10
The BRI uses bright minds and brawny
resources to propel efforts in
personalized medicine, targeted
therapeutics, and more
BWH’s OurGenes project seeks
to predict risk, prevent disease,
personalize care, and promote
patient participation
hospital researchers are exploring
the brain, our master organ, with
the hope of improving treatment for
mental illness
It’s in our genes. Investigators at
BWH study how and when environmental factors trigger genetic
disease and whether they can
predict risk
The BRI BRIght Futures Fund
targets brilliant young scientists
so they make discoveries that
transform medicine
2 010 Pr e v i e w i s s u e
T h e R e s e a r c h m a g a z i n e o f B ri g h a m a n d W o m e n ’ s H o s p it a l
The BWH Biomedical Research Institute
BRI Executive Committee
BRI Director
Cynthia C. Morton, PhD
BWH SVP, Research
Barbara E. Bierer, MD
BRI Co-Director
Joseph Loscalzo, MD, PhD
BRI Past-Director
Thomas S. Kupper, MD
BRI Executive Director
Jacqueline Slavik, PhD
BRI Research Oversight CommittEE
Anesthesia
Paul Allen, MD, PhD
Regenerative Therapeutics
Jeffrey Karp, PhD
Annarosa Leri, MD
Shiladitya Sengupta, PhD
Genetics/Genomics
Beth Karlson, MD
Christine Seidman, MD
BRI Program Co-Chairs
Animal Models
Arlene Sharpe, MD, PhD
Imaging
Steve Seltzer, MD
Clare Tempany, MD
Bioinformatics
Scott Weiss, MD, PhD
Dermatology
Rachael Clark, MD, PhD
Technology Innovation
Fred Schoen, MD, PhD
Emergency Medicine
Daniel Pallin, MD, MPH
Clinical Investigation
Gordon Williams, MD
Medicine
Richard Blumberg, MD
Neurology
Vijay Kuchroo, DVM, PhD
Neurosurgery
A. John Popp, MD
Obstetrics/Gynecology
Robert Barbieri, MD
Orthopedic Surgery
Julie Glowacki, PhD
Elected Representatives
Postdoctoral Fellows:
Rolf Stottman, PhD
Manu Rangachari, PhD
Junior Faculty:
Basic
Mathew J. Lavoie, PhD
Clinical Science
Sushrut Waikur, PhD
BRInk, the research magazine of Brigham and
Women’s Hospital, is published once a year for
contributors of $100 or more to the hospital,
volunteers, patients, and staff.
For additional copies, call (617) 424-4300,
email [email protected], or write to:
Brigham and Women’s Hospital
Office of Development
116 Huntington Avenue, Fifth Floor
Boston, MA 02116-5712
President
Elizabeth G. Nabel, MD
Chief Medical Officer
Anthony Whittemore, MD
Senior Vice President of Research
Barbara E. Bierer, MD
Vice President and Chief Development Officer
James W. Asp II
Population Science
Janet Rich Edwards, ScD
Communications Director
Kathryn Goodfellow
Psychiatry
David Silbersweig, MD
Senior Faculty:
Basic
Elizabeth Henske, MD
Editor
Noelle Shough
Radiation Oncology
Alan D’Andrea, MD
Clinical Science
Steven Shea, MD
Radiology
Ferenc Jolesz, MD
Population Science
Jennifer Haas, MD
Pathology
Michael Gimbrone, MD
Surgery
Steven Mentzer, MD
BRI Center Co-Chairs
Cancer
Jon Aster, MD, PhD
Sue Hankison, ScD
David Sugarbaker, MD
Cardiovascular
Gail Kurr Adler, MD, PhD
Andrew Lichtman, MD, PhD
Marc Pfeffer, MD, PhD
Infection/Immunity
Vijay Kuchroo, DVM, PhD
Dan Kuritzkes, MD
Arlene Sharpe, MD, PhD
Musculoskeletal
Julie Glowacki, PhD
Dan Solomon, MD, MPH
Neurosciences
Ron Kikinis, MD
Dennis Selkoe, MD
Women’s Health
Julie Buring, ScD
Jill Goldstein, PhD
Additional Members
Elliot Antmann, MD
Simon Gelman, MD
Elizabeth Nabel, MD
Jim Asp
Nan Doyle
BRI Administrative Staff
Executive Director
Jacqueline Slavik, PhD
Program Managers
Keri Siggers, PhD
Anu Swaminathan, PhD
Portal Coordinator
Christine Michael
Communications Specialist
Jessica Podlaski
Internet and Web Assistant
Alexandra Gallant
Administrative Coordinator
Melissa Smith
Staff Writers
Jennifer Nejman Bohonak
Jennifer B. Wells
Art Director
John Bach
Design
Pangaro Beer Design
Writing and Editorial Assistance
Kristin DeJohn
Photography
Larry Maglott, Stu Rosner, Jeff Thiebauth
Visit our website at www.brighamandwomens.org.
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Thank you.
front cover image: Science Photo Library
CONTENTS
brink 2010 pre view Edition
02
The house that
research built
Predictive, proactive, and
preventive. Using our burgeoning knowledge
of the genome, vast resources from our tissue
banks, and the brightest minds in medicine
and science, the Biomedical Research Institute
of BWH approaches disease where it starts.
05
BRI by the
numbers
Interesting statistics from
Brigham and Women’s BRI.
The future of medicine:
BWH’s OurGenes, OurHealth,
OurCommunity Project
Your genes are like a hand of cards that you’re dealt at birth. BWH will engage 100,000 patients
to create an integrated database of medical information that researchers can use to help you do
the best you can with the cards you have.
06
10
The brain:
Our final frontier
Today’s neuropsychiatry is
a biomedical revolution. By
harnessing imaging and genetics, researchers
at Brigham and Women’s Hospital can better
understand the brain and disease.
14
Measuring
genetic risk
BWH researchers are
investigating overlapping
genetic connections between inflammatory
diseases and are working on a model to predict
a person’s genetic risk of developing multiple
sclerosis.
16
Bright ideas,
BRIght futures
BWH’s BRIght Futures Fund,
supported both by the
hospital and our generous donors, seeds and
supports biomedical research and the people
who make the life sciences their life’s work.
ON THE COVER: Pictured is a DNA (Deoxyribonucleic acid) double helix, which holds the
genetic recipe that is the basis for all living
things. For some BRI scientists, their life’s
passion is decoding that recipe.
brink 10 > table of contents
01
The
house
that
research
built
1
2
3
4
SHARED
PERSONALIZED
TARGETED
COMPARATIVE
MECHANISMS
OF DISEASE
MEDICINE
5
THERAPEUTCS EFFECTIVENESS
HEALTH DISPARITIES
By Noelle shough
The Biomedical Research Institute
How the BRI IS
re-engineering
healthcare
Think about how healthcare currently works. Generally, you are healthy until you’re not.
Then you see your physician, who first tries to diagnose and treat your ailment by looking
at it on the surface and perhaps ordering blood tests or imaging.
What if physicians had a more sophisticated set of tools at their disposal? Picture a toolbox
of genetic information, a deep understanding of environmental factors, your family history,
and your own personal history all mapped out for physicians. Not only would they have an
easier time diagnosing and curing your malady, but they could also, in many cases, give you
the knowledge and resources to prevent that disease from ever happening in the first place.
That’s the vision of the Biomedical Research Institute (BRI) at Brigham and Women’s
Hospital. At the BRI, we’re approaching medicine from the inside. This re-engineering of
healthcare will give patients personalized, more efficacious results, and preventive
measures and earlier diagnoses will result in less long-term cost. But it’s going to take
some hefty investment in our research.
Our physicians and scientists are already uncovering eye-opening connections between
diseases—connections which are bringing to light new ways to understand and treat illness.
These researchers examine a multitude of initiatives, such as the possible links between heart
disease and depression. They run large-scale studies to look at how a lack of vitamin D might
not only cause weak bones, but could also be a factor in asthma, and even certain cancers.
They analyze the possible damage of inflammation, caused after the body’s immune response
engages to fight infection.
“That’s what the BRI is—a
virtual institute that creates
infrastructure, promotes
collaboration, and raises
public and internal perception to advance innovative
projects.”
Jackie Slavik, PhD,
BRI Executive Director
“We’re building real change
in the way that we approach
patients—and the way
that patients can participate
in their future care.”
Barbara Bierer, MD,
BWH Senior Vice President
of Research
“We are clearly planning
to roll out a different type
of medicine here, one
that’s based on genetic
information.”
Cynthia Morton, PhD,
BRI Director
“Research is incredibly
important to me. I revel
in all the opportunities
to transform medicine
available at the BRI.”
Betsy Nabel, MD,
BWH President
Predictive, proactive, and preventive—this is the BRI’s vision for healthcare, says Barbara
Bierer, MD, senior vice president of research at BWH. “Using our burgeoning knowledge
of the genome, vast resources from our tissue banks, and the brightest minds in medicine
and science, the BRI approaches disease where it starts: at the cellular and molecular level,”
she says. This approach will allow us to personalize treatment—and halt disease before it
occurs. >>>
brink 10 > the house that research built
03
BRI: The “front porch” of clinical care
Think of the Biomedical Research Institute as the front porch of a house, with five pillars supporting the roof.
Each pillar represents a strategic research priority of the BRI. Here are those five pillars in depth:
Shared mechanisms
of disease are effects
like inflammation,
says BRI Executive
Director Jacqueline
MECHANISMS
Slavik, PhD. InflamOF DISEASE
mation can be the
result of or play a role in many different
medical conditions—like arthritis or heart
disease—but is not itself a disease. “Inflammation isn’t a causative thing; it’s a response,”
she explains. “The more you know about
why inflammation triggers, the more you
can treat or prevent the problems that
cause the inflammation in the first place.”
Researchers at the BRI who study inflammation can share and apply their knowledge
across their different areas of research. This
collaboration allows for progress in one area
to benefit another area of research.
1
SHARED
Targeted therapeutics
are specially crafted
to tackle disease at
the molecular or celTHERAPEUTCS lular level, or by the
location in the body.
Just as physicians now prescribe the antibiotic that research shows has the greatest
efficacy against a particular bacteria, in
the future they will understand the genetic
mutations and environmental influencers
of each particular kind of cancer and
use drug therapy tailored to tackle them
specifically. And patients will suffer fewer
drug reactions and receive more effective
treatment as a result.
3
TARGETED
Personalized medicine considers genetics, environment, nutrition,
family medical history, and other factors unique to the individual,
so that clinicians can tailor treatments to a patient’s specific makeup
PERSONALIZED
and situation. For instance, BWH’s cutting-edge OurGenes, OurHealth
and OurCommunity Project (see story on p. 6) will gather comprehensive information from 100,000 patients—genetic, environmental,
family medical history, and medical record—with the vision that the data will show trends
that can drive future medical advice and treatment.
2
MEDICINE
BRI Director Cynthia Morton, PhD, for example, underwent genetic testing and discovered
that she had an increased sensitivity to the blood-thinner warfarin. “If I were ever to be
prescribed warfarin, we could look up my readings of the enzyme that actually metabolizes
the drug to determine how I am likely to react to it,” she says.
When genetic scans are the norm, they will inform medical practice from the moment a
person is born, Morton says. We currently screen newborns for a limited number of metabolic
syndromes with devastating effects. In the future an infant will undergo a gene scan for
mutations yet to be discovered—if a mutation is uncovered, the infant might be placed on
a special diet like the one now practiced for phenylketonuria, which staves off the ill effects
of a disease before they occur.
And Bierer points out that it is not only about genetics. “It’s important to take a holistic
approach, as well as to understand the molecular causes that make a cell go awry,” she says.
“The more we understand specific factors that cause a certain response, the better we’re going
to be able to find targets we can treat.”
4
COMPARATIVE
EFFECTIVENESS
Comparative effectiveness is the method of comparing different treatments to determine which work better under which set of parameters.
Why does one cancer patient respond differently to chemotherapy
than another patient with the same kind of cancer? When is a physical
therapy regime likely to yield a better outcome than a knee replacement? Comparative effectiveness seeks to solve these riddles.
Addressing health disparities permeates all research, as investigators
consider ways to address inequalities in healthcare access and delivery.
For instance, ensuring that clinical trials or research studies include
subjects of both genders and different ethnicities can uncover
differences in susceptibility to disease, as well as show differences
disparities
in the quality of care groups of patients have historically received.
Implementing true personalized medicine—which takes into account genetics, environment,
and more—should further help reduce health disparities.
5
health
For now, BRI researchers are encouraged to think about how to eradicate health disparities
in all their scientific endeavors. “I think we are unique in our commitment to health equity
and community health,” says Bierer. “We strive to understand the causative factors of health
inequalities and to take the corrective action that will make a difference for the community.”
By Name goes here
Author’s Affiliation goes here
photos: XXXXXX XXXXXXXX
BRI by the numbers
3,500 researchers, 1,000 of whom are
principal investigators
Funding
innovative
projects
Ranked in the top ten list for best
hospitals in the nation by U.S. News &
World Report, Brigham and Women’s
is renowned for its exceptional patient
care. What you may not know is that
BWH is also ranked the second largest
#2 recipient of National Institutes of Health (NIH)
funding for the past decade among independent
hospitals in the United States
$485 million in research support annually
(about 24% of the total hospital budget)
54% of funding comes from the NIH;
15% from industry; 31% from other sources
including licensing and philanthropy
recipient of research funding from the
National Institutes of Health to independent hospitals. “And it’s not like the NIH
is just handing out money,” points out
Jacqueline Slavik, PhD, BRI director. “We
receive these funds based on the top
quality of research proposals that our
750,000+ sq ft of laboratory space in Boston,
Cambridge, and beyond
42 research locations, including buildings
in Boston, Cambridge, and Chestnut Hill
investigators submit.”
Unfortunately, funding from the NIH is
4 MacArthur fellows (the ‘genius’ grant)
still difficult to come by. BWH must
increasingly look to philanthropically
minded foundations and individuals who
understand the importance of supporting research in its earlier stages. “We
want to move the field ahead by allowing
more innovative research,” Slavik says.
3 Nobel Laureates
(2 Physiology or Medicine; 1 Peace)
42 is the average investigator’s age at his or
her first independent NIH grant
To support the BRI’s visionary research,
please contact Nan Doyle in the
Development Office at 617-424-4307
or [email protected].
brink 10 > BRI by the numbers
05
BWH’s OurGenes, OurHealth, OurCommunity
Research Project: Personalized Prediction, Prevention,
and Treatment of Disease
By Jennifer B. Wells
The Biomedical Research Institute
photo: Stu Rosner
location: Museum of Science
[Left to right] Elizabeth Karlson, MD;
Christine Seidman, MD; and Cynthia Morton, PhD
brink 10 >Our Genes, our health, our community
07
Predict risk. Prevent disease. Personalize care. The fourth “p”
A 45-year-old man comes to the hospital for gallbladder surgery, but
during the operation, he develops an irregular heartbeat. Surgeons
stop the procedure and restore his heart’s rhythm. Then they discover
the patient has significant blockages in his coronary arteries that
require immediate attention. There is good news in this story—
physicians identified and prevented a patient’s potentially lethal heart
disease. There is also bad news—the patient needs cardiac as well as
gallbladder surgery. Moreover, the healthcare dollars spent to treat
this patient expanded exponentially.
This example demonstrates how
medicine works today. People usually
get medical care when a condition
causes symptoms. But many serious
conditions (such as heart disease) can
be silent. What if, instead, physicians,
scientists, and patients could work
together to identify individuals at risk
for disease before damage is done?
Could they predict, manage, or even
prevent some disorders?
environment, and provide a family medical history, all of which will
be linked to their medical records. High-level security measures will
protect patients’ personal information contained in the database.
Led by Christine Seidman, MD, and Elizabeth Karlson, MD co-chairs
of the BWH Biomedical Research Institute Center for Human
Genetics, OurGenes has the potential to change the way medicine
is practiced—from a focus on treatment and disease to a focus on
prevention and health. “OurGenes is
a sweeping endeavor,” says Seidman.
“We are creating the infrastructure
that will drive BWH research for
decades to come.”
Genetics
is personal
Genetics is not only about disease. It’s
not by chance that family members look
and act alike. Your genes also affect
certain traits.
Predicting risk
Take sensitivity to caffeine. Some people
Your genes are like a hand of cards
that you’re dealt when you’re born.
Some genes are good; others make you
more susceptible to diseases. Genes
are not the only factor that determines
your health. How you play the “hand”
you are dealt is also important. What
you eat, how much you exercise, and
where you live are some of the things
that can amplify or reduce the effect of
your genes. One of the big challenges
in medicine is to discover how genes,
behavior, and the environment interact,
and how to use that knowledge to
predict, prevent, and treat disease for
individual patients.
can’t drink a single cup of coffee without
shaking while others can knock back
a double espresso at night without any
effect on their sleep. Cynthia Morton,
PhD, thought she was in the second
group, but it wasn’t until her hunch was
Cynthia Morton, PhD, is a medical
geneticist and director of the BWH
Biomedical Research Institute, which
is spearheading the OurGenes initiative. She is passionate about the potential of OurGenes, and says that the
number of patients who participate
is critical. “If you’re looking for genetic
variants, it takes big numbers to
study subsets of interacting conditions,”
Morton says. “Even in common diseases like deafness, there are a number
of causes. If we want to prevent
deafness, we need to understand the
molecules involved in the biology
of deafness.”
Research studies linking genetics with
clinical data on a large scale has never
been done before. Previous research
switched from decaf to regular coffee
studies have concentrated on select
after dinner. “Seeing the results in black
populations or patients with a single
and white set me free,” says Morton.
disease like diabetes. In contrast,
“I now have coffee at all hours.”
OurGenes will look at the entire BWH
patient population who consent to
be part of the study. The project will
benefit from the rich diversity of
Brigham and Women’s Hospital (BWH) is rising to this challenge
BWH patients, the exceptional skills of BWH physicians, and the outwith its pioneering project OurGenes, OurHealth, OurCommunity.
standing creativity of BWH researchers. Furthermore, OurGenes will
Using blood samples and health information collected from more
include a community advisory board to ensure that patients’ privacy
than 100,000 participants, OurGenes will be a databank containing
is protected and that the research applies to many different groups.
genetic, medical, and lifestyle information that researchers can use
to discover health and disease patterns. These patterns may help sciPreventing disease
entists discover which people are more likely to get certain diseases,
The case presented at the beginning of this article focused on one
which patients will have good responses to medical treatment, and
patient and what happened to him in the operating room. But had
which lifestyle factors can be changed to improve health.
doctors known that the patient’s family history included strokes
and heart attacks in his parents and grandparents, his care might
Patients who consent to participate in the program will donate
have been different. Today, clinicians know many factors that
blood samples, respond to a survey about lifestyle, behavior, and
confirmed from a genetic test that she
that defines OurGenes is actually two—patient participation.
increase a patient’s risk for heart disease, including family history,
high cholesterol levels, high blood pressure, cigarette smoking, and
a sedentary lifestyle. In addition, researchers have discovered genetic
risk factors for several forms of heart disease.
Had familial, genetic, and clinical information been available when
this patient was a young man, his gall bladder surgery might have
been uneventful. His physician could have educated him about a
high genetic risk for heart disease,
encouraged him to stop smoking
and eat a healthy diet, and prescribed medication to lower his
cholesterol starting early in life.
Such strategies might have prevented
the need for heart surgery at the
young age of 45.
doctors can reduce the dose and can safely provide the benefits of
warfarin to all patients.”
OurGenes will help physicians understand how patients’ genes
affect the way they respond to medicine. Says Karlson, “If you
develop rheumatoid arthritis, there are five different drugs you can
take—all have side effects, and all take time to take effect. But if
you’re stiff and swollen, you want relief quickly. Today, doctors have
no idea what works best for you with
the lowest chance of side effects such
as infection.”
You can support
OurGenes
While your genes certainly matter
when it comes to disease, so do
factors like your sun exposure and
diet and the places you live and
work. In many ways, your zip code
is as important as your genetic code.
For example, residents in poor urban
areas may not have access to fresh
produce or a safe place to exercise.
As a consequence, they may be more
susceptible to diseases aggravated
by poor nutrition and sedentary
lifestyles.
OurGenes will obtain information
on both genes and lifestyle—something that distinguishes OurGenes
from other studies. Research from
the OurGenes databank will help
patients make better choices about
how to reduce their risk factors and
stay healthy.
Investing in OurGenes is an investment
Partnership with patients
in the future of medicine and the health
Predict risk. Prevent disease. Personalize care. The fourth “p” that defines
OurGenes is actually two—patient
participation.
of future generations. Public funding
is limited for big, bold projects like
OurGenes. More than ever, philanthropic
support is necessary. Your contribution
will help recruit 100,000 patients; collect,
track, and store samples and data; and
educate patients and healthcare providers.
To make a gift to the OurGenes project,
please contact Nan Doyle, BWH
Development Office, at 617-424-4307
or [email protected].
“One goal of OurGenes is to educate
patients and providers about how a person’s genes interact with
cetain risk factors,” says Karlson. “This is powerful information that
can change the way doctors treat patients and patients manage their
own health.”
Personalizing care
As scientists learn more from OurGenes research, doctors will be
able to prescribe drugs based on a patient’s genetic profile. Genetics
affect how people respond to different drugs. Medicine dosages that
work well in some patients may be harmful to others. “We already
know that warfarin, a blood thinning medicine given to people with
heart disease, can cause serious bleeding in other people with certain
genetic variants,” says Seidman. “By knowing these genetic variants,
Instead of relying on generic treatment
plans given to all patients with a
disease, OurGenes will help physicians
treat patients based on their individual
risk factors.
The success of the OurGenes project
hinges on participation by all BWH
patients. Patients must consent to participate in OurGenes, provide a blood
sample, and respond to a questionnaire.
Researchers will pilot the study in six
BWH clinics. Through patient education,
the OurGenes team aims to recruit 600
patients with diverse backgrounds and
medical conditions for the pilot. The
full project will launch after evaluation
of the pilot studies and will become
an expanding effort across Partners
institutions.
Morton says, “Every patient should rest
easy knowing that there’s a dedicated
team to take care of you, who are simultaneously learning from
you how to treat the next patient better. And every patient should
know that he or she is part of moving that knowledge forward.”
“Patients know that there is still a great deal to learn about human
health and disease,” adds Seidman. “Participating in this project
gives incredible new opportunities for discoveries to be made
that will help those who come after us. It’s not just for the health
of your children or grandchildren; it’s for everyone’s children
and grandchildren.”
Not everyone gets a hand with four aces, but OurGenes will help
patients do the best they can with what they’ve got. l
brink 10 > Our Genes, our health, our community
09
THE
Our final Frontier
Research in imaging and genetics is improving our
understanding of our master organ
By Jennifer Nejman Bohonak
Neurosciences Research Center
photos: Science Photo Library, Stu Rosner
The brain is maestro of the body’s orchestra of nerves, organs, and
limbs. With grace and precision, this master organ inspires and coordinates performance after performance, every moment of our lives.
Through our brain, we interact with the world outside our bodies,
and we guide ourselves.
“The brain mediates and underlies all thought and feeling and every
sphere of human experience,” says David Silbersweig, MD, chair of
the Department of Psychiatry at Brigham and Women’s/Faulkner
Hospitals and chair of the Institute for the Neurosciences. “It is what,
through evolution, makes us who we are, and allows us to be able to
even ask questions about who we are.”
To understand the conductor of our mind and body, we need to be
able to see what is going on. With imaging machines, we can safely
look inside to study the brain, heart, and other organs. The hope is
that through imaging research, we might be able to find connections
between disease processes in seemingly unrelated diseases, such as
depression and heart disease.
By harnessing imaging and genetic research tools, one day we may be
able to alert patients of their risks and intervene—long before they
experience symptoms.
If we could intervene in schizophrenia, multiple sclerosis, and
Alzheimer’s disease before these conditions have taken their toll, we
might be able to ease suffering and help people live longer, healthier
lives. For mental illness, improved treatments could mean preventing
suicides, hospitalizations, mental suffering, family turmoil, and loss
of income from disability.
Fighting stigma with science
In the United States, one in four adults, 57.7 million Americans, will
have a diagnosable mental disorder during any given year, according
to the U.S. National Institute of Mental Health.
Sadly, even today, disorders of the mind still carry a stigma that
affects both those who live with mental illness and their loved ones.
“If someone has a psychiatric disorder, they have a double hit. They
not only suffer tremendously and poignantly, but they’re misunderstood and blamed very often—as if it’s some moral failing or some
weakness, or they should pull themselves up by their bootstraps
or snap out of it. That’s just as ridiculous as saying that someone
with a kidney stone should snap out of it,” Silbersweig says.
He believes that one of the most effective ways to reduce societal
stigma is through science. If we can understand the biology of
mental illness, we can create better treatments, shatter stereotypes,
and objectively examine the disease process.
Emily Stern, MD, director of the functional neuroimaging laboratory
at BWH, is using imaging to study premenstrual dysphoric disorder
David Silbersweig, MD
(PMDD), a condition some people have claimed is not real or tagged
as only psychological. The disorder—more severe than the betterknown PMS—causes disabling mood and behavioral changes,
resulting in women having problems at work and in relationships.
PMDD is estimated to affect between 2–8 percent of women.
Stern and her colleagues are studying women diagnosed with the
disorder and women who have steady emotions. In this ongoing
National Institutes of Health–funded study, they are seeking information about the location of hormonal changes; how the brain responds;
individual predispositions; and where dysfunction exists.
The women’s brains are scanned when they are premenstrual and
postmenstrual using a technique called functional magnetic resonance imaging (fMRI). While in the fMRI, the women view words
that evoke emotions and press buttons. Similar to a stress test that
measures the heart’s capacity, through fMRI, researchers test the
brain’s systems, circuits, and functions.
FMRI allows researchers to look noninvasively at the pattern and
location of brain activity—at rest, and in response to particular
mental tasks—and begin the creation of brain maps. With the
advanced technology and analytic tools, Stern and her colleagues
track blood flow and oxygen changes that occur when the brain’s
neurons are active and using more energy, blood, and oxygen.
Stern and her colleagues proved that parts of the brain’s frontal lobe
(the section that sits behind your forehead) are more active during a
brink 10 > the brain
11
woman’s premenstrual phase, even if the woman has no symptoms.
These areas help to regulate emotion, which remains stable in
women who do not have PMDD. Stern explains that the brain works
harder during a woman’s premenstrual phase, so women who do
not have the disorder will not experience symptoms.
The study found abnormalities in the brains of women diagnosed
with premenstrual dysphoric disorder. Researchers pinpointed
changes within the orbitofrontal cortex, in an area that mediates the
interaction of emotion and behavior, particularly negative emotions
and the inability to control impulses. They also found abnormalities
in the amygdala, an area associated with fear-conditioning and negative emotions, and in the nucleus accumbens, which is involved in
positive emotions and rewards.
BWH’s Jill Goldstein, PhD, and her research colleagues are also using
fMRI. They are investigating how fetal antecedents—risk factors for
diseases that develop during pregnancy—relate to sex differences in
psychiatric disorders.
Her team is studying fetal antecedents to sex differences in adult
psychoses and depression, as well as shared fetal antecedents to
depression and cardiovascular disease. The findings will be important
for the development of sex-specific hormonal and immunoregulatory
treatments and also for sex-specific prevention strategies.
Inside our minds
FMRI uses thousands of pictures and mathematics to pull out patterns and highlight areas in the brain associated with a change in
cognition, emotion, perception, behavior, or interactions of these
processes, as well as what happens when something goes awry.
BWH researcher Seung-Schik Yoo, PhD, MBA, who directs fMRI
services, plans to use fMRI to gather data from people in real time.
His theory is if you know what’s happening in the brain because
you can see a high resolution image as the person is in the fMRI
scanner, then you can work on a better rehabilitation strategy.
Yoo gives the example of a stroke patient. Often, a stroke patient
will have trouble moving one arm due to damage in the responsive
brain area.
When the patient tries to grab something with the nonresponsive
hand, the patient, often unwillingly, engages the opposite, undamaged part of the brain to assist with that movement. But if the patient
could see a functional image of the brain, the patient might be able to
figure out where and how to get the correct brain cells working
to take over the role of the damaged brain cells.
This theory might also have implications for controlling addictions
because it examines modifying brain function associated with substance abuse, Yoo says.
Links between diseases, inflammation, and genes
At BWH, physicians and scientists are working together on common research themes, says Martin Samuels, MD, neurologist-in-chief
of BWH’s Department of Neurology. “I don’t think there is another
place that has a truly integrated program in Neurology, Neurosurgery,
Psychiatry, Neuroradiology, and Neuropathology, which spans clinical
care, training, and research,” he says.
He points to two theories researchers are investigating that link
diseases in a broader way than previously considered—inflammation
and shared genes.
One collaborative goal is to study the effect of neuroinflammation on
brain-mind disorders. Neuroinflammation may play a role in a wider
range of neuropsychiatric conditions than previously thought, which
could open the door to new therapeutic possibilities, Silbersweig says.
Researchers want to know: Is inflammation a common underlying pathophysiologic mechanism in many neuropsychiatric conditions? Are people depressed because they have heart conditions,
are stressed, and don’t feel well? Or are they depressed because the
mechanism that is contributing to their heart problem is also making
them depressed by affecting circuits in the brain that control mood?
For conditions like multiple sclerosis, evidence already exists of an
inflammatory process in the body. But for others like epilepsy, schizophrenia, or psychotic disorders, finding a link to inflammation would
be a breakthrough.
In essence, excess inflammation is a miscalculation by the body of
how much help it needs to heal itself. While some inflammation is
natural, too much can have disastrous effects.
BWH researchers use tools such as positron emission tomography
(PET) to scan the brain to study the inflammatory process.
Stern and her colleagues use 11C-PK11195—a radioactive molecule
that helps them to make images of neuroinflammation in the brain
with PET. Magnetic resonance imaging (MRI) techniques are also
used to study neuroinflammation. BWH’s Martha Shenton, PhD,
analyzes neuroinflammation in patients through the use of diffusion
imaging, a novel MRI procedure. With funds from a recently awarded
traumatic brain injury grant, Stern and Shenton, the grant’s principal
investigator, will use imaging to study patients who have head
injuries caused by vehicle accidents or sports.
The goal is to study inflammation, over time, in injured patients.
Stern says if researchers learn that too much inflammation is
harmful, possible treatments include anti-inflammatory drugs or
other interventions. So many soldiers with traumatic head injuries,
who are otherwise young and healthy, are returning home from
Iraq and Afghanistan and could benefit from improved treatments,
Shenton says.
The future
The hope for all of medicine, and especially for clinical neuroscience,
is that in the future, physicians will have the ability to treat a person
based on individual genetic and biological profiles.
In addition to inflammation, the interplay of variation in an individual’s genes and environmental risk factors can ultimately trigger
the disease process, says Philip De Jager, MD, PhD, director of the
Program in Translational Neuropsychiatric Genomics in BWH’s
Department of Neurology and Psychiatry.
photo: Stu Rosner
“One fascinating story that’s emerged over the past few years is that
while diseases like type I diabetes, multiple sclerosis, and lupus, for
example, look very different and affect different organ systems, they
share a remarkable number of genetic risk factors,” De Jager says.
Strides have been made for certain breast cancer genes, but for
mental illness treatment, doctors must rely on descriptive categories,
not biological markers, when prescribing medication. Antidepressants can take four to six weeks to kick in. If the medicine prescribed
doesn’t work, it becomes a race against time, Silbersweig explains.
The healthcare provider could try another medication, but by then
weeks could have passed—and the patient may be suicidal.
Today, new approaches to treating depression and other brain
disorders are being developed at BWH as well, including neurological deep-brain stimulation of key brain circuits using mild electrical
signals that can help manage symptoms of mental illness.
And BWH researchers are working on ways to predict who might
be at risk for mental illness. If doctors could alert patients of their
genetic risk earlier, then patients could seek treatment when they first
notice symptoms. Healthcare providers could offer cognitive therapy,
a process of teaching a person how to alter negative thought patterns.
One day, there may even be personalized treatments to prescribe.
We live in an era in which we can continue to pose the questions
about life that philosophers and scientists have asked for thousands
of years, Silbersweig says. Why do some people get sick? Why do
we react differently to traumatic situations? We ask these questions
because, through evolution, we have developed a brain with the
ability to do so, he says.
And today, we have the imaging and research tools that allow us to
better understand and help our maestro. l
[Left] These functional magnetic resonance imaging (fMRI) pictures illustrate
differences in brain activity between women experiencing premenstrual dysphoric
disorder (PMDD) and those who do not have the disorder, which can cause disabling
mood and behavioral changes. Women with PMDD (top image) show decreased
activity in their frontal lobe, displayed in blue. In women who do not have PMDD
(bottom image), there is more activity, shown in yellow, in areas that are helpful
in regulating negative emotions and controlling impulses.
[Right] Emily Stern, MD, and Seung-Schik Yoo, PhD, MBA, in a BWH lab with the fMRI
equipment they use to study brain activity.
Historic strides
BWH has a long history of leading advances in the fields of
neurology, neurosurgery, and psychiatry. In 1913, the Peter Bent
Brigham Hospital, one of BWH’s founding institutions, named
Harvey Cushing, MD, who is considered the founder of modern
neurosurgery, its surgeon-in-chief. One of Cushing’s first interns
at the Brigham, Stanley Cobb, MD, helped create the field of
modern neurology and psychiatry in the United States. He was
the first to classify anorexia nervosa as a disease in its own
right, and not a manifestation of schizophrenia. Today, David
Silbersweig, MD, is chair of the Department of Psychiatry
at Brigham and Women’s/Faulkner Hospitals and the Stanley
Cobb Professor of Psychiatry at Harvard Medical School.
To make a gift to benefit mental illness treatment or other brain
research, please contact Kristin Garrity in the BWH Development
Office at 617-424-4325 or [email protected].
brink 10 > the brain
13
Measuring
Genetic
Risk
Your genes define a continuum of genetic
risk for developing a disease.
This genetic potential for developing a disease may be triggered, in
part, by the environment outside of your body, says Philip De Jager,
MD, PhD, director of the Program in Translational Neuropsychiatric
Genomics in the Brigham and Women’s Hospital Department of
Neurology and Psychiatry.
“You have a certain genetic risk that doesn’t change, but the likelihood of getting a disease is also influenced by other factors that you
experience over the course of your life,” he says.
De Jager studies multiple sclerosis (MS) and aging-related cognitive
decline, both of which are believed to be influenced by multiple
genetic and environmental risk factors. Today’s research seeks to
identify genes involved in a disease process and whether those genes
also relate to the development of other diseases.
Genes and risk scores
In January 2008, with funding from BWH, De Jager initiated the
Phenogenetic Project as a resource for the hospital’s research community to study the effects of genetic variation in healthy people.
The name, Phenogenetic Project, refers to the project’s core mission
to support the study of human phenotypes—specific traits such as
risk of MS or someone’s eye color—and those traits’ relationship to
variation in genes.
All data for the project becomes public and is available to researchers.
Today, more than a dozen labs use the archive of human samples
and database.
The samples collected allow researchers to screen participants and
call in those individuals who have genetic variants they want to
study. The National Institutes of Health has provided funding for
De Jager and his colleagues to produce data during the next two years
on 600 people from their sample collection. They will generate the
first human atlas that relates human genetic variation throughout
the genome to detailed records of the expression of molecules inside
human immune cells, of proteins on the surface of the cells, and of
the responses of certain immune cells when stimulated.
By JENNIFER NEJMAN BOHONAK
Neurosciences Research Center
photo: Stu Rosner
Philip De Jager, MD, PhD, and his colleagues are
developing a model to predict a person’s risk of
developing multiple sclerosis.
De Jager predicts that by the end of 2010, they will have a better
model. The model is not useful in clinical settings today, but one day
may become part of doctors’ evaluations.
This summer, in another stream of research, De Jager’s lab will begin
recruiting 5,000 healthy, first-degree relatives of MS patients to
determine the tool’s effectiveness at predicting whether people with a
high risk score will develop the disease. They will do this by looking
at intermediate phenotypes. Intermediate phenotypes are expressions
of genetic traits, such as subtle changes in blood tests or MRI studies
that correlate with characteristics of a disease, but do not mean that a
person will absolutely develop that disease.
With a growing body of research pointing to overlapping genetic
connections between inflammatory diseases, the Phenogenetic Project
will serve as a powerful tool for investigation. Scientists do not understand just yet how the connections work, but they know, for example,
that in families with a history of one inflammatory disease, such as
MS, they are more likely to see other inflammatory diseases. And they
wonder about the connections between MS and other neurodegenerative diseases such as Alzheimer’s.
In an effort to translate the results of their gene discovery efforts,
De Jager and his colleagues have also developed a genetic risk score
for MS that could be applied to other diseases. The score estimates a
person’s genetic risks based on the gene variants that they carry in
their DNA and also considers environmental factors such as smoking
and exposure to the Epstein-Barr virus, which causes mononucleosis
and may have a role in triggering MS. Physicians can then gauge
whether a person’s risk is greater than that of the general population—a move toward a more personalized interpretation of one’s
risk of developing MS.
Silent signals
MS often launches silently with no outward symptoms. Brain lesions
are its calling cards. Lesions appear in the brain and swell. Tissue is
destroyed. Over time, the brain repairs itself, but, when MS symptoms occur, the effect on a person’s life and family can be devastating, even if symptoms are temporary. The disease most often strikes
people in their 30s, who are in the prime of their lives, juggling
careers and families, and it is more common in women. Symptoms
include fatigue, loss of balance, weakness, and cognitive problems.
Early intervention can stop the inflammation and, hopefully, delay
the neurodegenerative aspect of the disease, De Jager says.
“Everybody’s brain shrinks over time. But this process appears to be
accelerated in MS. You can measure this accelerated atrophy of the
brain by MRI,” he explains. “You can see that some people with MS,
even in their 30s, have an accelerated shrinkage of their brain, and
this loss of brain volume correlates with disability.”
BWH scientists are now beginning to turn recent discoveries of MS
genes into tools that could one day help the assessment of people at
risk for MS, but, as yet, they cannot determine, from a person’s genes,
who will have a benign course and who will have a severe course or
who will respond to a particular treatment. That is our next endeavor,
De Jager says. l
To make a gift to support genetic research, please contact the
BWH Development Office’s Nan Doyle at 617-424-4307 or
[email protected].
brink 10 > Measuring Genetic Risk
15
Bright Ideas,
BRIght Futures
Seed money supports gifted scientists so they can strategize for success
Researchers’ lives can be filled with uncertainty—at least when it comes to funding.
They spend their days conducting time-consuming experiments and wrestling with
reams of data, all to tackle critical questions that could change medicine.
How important is cigarette smoking to developing rheumatoid arthritis?
• Could something in the body called a sodium-magnesium transporter be a biomarker
for type II diabetes?
• Might huge amounts of vitamin D or fish oil reduce the risk of getting lupus?
•
But without funding, these important projects come to a screeching halt.
Leaders at the Biomedical Research Institute (BRI) of Brigham and Women’s Hospital
recognize that federal monies fluctuate and competition for awards is fierce. “Creative
approaches that might get left by the wayside need the foresight of thought leaders in
private philanthropy,” explains Jacqueline Slavik, PhD, BRI executive director.
Our BRIght Futures Fund, supported both by the hospital and our generous donors,
seeds biomedical research and bolsters the passionate people who make the life
sciences their life’s work. BRI researchers are eligible for BRIght Futures
Awards—of up to $50,000—for innovative, exploratory lines of study that
may be too risky for prime-time grant funding.
Some young researchers may be transitioning out of a postdoctoral fellowship to start their own labs, while others may
have submitted a competitive grant proposal to the
National Institutes of Health (NIH) but only narrowly missed approval. Some researchers could
be launching a career and a family simultaneously; others may need funds to bridge the
gaps between the conclusion of one grant
and the beginning of the next. The BRI
BRIght Futures Fund targets our best
and brightest scientists so they can
continue to reach conclusions that alter
how medicine is practiced.
By Noelle shough
BRI BRIght Futures Fund
photos: Jeff Thiebauth, Larry Maglott
Support a scientist!
If you are interested in supporting
a researcher through the BRIght
Futures Fund, please contact
BRI Director of Development
Nan Doyle at 614-424-4307
or [email protected].
Jose R. Romero, PhD
Karen Costenbader, MD, MPH
The making of a scientist
Jose R. Romero, PhD, has spent his entire
scientific career at BWH. “I started here at
the Brigham in the ‘80s as an undergraduate
student from the University of Puerto Rico.
I’ve had great support my whole time here
from a lot of people,” he says.
Last year, Romero was continuing his work
looking at possible biomarkers that would
help physicians further classify type II diabetes. Special transporters move ions across
the cell membrane to maintain proper levels
of sodium, magnesium, and potassium in the
body. Romero is examining how these transporters might alter the level of magnesium in
the blood, which could adversely affect someone with type II diabetes—or even cause the
diabetes in the first place.
Unfortunately, Romero was unsuccessful in
his original research grant application to the
NIH. Then, he got holdover funding from
the BRI. “The money allowed us to complete additional experiments, propose some
new things, and we resubmitted and got a
significantly better score,” he explains. As
BRINK went to press, he had one NIH grant
funded, with a second highly likely to obtain
financial backing as well.
But the BRI BRIght Futures Fund did more
than give Romero a second chance at his
grant. “Just as critical, it allowed me to
interact with [BWH cardiologist] Dr. Rich
Lee, who gave me a lot of interesting
pointers to hone my idea,” says Romero.
Romero praises the support of Lee and other
great mentors he’s had during his BWH
career. The BRI’s structure encourages collaboration, making it easier for scientists
to share ideas and results across disciplines.
Also noteworthy, the BRI led Romero to
prestigious awards to support another
passion of his—training and mentoring
minority students in translational medical
research. Romero’s mentoring has even
been recognized by a nomination for the
Excellence in Mentoring Award from
Harvard Medical School.
Filling the grant gaps
Even while she was still a medical student,
Karen Costenbader, MD, MPH, found autoimmune diseases such as systemic lupus
erythematosus and rheumatoid arthritis
(RA), in which the body’s immune cells
attack healthy cells, intriguing diseases. “I
wondered, ‘Why do predominantly young
women get these rare diseases? Why are
they more prevalent in non-Caucasians? And
why are they so much more severe in some
people?’ ” Costenbader focuses on the complex recipe of genetic factors and environmental exposures for better understanding
both lupus and RA.
Unfortunately, she was a victim of ill-timing
when it came to research grants. “Last year,
I had two grants finish up in June. I was writing new grants like crazy, but I was also on a
private training program at Harvard Medical
brink 10 > Bright Ideas, Bright futures
17
School.” When the grants ended, it would
leave her—and her research team—high
and dry.
Thanks to funding from the BRI, she was
able to continue her research without pause.
“As it turned out, I only needed the BRI
‘bridge’ funding for three months, and then
three new grants came through,” she says.
Now Costenbader has her hands full. In
addition to her other research, she’s examining an early indicator of RA called telomere
shortening. Picture telomeres as the ends
of your chromosomes, protecting you from
mutations and genetic damage throughout
your lifetime. Though long when you are
born, telomeres get ever shorter as you age,
Costenbader explains. Women have longer
telomeres than men do, which may explain
why women live longer.
“Certain things drive telomere shortening;
in particular, inflammation does,” she says.
And it’s been shown that people with RA
have shorter telomeres. “I’m looking at which
comes first—the inflammation or the RA or
the telomere shortening.” Armed with that
information, Costenbader could make a real
difference in treating—or even preventing—
this autoimmune disease. l
[Left) Located at the ends of this chromosome
are telomeres, which protect you from genetic
damage and mutation. As you age, these telomeres
shorten—but they may also shorten as a result
of inflammation.
Development office
116 huntington Avenue, 5th Floor
Boston, Massachusetts
02116-5712
(617) 424-4300