignant
hematopoiesis, spermatogenesis, and tumorigenesis
Aberrantly high levels of Cul4a were detected in a wide spectrum of tumor types,
including breast cancer, liver cancer, squamous cell carcinomas, medulloblastomas,
and methotheliomas. However, the role of Cul4a in tumor development has
remained largely elusive. During the past 11 years, Dr. Zhou’s lab has focused its
efforts on interrogating the physiological and pathological functions of the Cul4a
ubiquitin ligase. The hope is that by understanding the mechanistic basis underlying
Cul4a-dependent protein ubiquitination and destruction, they will determine how
misregulation of these pathways contributes to tumorigenesis and harness this
knowledge to design effective therapeutic strategies.
Dr. Zhou’s lab group is one of the first groups to initiate studies on Cul4a. Their initial
investigations led to the discovery of Cul4a binding to DDB1 and DDB2, and the
identification of DDB2, as well as the HOX homeodomain transcription factors as
the first substrates of Cul4a-mediated ubiquitination. The lab generated conditional
Cul4a knockout mice and revealed that Cul4a concurrently suppresses nucleotide
excision repair and the DNA damage checkpoint pathways. Strikingly, the skinspecific Cul4a knockout mice are hyper-resistant to UV-induced skin carcinogenesis.
Recently, the lab also generated the conditional Cul4b knockout mice and revealed
an essential role of this second Cul4 family member in extraembryonic tissue
development during mouse embryogenesis. Dr. Zhou’s lab also initiated collaborative
studies that revealed the X-ray co-crystal structure of the Cul4a-DDB1 E3 ligase
complex, generated conditional DDB1 knockout mice, and identified a novel function
of the tumor suppressor Merlin in antagonizing tumorigenesis. It is noteworthy that
Dr. Zhou’s recent NIH R01 grant application on delineating the tumorigenic role of
Cul4a ubiquitin ligase received a priority score of 1 percent, the highest score that an
NIH study section gives to exceptional applications.
Another direction of Dr. Zhou’s investigation involves further development and
optimization of the protein knockout technology. To achieve maximal and rapid
removal of target proteins, Dr. Zhou’s lab recently integrated the RNAi technology
into the protein knockout system to simultaneously block synthesis and accelerate
degradation of target proteins. These studies demonstrated dramatically improved
efficacy of the kinetics in depleting stable cellular proteins, therefore significantly
improved the ability to dissect cellular protein functions. This double knockdown
system is a novel method that is particularly relevant for proteins that are not
responsive to RNAi-mediated knockdown and for analyses that require the most
rapid and thorough target protein ablation possible.
SELECTED Publications
Li T, Chen X, Garbutt KC, Zhou P, Zheng N.
Crystal structure of DDB1 in complex with
simian virus 5 v protein: viral hijack of a
propeller cluster in ubiquitin ligase. Cell. 2006
Jan 13;124(1):105-17.
Zhou P. REGg: a shortcut to destruction. Cell.
2006 Jan 27;124(2):256-57.
Chen X, Zhang J, Lee J, Lin P, Ford JM, Zheng N,
Zhou P. A kinase-independent function of c-Abl
in promoting proteolytic removal of UV-DDB
on damaged DNA. Molecular Cell. 2006 May 19;
22:489-99.
Lee J, Zhou P. DCAFs, the missing link of the
Cul4-DDB1 ubiquitin ligase. Molecular Cell.
2007 June 22;26:775-80.
Liu L, Lee S, Zhang J, Peters SB, Hannah J,
Zhang Y, Yin Y, Koff A, Ma L, Zhou P. Cul4a
abrogation augments DNA damage response
and protection against skin carcinogenesis.
Molecular Cell. 2009 May;14;34(4):451-60.
Hannah J, Zhou P. Maximizing target protein
ablation by integration of RNAi and protein
knockout. Cell Research. 2011 Jul;21(7):
1152-54.
2012-2013 Research highlights
71
Core Facilities
Recognizing the need to provide its faculty with the tools to conduct state-of-the-art
research, Weill Cornell Medical College has developed 20 core facilities – from biomedical
imaging to X-ray crystallography – all managed by scientific experts. They provide
centralized access to equipment used by faculty in all departments, help to reduce
duplication of resources, and allow the Medical College to remain at the forefront of
biomedical research. Following are a few examples of the Medical College’s core facilities.
Belfer Gene Therapy Core Facility
The laboratory of Dr. Anna Di Gregorio is studying
Ciona intestinalis, a common sea squirt closely
related to vertebrates on the evolutionary tree, to
characterize genes controlling notochord formation
and the molecular mechanisms that turn them on
at the right time during embryonic development.
(Courtesy of Dr. Anna Di Gregorio]
The Belfer Gene Therapy Core Facility, a fully equipped core facility devoted
exclusively to developing and assessing gene transfer vectors, provides the
infrastructure to carry out basic, translational, and clinical research utilizing
gene transfer. The Vector Core functions as a resource to investigators to provide
centralized expert services and training in the design, creation, and production of
gene transfer vectors, and to provide a characterized repository of gene transfer
vectors and related reagents for use by investigators. The primary resource of the
Vector Core is the expertise to efficiently design, construct, and produce gene
transfer vectors, including adenovirus (Ad), adeno-associated virus (AAV), lentivirus,
retrovirus vectors, as well as non-viral or plasmid vectors. Its analytical resources
include quantitative PCR, 2 HPLCs, plate readers, a luminometer, a flow cytometer,
automated liquid handling devices, equipment for rodent behavior analysis, and a
database of the available vectors and plasmids that includes extensive sequence
and restriction mapping data. The Good Manufacturing Practice Core facility
occupies approximately 2,400 square feet devoted exclusively to production of gene
transfer vectors and gene modified cells for human therapeutic trials.
Citigroup Biomedical Imaging Center
The Citigroup Biomedical Imaging Center at Weill Cornell Medical College is a stateof-the-art 15,000-square-foot research facility dedicated to the development of
cutting-edge imaging technologies applied to a wide range of human diseases. Major
equipment includes two 3.0 Tesla magnetic resonance imaging and spectroscopy
systems, combined positron emission tomography/computed tomography, as well as
comprehensive pre-clinical imaging instrumentation, including a 7.0 Tesla magnetic
resonance imaging system and a newly installed combined positron emission
tomography/computed tomography system. Fluorescence and luminescence
imaging are also available. The Center also houses a 19 MeV dual beam cyclotron
and complete radiochemistry facilities for the production of radiotracers.
The Citigroup Biomedical Imaging Center is staffed with physicists, radiochemists,
engineers, technologists, and administrative personnel devoted to the development of
novel imaging techniques that are available to investigators from across the University,
as well as institutional partners including Memorial Sloan-Kettering Cancer Center, The
Rockefeller University, Hospital for Special Surgery, and Hunter College.
Computational Genomics Core Facility
The Computational Genomics Core Facility provides access to state-of-the-art
desktop bioinformatics software and computational tools for the analysis and
management of gene expression data. The facility also offers consulting services in
various areas of bioinformatics and computational biology and facilitates access to
the larger infrastructure of the Institute for Computational Biomedicine.
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WEILL CORNELL MEDICAL COLLEGE
Core Facilities
Services provided by the Computational Genomics Core Facility include:
Analysis of gene expression data. The core provides users with commercial gene
expression analysis programs and general data mining and statistical tools.
Storage and organization of expression data. The core provides and maintains
GeNet, a web-based microarray data repository that facilitates sharing of microarray data. GeNet is seamlessly integrated with GeneSpring and helps individual
labs store, archive, and search microarray data.
Discovery through bioinformatics. Gene expression profiles often highlight genes
of unknown function. The core offers popular bioinformatics desktop tools, such as
Vector NTI, Lasergene, Sequencher, Artemis, and ClustalX, to support a variety of
sequence analysis tasks.
Resources for advanced projects, collaboration, and training. The Institute for
Computational Biomedicine broadens the capabilities of the Computational
Genomics Core Facility by offering an advanced bioinformatics infrastructure,
expertise in bioinformatics, and computational biology methods and tools.
Nuclear Magnetic Resonance
This figure displays the NMR structure of neurophysin-I.
The ribbons represent the structured protein backbone,
stable regions are shown in blue, and the most flexible
regions in red. Neurophysin-I is the precursor protein
involved in the folding, processing, storage, and release
of oxytocin – a hormone with involvement in lactation,
social bonding, and trust. Deficiencies in oxytocin signaling
are implicated in autism and antisocial behaviors.
(Courtesy of the NMR Core; prepared from coordinates
in 2LBH.pdb; published 2012)
The NMR core provides access to NMR instrumentation for the investigation of
biological molecules. The facility consists of Varian 600 MHz and Bruker 500 MHz NMR
spectrometers equipped for multidimensional heteronuclear NMR experiments. The
500 MHz NMR is primarily used for basic 1D and 2D NMR applications employed for
characterization of synthetic products, chemical analysis, and determination of ligand
binding. The 600 MHz NMR is utilized for solution studies of protein structure and
motional dynamics. The core facility provides project consultation, training in NMR
operation, and assistance in setting up NMR experiments.
Faculty associated with the core have expertise in protein NMR applications aimed
at investigating biologically relevant proteins with disordered structure. There
is a growing recognition that unfolded states of proteins play significant roles in
important life processes and pathologies associated with protein folding, binding,
signaling, and amyloid diseases. NMR spectroscopy is uniquely suited to examine
changes in the conformation, structure, and mobility of proteins in solution using
conditions closely approximating the biological environment.
Epigenomics Facility
The Epigenomics Facility of the Cornell University Life Sciences Core Laboratories
Center and Weill Cornell Medical College provides an array of epigenomics research
resources and services to the university community and to outside investigators. This
inter-campus facility, with resources and services located at both Cornell University
and Weill Cornell Medical College, offers DNA methylation sequencing and microarrays using novel methods developed by the core, protein-nucleic acid association
(ChIP-Seq) analysis, RNA-seq, exon capture sequencing, and Sequenom Epityping. The
core also provides complete data analysis services, including primary and secondary
data interpretation, and hosts several data visualization tools for customers to view
and compare and contrast their data with local and public datasets. The goal of the
Epigenomics Facility is to meet the increasing need of investigators for rapid and
accurate epigenomics project design, sample preparation, data generation, and data
analysis of both targeted regions and genome-scale studies of DNA methylation,
histone modification, and transcriptional programming.
2012-2013 Research highlights
73
Research Environment
“Coupled with the brilliant scientists already on staff and with additional ones being recruited, the
building is certain to house discoveries that will benefit my family, New Yorkers, and all mankind.”
— Robert A. Belfer
With the planned opening of the Belfer Research Building in 2014 and the 2010
opening of the Gertrude and Louis Feil Family Research Building, Weill Cornell
Medical College has been developing an enviable research environment that will
enable faculty to continue a rich history of scientific achievements.
Gertrude and Louis Feil Family Research Building
The Gertrude and Louis Feil Family Research Building, which was made possible
by a $30 million gift from the Louis Feil Charitable Lead Annuity Trust, is a sevenstory state-of-the-art research facility that is home to Weill Cornell’s Division
of Neurobiology and the Clinical and Translational Science Center. The Division
occupies 70,000 square feet, providing optimal space for investigations into stroke,
Alzheimer’s disease, and the factors that lead to both. Here some 40 scientists
study similar topics but have varied areas of expertise. Communication among
them is facilitated by the research building’s open design. A glass wall marks an
inner perimeter, within which laboratories run almost the entire length of the
building. In the lower level, the Clinical and Translational Science Center – a multiinstitutional partnership that promotes translational research and multidisciplinary
collaboration from bench to bedside and to the community – is also the hub of
investigator-initiated clinical and translational research at Weill Cornell.
On November 9, 2011, Weill Cornell Medical College dedicated the Belfer Research
Building, a pioneering facility that will double the amount of dedicated research
space at Weill Cornell, allowing for the initial recruitment of 30 additional
tenure-track faculty. A ceremony was held to recognize the generosity of the
building’s many donors, including a $100 million gift from Renée and Robert
Belfer, for whom the building is named.
When it opens in 2014, the 480,000-square-foot facility will rise 18 stories and
have 13 floors of research laboratories targeting some of the most daunting
health challenges, including cancer, cardiovascular disease, children's health,
neurodegenerative diseases, infectious diseases, and global health issues. The
building will include such features as an indoor terrace, an airy two-story lobby,
and an innovative double-paned glass curtain wall. The proximity of the new
research building to the Weill Greenberg Center, the Medical College’s awardwinning ambulatory care building, will further enhance communication
between investigative researchers and practicing clinicians.
The new Belfer Research Building will be environmentally friendly, energy efficient, and aesthetically
pleasing, with a glass façade that reduces energy
consumption and bathes interior areas with natural
sunlight.
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WEILL CORNELL MEDICAL COLLEGE
Designed by Ennead Architects, the Belfer Research Building has a unique open
floor plan to maximize collaboration among the Medical College’s scientists
and physician-scientists, and feature adaptable spaces that can accommodate
changing priorities. Core facilities on each floor will provide centralized shared
access to advanced technology, including high-throughput cell screening,
genomics, and imaging technology, for use by faculty across all research areas.
Space also will be dedicated to intercampus collaborations, offering a home for
Ithaca-based researchers working with Weill Cornell scientists. In addition, an
array of sophisticated lab equipment will be made available to partnering
medical and academic institutions in the community.
Research Environment
Located on 69th Street between York and First Avenues, the Belfer Research Building will be diagonally situated across from
the Weill Greenberg Center. With their similar design elements, the Belfer Research Building and the Weill Greenberg
Center are thematically connected.
2012-2013 Research highlights
75
FACULTY HONORS AND DISTINCTIONS
Weill Cornell Medical College research faculty are regularly cited for their professional achievements and elected as members to the nation’s
preeminent scientific and biomedical organizations and professional societies. Among those so honored in 2011 and 2012 are:
American Academy of Arts and Sciences
Fellow
Joseph J. Fins, MD, MACP
Chief, Division of Medical Ethics
E. William Davis, MD, Jr. Professor of Medical Ethics
Association of Professors of Medicine
Recipient, Robert H. Williams, MD, Distinguished Professor Award
Andrew I. Schafer, MD
Chairman, Department of Medicine
E. Hugh Luckey Distinguished Professor of Medicine
American Association for Cancer Research
Recipient, 2011 Prevent Cancer Foundation Award for Excellence
in Cancer Prevention Research
Andrew J. Dannenberg, MD
Henry R. Erle, MD – Roberts Family Professor of Medicine
Biophysical Society
Recipient, Distinguished Service Award
Olaf S. Andersen, MD
Director, Tri-Institutional MD-PhD Program
Professor of Physiology and Biophysics
American Association of Genitourinary Surgeons
Recipient, Barringer Medal
Peter N. Schlegel, MD
Chairman, Department of Urology
James J. Colt Professor of Urology
HIV Congress
Recipient, Lifetime Achievement Award for Invaluable
Contributions in the Field of HIV Medicine
Roy M. Gulick, MD
Chief, Division of Infectious Diseases
Professor of Medicine
American College of Cardiology
President
William A. Zogbhi, MD
Professor of Medicine
American College of Physicians, New York Chapter
Recipient, Laureat Award
Joseph J. Fins, MD, MACP
Chief, Division of Medical Ethics
E. William Davis, MD, Jr. Professor of Medical Ethics
American Heart Association
Champions of Heart & Stroke
O. Wayne Isom, MD
Chairman, Department of Cardiothoracic Surgery
Terry Allen Kramer Professor of Cardiothoracic Surgery
Richard C. Pasternak, MD
Clinical Professor of Medicine
Philip E. Stieg, PhD, MD
Chairman, Department of Neurological Surgery
Professor of Neurological Surgery
American Hospital Association
Member, Board of Trustees, Health Research and Educational Trust,
and Member, Committee on Research
Lawrence P. Casalino, MD, PhD
Chief, Division of Outcomes and Effectiveness Research
Livingston Farrand Associate Professor of Public Health
American Urological Association
Recipient, Gold Cytoscope Award
Ashutosh K. Tewari, MD
Director, Lefrak Center for Robotic Surgery
Ronald P. Lynch Professor of Urologic Oncology
Professor of Urology and Public Health
76
WEILL CORNELL MEDICAL COLLEGE
International Cytokine Society
Recipient, Honorary Lifetime Membership
Laurie H. Glimcher, MD
Stephen and Suzanne Weiss Dean,
Weill Cornell Medical College
Professor of Medicine
New York Academy of Medicine
Recipient, Academy Plaque for Exceptional Service
Anne Moore, MD
Medical Director, Weill Cornell Breast Center
Professor of Clinical Medicine
New York Surgical Society
President
Fabrizio Michelassi, MD
Chairman, Department of Surgery
Lewis Atterbury Stimson Professor of Surgery
Northeastern Group on Educational Affairs
Chair Elect
Carol F. Capello, PhD
Associate Director, Office of Curriculum and Educational Development
Associate Professor of Geriatric Education in Medicine
Robert J. and Claire Pasarow Foundation
Recipient, 24th Annual Robert J. and Claire Pasarow
Foundation Award
Antonio M. Gotto, Jr., MD, DPhil
Dean Emeritus and Co-Chairman, Board of Overseers,
Weill Cornell Medical College
U.S. Department of Health and Human Services
Senior Advisor, Office of the Assistant Secretary for
Planning and Evaluation
William B. Borden, MD
Nanette Laitman Clinical Scholar in
Public Health/Prevention – Women's Health
Assistant Professor of Public Health
Research Faculty
A
Faisel I. Abdulkader, BM
Erika Abramson, MD
Laith J. Abu-Raddad, PhD
Alessio Accardi, PhD
Cathleen A. Acres, BS, MA
Ronald D. Adelman, MD
Brandon Aden, MD, MPH
Badreldeen I. Ahmed, MB, ChB, PhD
Emre Aksay, PhD
Alexander Aledo, MD
Elizabeth L. Alexander, MD
George S. Alexopoulos, MD
Alicia Alonso, PhD
Abdulsalam Al-Qahtani, MB, ChB
Margaret Altemus, MD
Nasser K. Altorki, MB, BCh
William J. Ameres, BS
Jessica Ancker, PhD, MPH
Olaf S. Andersen, MD
Caitlin Anderson, MD
Josef Anrather, VMD
David R. Anthony, MD, MPH
Max M. April, MD
Margarita Arango-Lievano, PhD
Elizabeth K. Arleo, MD
Ashwin V. Asrani, MB, BS
Phyllis August, MD, MPH
Yong Ho Auh, MD
Meredith J. Aull, PharmD
B
Kemi T. Babagbemi, MD
Jason Baker, MD
Jeffrey E. Ball, PharmD, MD
Susan C. Ball, MD, MPH
Douglas J. Ballon, PhD
Satchit Balsari, MB, BS, MPH
Neil H. Bander, MD
Samprit Banerjee, PhD
Jason Banfelder, BE, MChE
Yuhua Bao, PhD
Xiaolei Y. Baran, MD
Francis Barany, PhD
Jack D. Barchas, MD
Charles L. Bardes, MD
Philip S. Barie, MD
John T. Barnard, MD
Paul Basciano, MD
M. Flint Beal, MD
Ann B. Beeder, MD
David A. Behrman, DMD
Lily M. Belfi, MD
Himisha Beltran, MD
Geoffrey W. Bergman, MB, BS
David A. Berlin, MD
Palmer Q. Bessey, MD
Doron Betel, BSc, PhD
Swetangi Bhaleeya, MD
Alexander V. Birk, PhD
Naomi B. Bishop, MD
Tara F. Bishop, MD
Scott C. Blanchard, PhD
John A. Boockvar, MD
William B. Borden, MD
Mathias P. Bostrom, MD
Susan Bostwick, MD, MBA
Brian P. Bosworth, MD
Gary J. Bouchard, EdM, PhD
Olga Boudker, PhD
Carla Boutin-Foster, MD
William C. Bracken, PhD
Risa Breckman, LCSW
Paula W. Brill, MD
David J. Brillon, MD
Benjamin Brody, MD
Kevin D. Brown, MD, PhD
Anthony M.C. Brown, PhD
Martha L. Bruce, PhD
Richard L. Bruckner, MD
Ruslana Bryk, PhD
Jochen Buck, MD, PhD
Kristin E. Burns, PhD
Harry L. Bush, Jr., MD
James B. Bussel, MD
Jason M. Butler, PhD
C
Juliet D. Caldwell, MD
David P. Calfee, MD
Noel Y. Calingasan, DVM, MS, PhD
Fabien Campagne, PhD
Thomas R. Campion, Jr., MS, PhD
Lewis C. Cantley, PhD
Carol F. Capello, PhD
Thomas A. Caputo, MD
Bridget T. Carey, MD
Karen-Sue B. Carlson, PhD, MD
Sheila J. Carroll, MD
Wallace Carter, Jr., MD
Their studies of neurons (left) and astrocyes are
enabling Weill Cornell researchers to advance the
understanding of brain development and further
the potential of stem cell based therapies for neurodegenerative diseases. (Courtesy of Dr. Tao Sun)
Lawrence P. Casalino, MD, PhD
Mary Casciano, MD
B.J. Casey, PhD
Leandro C.A. Cerchietti, MD
Ethel Cesarman, MD, PhD
Robison V.P. Chan, MD
Hyesook Chang, MD, MS, PhD
Jenghwa Chang, PhD, MS
Sung-Hee Chang, MS, PhD
K.S. Clifford Chao, MD
Macarthur Charles, MD, PhD
Mary E. Charlson, MD
Richard Charney, MD
Stephen T. Chasen, MD
Jonathan M. Chen, MD
Qiuying Chen, MS, PhD
Shuibing Chen, PhD
Selina Chen-Kiang, PhD
Daniel Cherqui, MD
Frank A. Chervenak, MD
Jim W. Cheung, MD
Gloria C-Y Chiang, MD
Russel L. Chin, MD
Kevin J. Ching, MD
Maria J. Chiuchiolo, MS, PhD
Ina N. Cholst, MD
Lotfi Chouchane, MS, PhD
David J. Christini, PhD
Paul J. Christos, DrPH, MS
Ellen Chuang, MD
Jen-Zen Chuang, PhD
Bilal Chughtai, MD
Pak H. Chung, MB, BS
Tessa Cigler, MD, MPH
Sunday Clark, MPH, ScD
Marc A. Cohen, MD
2012-2013 Research highlights
77
Research Faculty
Curtis L. Cole, MD
Andrew J. Collins, MD
Joseph P. Comunale, Jr., MD
Peter H. Connolly, MD
Joseph T. Cooke, MD
Amy E. Crane, MBA, MD
Carl V. Crawford, MD
Ronald G. Crystal, MD
Susanna Cunningham-Rundles, PhD
D
Darshana M. Dadhania, MD
Gregory F. Dakin, MD
Donald J. D'Amico, MD
Andrew J. Dannenberg, MD
Marilena D'Aurelio, PhD
Scott G. David, MD
Jessica G. Davis, MD
Owen K. Davis, MD
Robin L. Davisson, PhD
Ype P. de Jong, PhD, MD
Inmaculada de Melo-Martin, PhD
Ruba S. Deeb, PhD
Kirk W. Deitsch, PhD
Tessa M.L. del Carmen, MD
Joseph J. Del Pizzo, MD
Christal G. Delagrammatikas, PhD
Anna-Maria Demetriades, BM, BCh,
MA, PhD
Byron P. Demopoulos, MD
Maria T. DeSancho, MD, MSc
Richard B. Devereux, MD
Randi R. Diamond, MD
JoAnn Difede, PhD
Anna Di Gregorio, PhD
Annarita Di Lorenzo, PhD
Ruchuang Ding, BM, MS
Bisen Ding, MS, PhD
Hong Ding, PhD
Marc J. Dinkin, MD
Jennifer DiPace, MD
Leonard DiRe, MD
Jeremy Dittman, PhD, MD
Gary S. Dorfman, MD
Jennifer A. Downs, MD
Joan H. Drosopoulos, MS, PhD
Michele B. Drotman, MD
Lewis M. Drusin, MD, MPH
Yi-Chieh N. Du, PhD
Niels Dua, MS, MD
78
WEILL CORNELL MEDICAL COLLEGE
Marc J. Dubin, PhD, MD
Joachim W. Dudenhausen, MD
Jonathan P. Dyke, PhD
E
Soumitra R. Eachempati, MD
Matthew R. Ebben, PhD
Sabine Ehrt, PhD
Carolyn S. Eisen, MD
Brian Eiss, MD
Olivier Elemento, PhD
Rony T. Elias, MD
David Eliezer, PhD
Lora H. Ellenson, MD
Eric H. Elowitz, MD
Rebecca Elstrom, MD
Zuhal Ergonul, MD, PhD
Orli R. Etingin, MD
Todd R. Evans, PhD
F
Thomas J. Fahey III, MD
Erik S. Falck-Pedersen, PhD
Domenick J. Falcone, PhD
Giuseppe Faraco, MD, PhD
Brenna M. Farmer, MD
Dmitriy N. Feldman, MD
Eric J. Feldman, MD
Diane Felsen, PhD
Jose L. Fernandez, MD
Stephen J. Ferrando, MD
Edgar Figueroa, MD, MPH
Matthew E. Fink, MD
Madelon L. Finkel, PhD
Emily S. Finkelstein, MD
Joseph J. Fins, MD, MACP
Daniel W. Fitzgerald, MD
Peter Fleischut, MD
Neal E. Flomenbaum, MD
Conor P. Foley, PhD
Alyson N. Fox, MD
Maura D. Frank, MD
William W. Frayer, MD
Joel M. Friedman, DDS
Oren A. Friedman, MD
Gustavo F. Frindt, BSc, MD
Christine L. Frissora, MD
Kai-Ming G. Fu, MD, PhD
Hibiki K. Fujita, PhD
Michele Fuortes, MD, PhD
Richard R. Furman, MD
G
Christopher L.F. Gade, MD
James J. Gallagher, MD
Maya Gambarin-Gelwan, MD
Shanmugam Ganesan, MB, BS
Fran A. Ganz-Lord, MD
Dingcheng Gao, MS, PhD
Daniel Gardner, PhD
Kelly A. Garrett, MD
Francine E. Garrett-Bakelman, MD, PhD
Susan A. Gauthier, DO
Shari E. Gelber, MD
Joy M. Gelbman, MD
Mehmet R. Genc, MD, PhD
Fuqiang Geng, MM, PhD
Paul Gerardi, MD
Linda M. Gerber, PhD
Usama Gergis, MB, ChB
Hassan Ghomrawi, PhD
Paraskevi Giannakakou, PhD
Patricia-Jane V. Giardina, MD
Sarah Giardina, PhD
Leonard N. Girardi, MD
Alicia E. Gittleman, MD
Michael J. Glass, PhD
Charles E. Glatt, MD, PhD
Marshall J. Glesby, MD, PhD
Laurie H. Glimcher, MD
Yves P. Gobin, MD
Benjamin S. Gold, MA, PhD
Dan E. Goldschlag, MD
Stanley J. Goldsmith, MD
Peter A. Goldstein, MD
Marc Goldstein, MD
Linnie M. Golightly, MD
Eva Gonzalez, MS, PhD
Gerry E. Goodrich, JD, MPH
John T. Gossey, MD, MS, MPH
Antonio M. Gotto, Jr., DPhil, MD
Bernice Grafstein, PhD
Richard D. Granstein, MD
Johannes Graumann, MS, PhD
Diego Gravotta, PhD
Jeffrey P. Greenfield, MD, PhD
Bruce M. Greenwald, MD
Kenneth W. Griffin, PhD
Elizabeth A. Grill, PsyD
Steven S. Gross, PhD
Amos Grunebaum, MD
Victor H. Guaiquil, MS, PhD
Research Faculty
Rosalinda G. Guce, MD
Lorraine J. Gudas, PhD
Kirana Gudi, MD
Roy M. Gulick, MD, MPH
Naveen Gumpeni, MD
Zeynep Gumus, MS, MA, PhD
Faith Gunning-Dixon, PhD
Ming Guo, MS, MPhil, PhD
Ajay Gupta, MD
Divya Gupta, MD
Monica L. Guzman, PhD
Hanson Hsu, MD
Xiaoyan Hu, MS, PhD
Ye Hu, PhD
Chaorui Huang, PhD
Xiangao Huang, BSc, MSc
Xin-Yun Huang, PhD
Yujie Huang, PhD
Marisela Huerta, PhD
Daniel H. Hunt, MD
Nathaniel Hupert, MD, MPH
I
H
Mingming Hao, PhD
David P. Hajjar, PhD
Katherine A. Hajjar, MD
Alexis Halpern, MD
Heidi J. Hansen, DMD
Christina Harris, MD
Roger Hartl, MD
Ben-Gary Harvey, MD
Ibrahim M.W. Hassan, MB, BCh, MS, PhD
Duane C. Hassane, MS, PhD
Cathy J. Hatcher, PhD
Mary K. Hayes, MD
Bin He, PhD
Paul M. Heerdt, MD, PhD
Linda A. Heier, MD
David L. Helfet, MD
Caren A. Heller, MD, MBA
Hugh C. Hemmings, Jr., MD, PhD
Barbara L. Hempstead, MD, PhD
Claire Henchcliffe, DPhil, MD
Keith D. Hentel, MD
Michael Herman, MD
Doris A. Herzlinger, PhD
Ronit Herzog, MD
Catherine F. Hicks, MD
Timothy T. Hla, PhD
Karin Hochrainer, PhD
Kevin M. Holcomb, MD
James P. Hollenberg, MD
William K. Holloman, PhD
Evelyn M. Horn, MD
James M. Horowitz, MD
Yariv J. Houvras, MD, PhD
Louise R. Howe, PhD
Joy D. Howell, MD
Ingrid Hriljac, MD
Deyin D. Hsing, MD
Costantino Iadecola, MD
Julianne L. Imperato-McGinley, MD
Charles E. Inturrisi, PhD
James E. Ip, MD
Nithila D. Isaac, MS, PhD
O. Wayne Isom, MD
Natalia Ivascu, MD
J
Vinita E. Jacob, MD
Jonathan L. Jacobs, MD
Elizabeth L. Jacobson, MD
Ira M. Jacobson, MD
Samie R. Jaffrey, MD, PhD
Daylon James, PhD
Nimali Jayasinghe, PhD
Moonsoo M. Jin, MS, PhD
Deqiang Jing, PhD
Thanakorn Jirasevijinda, MD
Carl E. Johnson, MD
Stephen B. Johnson, PhD
Valerie L. Johnson, MD, PhD
Warren D. Johnson, Jr., MD
Ashu Johri, MSc, PhD
Sian Jones, MD
Krishna Juluru, MD
K
Ashutosh Kacker, MD
Michel Kahaleh, MD
Amir Kaki, MD
Robin B. Kalish, MD
Hooman Kamel, MD
Stephen M. Kaminsky, MPhil, PhD
Padmaja Kandula, MD
Robert J. Kaner, MD
Hey Joo Kang, MD
Yoon Kang, MD
Brain imaging with positron emission tomography
(PET) reveal normal cerebral metabolism during an
awake state (left) versus low cerebral metabolism
during a minimally conscious or vegetative state.
(Courtesy of Dr. Nicholas D. Schiff)
Steven A. Kaplan, MD
Michael G. Kaplitt, MD, PhD
Sandip Kapur, MD
Steven C. Karceski, MD
Marianna Karounos, DO
John K. Karwowski, MD
Ericalyn Kasdorf, MD
Melissa D. Katz, MD
Janine T. Katzen, MD
Rainu Kaushal, MD, MPH
Jeffrey H. Kern, MD
Lisa M. Kern, MD
Sotirios Keros, MD, PhD
Gregory E. Kerr, MD
Ahmed N. Khan, MB, BS
George Khelashvili, BSc, MSc, PhD
Stanislav Kholmanskikh, PhD
Agnes S. Kim, MD, PhD
Jim Kim, MD
Luke K. Kim, MD
Robert J. Kim, MD
Yoon-Seong Kim, MD, PhD
Thomas K.C. King, MB, BCh, MD
Dimitris Kiosses, PhD
Brian J. Kirby, MSE, PhD
Laura A. Kirkman, MD
Szilard Kiss, MD
Jorge R. Kizer, MD, MSc
Per J. Klasse, MD, PhD
Harvey Klein, MD
Paul D. Kligfield, MD
Isaac Kligman, MD
Michael D. Kluger, MD
Jared Knopman, MD
James H. Kocsis, MD
Milorad Kojic, PhD
David Kopman, MD
2012-2013 Research highlights
79
Research Faculty
Rachel Koshi, MB, BS, MS, PhD
Barry E. Kosofsky, MD, PhD
Paresh J. Kothari, MS, PhD
Arzu Kovanlikaya, MD
Ilhami Kovanlikaya, MD
Geri E. Kreitzer, PhD
Ana C. Krieger, MD, MPH
Karl H. Krieger, MD
Trine Krogh-Madsen, MSc, PhD
Ziad Kronfol, MD
Nicole Kucine, MD
William I. Kuhel, MD
Juhi Kumar, MD
Sonal Kumar, MD, MPH
David I. Kutler, MD
Charles O. Kwon, MD
L
Douglas R. Labar, PhD, MD
Mark S. Lachs, MD
Moncef Ladjimi, MSc, PhD
Yulia Landa, MS, PsyD
Harry M. Lander, PhD
Diane A. Lane, PhD
Joseph M. Lane, MD
Maureen E. Lane, PhD
Jennifer A. Langsdoff, MD
Richard I. Lappin, PhD, MD
Vassilios Latoussakis, MD
Norman A. Latov, MD, PhD
Jeffrey C. Laurence, MD
Francis S.Y. Lee, MD, PhD
Jennifer I. Lee, MD
Paul C. Lee, MD
Richard Lee, MBA, MD
Sang W. Lee, MD
Dana Leifer, MD
Gary J. Lelli, Jr., MD
80
WEILL CORNELL MEDICAL COLLEGE
John M. Lemery, MD
John P. Leonard, MD
Bruce B. Lerman, MD
Roberto Levi, MD
Lonny R. Levin, PhD
Benjamin M. Levine, MD
David S. Levine, MD
Joshua I. Levinger, MD
Allison Levy, MD
Richard L. Levy, MD
Baoqing Li, PhD, MD
Philip S. Li, BM
Michael D. Lieberman, MD
Cynthia A. Lien, MD
Fay Y-H Lin, MD
Gang Lin, MSc, PhD
Michael T. Lin, MD
Sophia Lin, MD
Steven M. Lipkin, MD, PhD
Shari R. Lipner, MD, PhD
Christopher F. Liu, MD
He Liu, BM
Hung-Ching Liu, PhD
Wencheng Liu, PhD
Sarah M. Lo, MD, MPH
Veronica M. LoFaso, MD, MS
Lia S. Logio, MD
Cathleen G. London, MD
Catherine E. Lord, PhD
Dean G. Lorich, MD
Neal F-N Lue, MD, PhD
Wensie Luo, PhD
David C. Lyden, PhD, MD
John P. Lyden, MD
M
Hongtao Ma, PhD
Xiaojing Ma, PhD
Yinghua Ma, PhD
Yuliang Ma, MS, PhD
Khaled Machaca, PhD
David C. Madoff, MD
Jordi Magrane, PhD
Ziyad Mahfoud, MS, PhD
Joel A. Malek, MS, PhD
Jaideep Malhotra, MD
Sameer Malhotra, MD
Charles Maltz, PhD, MD
Ravinder Mamtani, MB, BS, MD
Giovanni Manfredi, MD, PhD
Halinder S. Mangat, MB, BS
Samuel J. Mann, PhD
Aaron J. Marcus, MD
Patricia Marino, PhD
Tomer M. Mark, MD
Steven M. Markowitz, MD
Kristen M. Marks, MD
Peter Martin, MD
Johanna Martinez, MD
Christopher E. Mason, PhD
Bassem Masri, MD
Usha Mathur-Wagh, MB, BS, MPH
Frederick R. Maxfield, PhD
Sebastian A. Mayer, MD
Nayef Mazloum, PhD
Madhu Mazumdar, MS, MA, PhD
Kate E. McCarn, MD
Patricia McDonald, DSW
Timothy E. McGraw, PhD
Ferenc Mechler, MSc, PhD
Carlos Medina, MD
Sonal S. Mehta, MD
Ari M. Melnick, MD
Andrew J. Meltzer, MD
Ellen C. Meltzer, MD, MSc
Kevin Mennitt, MD
Anant K. Menon, PhD
Sabiha Merchant, MB, BS
Samuel T. Merrick, MD
Nasrin Mesaeli, MSc, PhD
David B. Messinger, MD
Barnett S. Meyers, MD
Jason G. Mezey, PhD
Fabrizio Michelassi, MD
Shari R. Midoneck, MD
Raffaele Milizia, MD
Carlyle H. Miller, MD
David H. Miller, MD
Teresa A. Milner, PhD
Jeffrey W. Milsom, MD
Robert J. Min, MD
Robert M. Minutello, MD
Ajay Mirani, MD
Vivek Mittal, PhD
Nurru L. Mligiliche, MD, PhD
Vikash K. Modi, MD
Joseph J. Montano, MD
Anne Moore, MD
John P. Moore, PhD
Research FACULTY
Silvia D. Moore, PhD
Anne Moscona, MD
Paul D. Mozley, MD
Estomih Mtui, MD
Oliver J. Muensterer, MD
Sushmita Mukherjee, PhD
Mary R. Mulcare, MD
Paul Mullin, MD
Henry W. Murray, MD
Matthew Murrell, MD, PhD
Thomas Murry, PhD
Sergey Musatov, PhD
Alvin I. Mushlin, MD, ScM
Thangamani Muthukumar, MD
Monn M. Myat, PhD
N
Ralph L. Nachman, MD
Nady E. Nady-Mohamed, MB, ChB
S. Hani Najafi-Shoushtari, PhD
Govind Nandakumar, MD
David M. Nanus, MD
Syed Naqi, PhD
Carl Nathan, MD
Babak Navi, MD
Nancy M. Nealon, MD
Joshua P. Needleman, MD
Thanh D. Nguyen, MS, PhD
Yutaka Nibu, PhD
Ruben Niesvizky, MD
Crina M. Nimigean, PhD
Sheila Nirenberg, PhD
Marcelo M. Nociari, MS, PhD
Dattatreyudu Nori, MD, MB, BS
Bakr M. Nour, MD
O
Mallay Occhiogrosso, MD
Allyson J. Ocean, MD
Oksana Ocheretina, MS, PhD
Michael W. O'Dell, MD
Ji-eun Oh, MSc, PhD
Michiko Okamoto, MS, PhD
Peter M. Okin, MD
Sonja K. Olsen, MD
Matthew T. O'Neill, MD
Joseph R. Osborne, MD, PhD
James A. Osorio, MD
S. Nina Osorio, MD
David M. Otterburn, MD
Karin-Elizabeth M. Ouchida, MD
P
Darius A. Paduch, MD, PhD
Ji-Hye Paik, PhD
Gianpiero D. Palermo, MD, PhD
Lawrence G. Palmer, PhD
Ankur Pandya, MPH, PhD
Susan C. Pannullo, MD
Juliann M. Paolicchi, MD
Jean W. Pape, MD
Bhupesh Parashar, MB, BS
Laibaik Park, PhD
Athos Patsalides, MD, MPH
Steven M. Paul, PhD
Subroto Paul, MD
Roger N. Pearse, PhD, MD
Robert N. Peck, MD
Mark S. Pecker, MD
Eduardo M. Perelstein, MD, MPH
Francheska Perepletchikova, PhD
Jeffrey M. Perlman, MB, ChB
Jai S. Perumal, MD
Janey C. Peterson, EdD
Gregory A. Petsko, DPhil
Erica G. Phillips-Caesar, MD
Virginia M. Pickel, MS, PhD
Shari Platt, MD
Margaret M. Polaneczky, MD
Elizabeth Poole-Di Salvo, MD
Alfons Pomp, MD
Steven Pon, MD
Elizabeta C. Popa, MD
Dix P. Poppas, MD
Matteo Porotto, PhD
Jeffrey L. Port, MD
Mukesh Prasad, MD
Matthew J. Press, MD
Martin R. Prince, MD, PhD
R.A. Rees Pritchett, MD
Alexander Proekt, PhD, MD
Jane M. Prosser, MD
Kane O. Pryor, MB, BS
Bradley B. Pua, MD
Keith P. Purpura, PhD
Q
Lidong Qin, PhD
Mayed M. Radi, MB, ChB
Shahin Rafii, MD
Barrie L. Raik, MD
Roheen Raithatha, MD
Ashish Raj, MS, PhD
Anjali M. Rajadhyaksha, PhD
Praveen B. Raju, MD, PhD
Kapil K. Rajwani, MD
Bharathi Raman, MD
Mayra Ramirez, MA
Sharda D. Ramsaroop, MD
Rama B. Rao, MD
Patrick J. Raue, PhD
Lisa D. Ravdin, MS, PhD
Akkamma Ravi, MB, BS, MD
M. Cary Reid, MD, PhD
William R. Reisacher, MD
Norman R. Relkin, MD, PhD
Joseph G. Rella, MD
Hanna Rennert, PhD
Kyu Y. Rhee, MD, PhD
David S. Rickman, PhD
Arleen B. Rifkind, MD
Ellen K. Ritchie, MD
Stefano Rivella, PhD
Gail J. Roboz, MD
Scott A. Rodeo, MD
Enrique J. Rodriguez-Boulan, MD
Pablo Rodriguez del Pozo, MD, JD, PhD
Mary J. Roman, MD
Mark I. Rosenblatt, MD, PhD
Isadore Rosenfeld, MD, CM
Axel J. Rosengart, MD, PhD
Zev Rosenwaks, MD
Gail S. Ross, PhD
M. Elizabeth Ross, MD, PhD
Lisa Roth, MD
Neeta S. Roy, MS, PhD
S. Robert Rozbruch, MD
Jia Ruan, PhD, MD
Elayna O. Rubens, MD
Mark A. Rubin, MD
Francesco Rubino, MD
Joseph T. Ruggiero, MD
Andrew Ryan, PhD, MA
Timothy A. Ryan, PhD
Jae-Wook Ryou, MA, PhD
R
Pouneh K. Rabbany, PhD
Nathan M. Radcliffe, MD
2012-2013 Research highlights
81
Research Faculty
Isoflurane – a member of the modern family of
halogenated ether anesthetics currently in widespread
clinical use – is the subject of research at Weill Cornell,
with a particular focus on its molecular properties and
effect on neurotransmitters. (Courtesy of Dr. Hugh C.
Hemmings, Jr.)
S
Arash Salemi, MD
Christine M. Salvatore, MD, MS
Mirella Salvatore, MD
Abraham Sanders, MD
Vladislav M. Sandler, MS, PhD
Pina C. Sanelli, MD
Santosh K. Sangari, MB, BS
Michael J. Satlin, MD
Anthony A. Sauve, PhD
Peter M.C. Savard, MD
John J. Savarese, MD
Andrea Sboner, MS, PhD
Joseph M. Scandura, MD, PhD
Bruce R. Schackman, PhD
Robert A. Schaefer, MD
Andrew I. Schafer, MD
Glenn L. Schattman, MD
Ronald J. Scheff, MD
Ellen J. Scherl, MD
Douglas S. Scherr, MD
Nicholas D. Schiff, MD
Marc Schiffman, MD
Peter N. Schlegel, MD
William S. Schley, MD
Anita M. Schmid-Frey, MSc, PhD
Dirk Schnappinger, PhD
Bryan J. Schneider, MD
Darren B. Schneider, MD
Felice H. Schnoll-Sussman, MD
Aaron P. Schulman, MD
Brian D. Schwartz, MD
Theodore H. Schwartz, MD
Beate Schwer, PhD
82
WEILL CORNELL MEDICAL COLLEGE
Thomas P. Sculco, MD
Marco Seandel, MD, PhD
Art Sedrakyan, MD, PhD
Samuel H. Selesnick, MD
Hector Peinado Selgas, PhD
Licia Selleri, MD, PhD
Sam Senturia, MD
Nitin K. Sethi, MB, BS
Manish A. Shah, MD
Shahrokh Shariat, MD
Aarti V. Sharma, MB, BS
Renat Shaykhiev, MD, PhD
Menachem M. Shemtov, MD
Haifa Shen, MD, PhD
Wen H. Shen, MS, PhD
Sujit Sheth, MD
Lei Shi, PhD
George Shih, MD
Jungho Shin, MD
Tsiporah B. Shore, MD
Jian Shou, MD
Parul Shukla, MD
Emily K. Shuman, MD
Dikoma C. Shungu, PhD
Benjamin M. Shykind, PhD
Lawrence J. Siegel, MD, MPH
Eugenia L. Siegler, MD
Randi B. Silver, PhD
Richard T. Silver, MD
Mary Simmerling, PhD
Rache M. Simmons, MD
Harjot K. Singh, MD
Harsimran S. Singh, MSc, MD
Naina Sinha, MD
Kimberly C. Sippel, MD
Jo Anne Sirey, PhD
Akhilesh K. Sista, MD
Lucy Skrabanek, PhD
Nikolaos Skubas, MD, DSc
Ralph L. Slepian, MD
Rachel Smerd, MD
Duane M. Smith, MD
Kendall A. Smith, MD
Michael J. Smith, MD
Rosemary Soave, MD
Irina Sobol, MD
Robbyn Sockolow, MD
Kristina Sole, MD
Lilja B. Solnes, MD, MBA
Aliza Solomon, DO
Gail E. Solomon, MD
Dolan Sondhi, PhD
Christian Song, MD
Toyooki Sonoda, MD
Mark M. Souweidane, MD
Steven D. Spandorfer, MD
Jason A. Spector, MD
Jeremy Sperling, MD
Arthur J. Spielman, PhD
Nitsana A. Spigland, MD
Pascal Spincemaille, PhD
Anatoly Starkov, PhD
Natalia N. Starkova, MS, PhD
Christopher E. Starr, ScB, MD
Michelle Staudt, PhD
Peter A.D. Steel, MB, BS, MA
Joel Stein, MD
Carolyn R. Steinberg, MD
Charles R. Steinberg, MD
Michael E. Stern, MD
Michael G. Stewart, MD
Philip E. Stieg, PhD, MD
Brendon M. Stiles, MD
Anne Stone, MD
Kingsley Storer, MB, BS, PhD
Carol L. Storey-Johnson, MD
Dean J. Straff, MD
Gladys W. Strain, PhD
Heidi Stuhlmann, PhD
Christopher V. Sturiano, MA, PhD
Kotha Subbaramaiah, MSc, PhD
Lucian Sulica, MD
Ali A. Sultan, MD, PhD
Grace Sun, MD
Tao Sun, PhD
Ching-Hwa Sung, PhD
Manikkam Suthanthiran, MB, BS
Rajesh V. Swaminathan, MD
Alexander J. Swistel, MD
Paul Szabo, PhD
Hazel H. Szeto, MD, PhD
Massimiliano Szulc, PhD, MS
T
Jeremie A.R. Tabrizi, MD, PhD
Scott T. Tagawa, MD
Andrew H. Talal, MD
Adam D. Talenfeld, MD
Mia Talmor, MD
Xiao-Han Tang, PhD
Research FACULTY
Debra A. Taubel, MD
Alexis E. Te, MD
Tiffany Tedore, MD
Thomas J. Templeton, PhD
Ashutosh Tewari, MB, BS
George Thomas, MD
Ann E. Tilley, MD
Miklos Toth, MD, PhD
Sima S. Toussi, MD
Henry A. Tran, MSc, MD
Chani Traube, MD
Koiana Trencheva, RN, BSN, MS
Christopher R. Triggle, PhD
David W. Trost, MD
Apostolos J. Tsiouris, MD
Judy Tung, MD
Brian G. Turner, MD
Renuka Tyagi, MD
U
Mark A. Unruh, MS, PhD
V
Carlos M. Vaamonde, MD
Linda T. Vahdat, MD
Medea Y. Valdez, MPAS
Shankar Vallabhajosula, MS, PhD
Koen van Besien, MD
Susan J. Vannucci, PhD
Timothy Vartanian, MD, PhD
Haviva Veler, MD
Joshua R. Vest, MPH, PhD
Jonathan D. Victor, MD, PhD
Maria G. Vogiatzi, MD
Mary A. Vogler, MD
Erich P. Voigt, MD
Michael J. Vortmann, MD
Henning U. Voss, PhD
W
John A. Wagner, PhD
John T. Walkup, MD
Thomas J. Walsh, MD
Matthew S. Walters, PhD
David W. Wan, MD
Baolin Wang, PhD
Gang Wang, PhD, BM
Song Wang, MS, PhD
Weidong Wang, MS, PhD
Yi Wang, PhD
Mary J. Ward, PhD
Robert F. Ward, MD
James D. Warren, PhD
Russell F. Warren, MD
Anthony C. Watkins, MD
Jonathan W. Weinsaft, MD
Alan M. Weinstein, MD
Harel Weinstein, MSc, DSc
Marc E. Weksler, MD
Suzanne Wenderoth, MD
Matthew M. Wessel, MD
Geoffrey H. Westrich, MD
Roger F. Widmann, MD
Jessica L. Widmer, DO
Horatio F. Wildman, MD
James R. Wilentz, MD
Timothy J. Wilkin, MD, MPH
Riley J. Williams III, MD
Erich E. Windhager, MD
Ginger Winston, MD, MPH
Steven S. Witkin, PhD
Matthew T. Witmer, MD
Felix Wolf, DVM, PhD
Franklin J. Wong, MD
Shing-Chiu Wong, MD
Stefan Worgall, PhD, MD
Jennifer Wright-McCarthy, MD
X
Jenny Z. Xiang, BM
Guoqiang Xu, PhD
Kangpu Xu, PhD, DVM
Yaquin Xu, PhD
Y
Hua Yang, MMS
Lili Yang, MS, PhD
Yi-Ming Yang, MD
Allen B. Yeroushalmi, MD
Hang Yin, PhD
Yuxin Yin, MSc, BM, PhD
Kaleb H. Yohay, MD
Cecilia J. Yoon, MD
Robert C. Young, MD
Eun Y. Yu, PhD
Joyce E. Yu, MD
Yunguo Yu, MS, PhD
Roger W. Yurt, MD
Weill Cornell scientists employ state-of-the-art
transmission electron microscopes in their research
enabling them to explore intricate biological systems
in three dimensions.
Z
Nikica Zaninovic, PhD
Dana Zappetti, MD
Rasa Zarnegar, MD
Jason D. Zevin, PhD
Jue J. Zhang, PhD
Hong Zhao, PhD
Lingzhi Zhao, MS, PhD
Mingrui Zhao, PhD
Pengbo Zhou, PhD
Ping Zhou, PhD
Xi Kathy Zhou, PhD
Zhiping Zhou, PhD
Yuan-Shan Zhu, BM, PhD
Robert D. Zimmerman, MD
Jonathan Zippin, MD, PhD
David Zylberger, MD
2012-2013 Research highlights
83
leadership
Weill Cornell Medical College and Graduate School of Medical Sciences
Senior Administration
department chairs
Laurie H. Glimcher, MD
Stephen and Suzanne Weiss Dean
Weill Cornell Medical College
Anesthesiology
John J. Savarese, MD
Joseph F. Artusio, Jr., Professor
of Anesthesiology
Ophthalmology
Donald J. D’Amico, MD
Betty Neuwirth Lee and Chilly Professor in
Stem Cell Research
Biochemistry
Frederick R. Maxfield, PhD
Vladimir Horowitz and Wanda Toscanini
Horowitz Distinguished Professor of
Neuroscience
Orthopaedic Surgery
Thomas P. Sculco, MD
Korein-Wilson Professorship in
Orthopaedic Surgery
Provost for Medical Affairs
Cornell University
David P. Hajjar, PhD
Dean
Weill Cornell Graduate School
of Medical Sciences
Javaid I. Sheikh, MD
Dean
Weill Cornell Medical College in Qatar
Brain and Mind Research Institute
Costantino Iadecola, MD
George C. Cotzias Distinguished Professor of
Neurology and Neuroscience
Cancer Center
Lewis C. Cantley, PhD
Cardiothoracic Surgery
O. Wayne Isom, MD
Terry Allen Kramer Professor of
Cardiothoracic Surgery
Cell and Developmental Biology
Katherine A. Hajjar, MD
Brine Family Professor of Cell and
Developmental Biology
Dermatology
Richard D. Granstein, MD
George W. Hambrick, Jr. Professor of
Dermatology
Genetic Medicine
Ronald G. Crystal, MD
Bruce Webster Professor of Internal Medicine
Medicine
Andrew I. Schafer, MD
E. Hugh Luckey Distinguished
Professor of Medicine
Microbiology and Immunology
Carl F. Nathan, MD
R.A. Rees Pritchett Professor of Microbiology
Neurological Surgery
Philip E. Stieg, PhD, MD
Professor of Neurological Surgery
Neurology and Neuroscience
Matthew E. Fink, MD
Professor of Clinical Neurology
Obstetrics and Gynecology
Frank A. Chervenak, MD
Given Foundation Professor of
Obstetrics and Gynecology
84
WEILL CORNELL MEDICAL COLLEGE
Otolaryngology – Head and Neck Surgery
Michael G. Stewart, MD
Professor of Otolaryngology
Pathology and Laboratory Medicine
Daniel M. Knowles, MD
David D. Thompson Professor of Pathology
Pediatrics
Gerald M. Loughlin, MD, MSc
Nancy C. Paduano Professor of Pediatrics
Pharmacology
Lorraine J. Gudas, PhD
Revlon Pharmaceutical Professor of
Pharmacology and Toxicology
Physiology and Biophysics
Harel Weinstein, DSc
Maxwell M. Upson Professor of Physiology
and Biophysics
Psychiatry
Jack D. Barchas, MD
Barklie McKee Henry Professor of Psychiatry
Public Health
Alvin I. Mushlin, MD, ScM
Nanette Laitman Distinguished Professor of
Public Health
Radiation Oncology
K.S. Clifford Chao, MD
Chu H. Chang Professor of
Radiation Oncology
Radiology
Robert J. Min, MD
John A. Evans, MD, Associate Professor
of Radiology
Surgery
Fabrizio Michelassi, MD
Lewis Atterbury Stimson Professor of
Surgery
Urology
Peter N. Schlegel, MD
James J. Colt Professor of Urology
leadership
Board of Overseers
Sanford I. Weill
Chair
Antonio M. Gotto, Jr., MD, DPhil
Co-Chair
Robert J. Appel
Barbara B. Friedman
Arthur J. Mahon
Vice Chairs
Tarek Abdel-Meguid
Michael M. Alexiades, MD
(Ex Officio)
Madelyn Antoncic, PhD
Robert A. Belfer
Jessica M. Bibliowicz
Her Highness Sheikha Moza Bint Nasser
Lloyd C. Blankfein
David S. Blumenthal, MD
Chelsea V. Clinton
Abby Joseph Cohen
Timothy C. Collins
Alberto Cribiore
Elizabeth Rivers Curry
Sanford B. Ehrenkranz
Israel A. Englander
Anne E. Estabrook
Jeffrey J. Feil
Samuel C. Fleming
Charlotte M. Ford
Gerald J. Ford
Harold E. Ford, Jr.
Kenneth C. Frazier
Laurie H. Glimcher, MD
(Ex Officio)
Paul A. Gould
Jeffrey W. Greenberg
Maurice R. Greenberg
David P. Hajjar, PhD
(Ex Officio)
Katherine A. Hajjar, MD
Leonard M. Harlan
Robert S. Harrison
(Ex Officio)
Lawrence A. Inra, MD
Michael Jaharis
John A. Kanas
Harvey Kaylie
James M. Kilts
Charles R. Lee
Michael T. Masin
Anna Sophia McKenney
Peter C. Meinig
Ronay A. Menschel
Howard P. Milstein
Edwin H. Morgens
Rupert Murdoch
Spyros Niarchos
Timothy O’Neill
Nancy C. Paduano
Nelson Peltz
Ronald O. Perelman
Bruce C. Ratner
Philip R. Reilly, MD, JD
Burton P. Resnick
Isadore Rosenfeld, MD
Zev Rosenwaks, MD
Lawrence Ruben
Richard G. Ruben
Lewis A. Sanders
Herbert J. Siegel
David J. Skorton, MD
(Ex Officio)
A.J.C. (Ian) Smith
Daisy M. Soros
Louis Wade Sullivan, MD
Samuel O. Thier, MD
Carolyn S. Wiener
Life Overseers
Raymond R. Herrmann, Jr.
Harvey Klein, MD
Margaret Osmer-McQuade
Frank H.T. Rhodes
Saul P. Steinberg
Patricia Carry Stewart
Harold Tanner
Roger J. Weiss
©2012 Weill Cornell Medical College. All rights reserved.
Weill Cornell Medical College
1300 York Avenue
New York, NY 10065
weill.cornell.edu
WEILL CORNELL MEDICAL COLLEGE AND
GRADUATE SCHOOL OF MEDICAL SCIENCES
Weill Cornell Medical College, the medical school of Cornell University, is among
the top-ranked medical research centers in the country. Founded in 1898, the
Medical College has been affiliated with what is now NewYork-Presbyterian
Hospital since 1927. In addition to offering degrees in medicine, Weill Cornell
also has PhD programs in seven broad programs of study in biomedical
research at the Weill Cornell Graduate School of Medical Sciences, and the TriInstitutional MD-PhD Program with neighboring Sloan-Kettering Institute and
The Rockefeller University. On January 1, 2012, Dr. Laurie H. Glimcher, one of
the nation’s leading physician-scientists and researchers, succeeded Dr. Antonio
M. Gotto, Jr., as the Stephen and Suzanne Weiss Dean of Weill Cornell Medical
College and Provost for Medical Affairs for Cornell University.
Weill Cornell Medical College is divided into 24 basic science and clinical
departments. Physicians and scientists are engaged in cutting-edge research
from bench to bedside, aimed at unlocking mysteries of the human body in
health and sickness and toward developing new treatments and prevention
strategies. Weill Cornell is the birthplace of many medical advances – including
the development of the Pap test for cervical cancer, the synthesis of penicillin,
the first successful embryo-biopsy pregnancy and birth in the U.S., the first
clinical trial of gene therapy for Parkinson’s disease, and most recently, the
world’s first successful use of deep brain stimulation to treat a minimally
conscious brain-injured patient.
In its commitment to global health and education, Weill Cornell has a strong
presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria, and Turkey.
Through the historic Weill Cornell Medical College in Qatar, the Medical College
is the first in the U.S. to offer its medical degree overseas.
In addition to its affiliation with NewYork-Presbyterian Hospital, Weill Cornell
Medical College and Graduate School of Medical Sciences maintain major
affiliations with Memorial Sloan-Kettering Cancer Center, The Rockefeller
University, Hospital for Special Surgery, as well as with the metropolitan-area
institutions that constitute the NewYork- Presbyterian Healthcare System. The
Medical College is also affiliated with The Methodist Hospital in Houston, Texas.