2015 Report to Investors - Children`s Discovery Institute

2015 Report to Investors
Wonder
at Work
A
every child inspires
us to collaborate,
to ask why, to wonder
what we can do better
and how, as physicianresearchers, we can
make a difference.
Wonder
at Work
A Message from CDI Leadership
On the cusp of the 10-year anniversary
of the Children’s Discovery Institute (CDI),
it is a good time to reflect on the progress this pediatric
research partnership between St. Louis Children’s Hospital
and the Washington University School of Medicine has made
to understand and seek better treatments and, ultimately,
cures for childhood diseases and disorders.
Since 2006, the CDI has invested more than $45 million
into 142 pediatric research grants. Many of these grants
have been awarded to young School of Medicine physicianscientists who otherwise may not have received funding
to explore their fresh ideas for solving the remaining
mysteries of childhood disease. CDI seed funding has
enabled researchers to generate the preliminary data
and discoveries that helped them compete for extramural
funding from sources, such as the National Institutes of
Health. In fact, they’ve been able to acquire nearly $192
million in funding to continue on their discovery pathways.
What does this mean for the children we treat at St. Louis
Children’s Hospital? It means that we know more about
the molecular basis for pediatric cancers. It means
we’ve been able to leverage the School of Medicine’s
genomics technologies to link childhood diseases of
growth and development, malnutrition, asthma, allergies
and cystic fibrosis to the trillions of microbes that live
in and on the human body. CDI researchers have made
strides in understanding the congenital heart, vascular,
musculoskeletal and lung disorders in many of the children
we treat. They’ve made important discoveries in childhood
diabetes, obesity and metabolic syndrome, as well as in
immune system and infectious diseases.
And, they are just getting started. The second 10 years
of the CDI will build on the synergy that comes with
collaboration despite many challenges. Overall, funding
for pediatric research continues to lag considerably behind
adult disease research, while the cost of all biomedical
research continues to rise. To ensure we can sustain our
momentum, we need your continued support. So, please,
stay engaged with us through childrensdiscovery.org and
encourage others to consider the CDI as an investment
in making the lives of children better in this and every
generation that follows.
Mary C. Dinauer, MD, PhD
Alan L. Schwartz, PhD, MD
Joan Magruder
Scientific Director
Executive Director
President
Children’s Discovery Institute
Children’s Discovery Institute
St. Louis Children’s Hospital
Fred M. Saigh Distinguished
Chair in Pediatric Research
St. Louis Children’s Hospital
The Harriet B. Spoehrer
Professor of Pediatrics
Pediatrician-in-Chief
St. Louis Children’s Hospital
1
as researchers, we
say we don’t know.
we wonder about
disease. we wonder
becomes mutated. w
the developmental
Can our inquiries lead to breakthroughs in our quest to
Because we know we can, we strive for more each
2
we’re the first to
w. so we wonder.
the origins of
er how a gene
we wonder about
al mysteries of life.
create better treatments and cures for childhood disease?
and every day, and we push harder to do better.
3
By analyzing the
genetic material of
patients with cancer,
researchers at
Washington University
School of Medicine
are finding ways to
tailor treatments.
Illustrated view of DNA strands.
we Wonder
4
How we can optimize our ability to
sequence the genome to accelerate
discovery and save more young lives.
5
Dr. Jeffrey Magee
Dr. Joshua Rubin
a conversation with
drs. joshua rubin
and jeffrey magee
Joshua Rubin, MD, PhD, is an associate professor of pediatrics, anatomy
and neurobiology and the co-director of the pediatric neuro-oncology
program at St. Louis Children’s Hospital. He also is the co-founder of
the CDI’s Brain Tumor Bank. Jeffrey Magee, MD, PhD, is an assistant
professor of pediatrics. He was awarded a CDI Faculty Scholar Award
in 2014 to support his research in pediatric leukemia.
6
What questions are your labs
currently pursuing?
Dr. Rubin: My lab has been interested in advancing our
understanding of the mechanisms that drive the genesis of
pediatric brain tumors in order to develop more effective
and less toxic treatments. Over the past few years our
primary interest has been studying the molecular basis for
sex differences in cancer, particularly brain tumors.
we use right now for treating brain tumors have different
efficacies in male and female cells in a tissue culture dish in
the laboratory. Thus, when we see mutations in a particular
gene and think the gene or mutation is targetable, we
should consider how genomics, and particularly patient
gender, might impact our choice of treatment.
More males than females get cancer. This is true across all
ages, not simply a function of the acute effects of circulating
sex hormones. It is also true in all regions of the world, which
means it is not about differences in occupations, activities or
any environmental exposures. And it is true across all races.
We are generating knowledge and cataloging these male
and female differences. This will enable us to design
clinical trials powered to detect them, in an effort to better
understand the mechanisms by which the process of sex
determination affects cancer incidence and outcome.
“When we see mutations
Dr. Magee: My lab is trying to understand how age
affects the mutations that cause childhood leukemia. The
fact that we see different mutations and different types
of leukemia in infants, young children, adolescents and
adults suggests that more is going on during the formation
of leukemia than just a random acquisition of mutations.
If it was random, everyone would get the same types of
leukemia with the same types of mutations irrespective of
age, and the incidence of adolescent and adult leukemia
would be much higher than in young children. In fact, young
children are more prone to leukemia than older children, and
the genetic changes that cause leukemia in early childhood
are much different. There has to be something about
normal early childhood development that accelerates the
process of leukemia formation, but only in conjunction with
specific types of mutations that are not commonly seen in
adolescents or adults.
in a particular gene and think the gene or mutation
is targetable, we should consider how genomics, and particularly patient
gender, might impact our choice of treatment.”
Last year, we published a very exciting paper about germline
(inherited) variations in a gene associated with brain tumor
risk but in a sex-specific fashion. Those variations actually
elevate the risk for females and decrease the risk for males.
That work continues, and we have several projects that are
drilling down into the molecular mechanisms by which the
process of sex determination — the process by which every
cell in your body becomes either a male cell or a female
cell— impacts the mechanisms that regulate growth and
make someone vulnerable to developing cancer.
We also are using genomic analysis to determine whether
specific therapeutic targets are more appropriate in male
versus female patients. We have a substantial body of
evidence to suggest that even the common therapeutics
We rely on mouse models to help us understand how
different stages of development shape a mutation.
Our investigations are focused on genes that instruct
blood-forming stem cells and leukemia cells to divide
indefinitely — a process called self-renewal. Self-renewal
allows normal cells to regenerate the blood system
throughout life. Leukemia cells often inappropriately activate
self-renewal genes to drive their growth. We have found that
certain mutations common among older children really have
little or no effect on stem cells and other immature blood
cells early in life.
Now, flipping back to early childhood leukemia, we are
collaborating with Dr. Todd Druley on his CDI-funded project
investigating genetic changes that cause infant leukemia.
One of the remarkable things about infant leukemia is that it
usually has only one mutation, called an MLL translocation,
7
and the leukemia genome is otherwise indistinguishable
from the patient’s normal cells. This is completely different
from adult leukemia, which usually comprises six to eight
genetic changes.
Dr. Druley has sequenced the DNA of patients with
infant leukemia, and he has found inherited variants that
may shape what the MLL translocation will do. Some of
the normal genetic differences among people may also
predispose to infant leukemia just as some of us have
variants that predispose to high blood pressure or heart
disease. Only in this case, leukemia is occurring in infants
who have multiple harmful variants and who also acquire
an MLL translocation. Moreover, the leukemia needs to
form early in life because the variants do not seem to cause
leukemia in older children or adults. You can see that there
is an enormous amount of complexity that we have to sift
through in order to determine whether one of these “normal”
variants may predispose to leukemia. This has profound
implications both in terms of genetic counseling for patients
who may be at risk and for development of novel therapies.
To sort through all of this complexity, my lab again has relied
on mouse models developed here. We have been able to
engineer combinations of variants into mouse genomes and
test which ones interact with MLL translocations to cause
leukemia. We are developing an efficient pipeline that will
allow us to analyze many different permutations of variants
since one variant alone does not predispose to leukemia.
This adds a powerful functional component to Dr. Druley’s
sequencing efforts and illustrates the benefits of developing
collaborations between investigators who possess different
skill sets.
Dr. Rubin: Jeff and Todd’s collaboration reminds me of
a recent sequencing project performed on specimens from
the CDI Brain Tumor Bank, along with other specimens
from around the world. It uncovered four different types of
medulloblastoma, the most common pediatric malignant
brain tumor, and showed that virtually 100 percent of
patients with a particular type of medulloblastoma, called
WNT, survive regardless of whether they have metastatic
disease. This indicated that we were probably over-treating
those patients. So, for the very first time since the 1950s,
when radiation therapy was introduced for medulloblastoma,
patients with WNT tumors are treated without radiation. This
is a huge change, considering that radiation therapy is so
damaging to young brains.
Image of genetic data.
Even though the two of you are focused
on different pediatric cancers, does your
work inform the other?
Dr. Rubin: I think there are relevant parallels. Both
pediatric brain tumors and leukemia are characterized by
mutations that don’t occur whenever these cancers occur in
adults, even though they look the same under a microscope.
Also, both of us work with malignancies that may involve
single mutations that affect gene expression across the
genome and are key determinants of what we refer to as
the cell state.
“With CDI subsidies for
genome sequencing
and genome editing, we
are able to take our
ideas and make
them bigger.”
8
And, just as there are types of leukemia that are agegroup specific, brain tumors can be age and brain-region
specific. It’s about susceptibility to the deleterious effects
the mutations presumably have with equal frequency
in all regions, but there are only particular windows of
vulnerability for particular mutations.
If the CDI did not exist, do you think the
projects you described here would have
received funding?
Dr. Magee: What the CDI has allowed me to do is
branch out and to pursue new lines of investigation that
would have been deferred without the CDI. For example,
the MLL project I talked about is a completely new area of
investigation for my lab. It needed preliminary data to get
up and running. The CDI seed funding helped my lab get
established and gave us the resources to try some things
that didn’t directly relate to other studies I pursue. Funding
new directions is where CDI has helped young investigators
distinguish themselves.
Dr. Rubin: In the area of pediatric brain tumors, the
biggest contribution the CDI has made is its investment in
the Brain Tumor Bank, a core resource that has informed
far-reaching research projects. So, in my mind, what
distinguishes the CDI is its support for infrastructure, like
the Brain Tumor Bank.
Dr. Magee: Yes, I agree with Josh. The importance of
these core initiatives cannot be overstated. There are
technical services – for example, tumor banking, sequencing
and mouse genome editing – that are best handled in a
centralized facility by people who perform the techniques
all day, every day rather than conducting experiments.
These services are obviously expensive, and that can be
rate limiting. With CDI subsidies for genome sequencing and
genome editing, we are able to take our ideas and make
them bigger. We can take something that we might have had
the funding to pursue at only one level and take it further to
really answer important questions.
wonder at
work: colin
schlereth
Drs. Rubin and Magee are fighting
for kids like Colin
At age 10, this hockey enthusiast knows his way
around an ice skating rink. That’s why, in early
December 2013, when skating suddenly became
a struggle for Colin, his parents, coaches and
teammates noticed. A cross-check from behind
during a hockey tournament resulted in a fall and
concussion. After 10 days, he was back on the
ice, but still not skating with his usual confidence
and balance. When he started complaining of
headaches and dizzy spells, his mom decided
to take him in for an MRI at St. Louis Children’s
Hospital. Before they knew it, the Schlereths were
meeting with the neurosurgeon on call. Colin was
diagnosed with a
brain tumor — stage 4
medulloblastoma.
After recovering from
surgery to remove
the tumor, Colin
had six weeks of
proton beam therapy
before beginning
nine rounds of
chemotherapy. It has
been a brutal journey.
The radiation affected Colin’s ability to retain and
retell stories. He loses focus more easily in school.
The chemotherapy drugs left him feeling sick,
exhausted and unable to enjoy food. But, through
it all, Colin and his family have found a way to get
through it by relying on laughter, smiles and a
fighting spirit.
9
The totality of
microorganisms and their
collective genetic material
in or on the human body –
known as the microbiome –
is unfathomable and ripe
for discovery.
Microscopic view of the small intestine.
we Wonder
10
How the microbial community of a child’s
gut influences the health of that child.
11
a conversation with
drs. barbara warner
and gautam dantas
Barbara Warner, MD, is a professor of pediatrics at Washington University
School of Medicine specializing in newborn medicine. She has several
active CDI projects. Gautam Dantas, PhD, is an associate professor
of pathology and immunology. According to his lab’s website, the
lab “works at the interface of microbial genomics, ecology, synthetic
biology and systems biology to understand, harness and engineer the
biochemical processing potential of microbial communities.”
12
What has made the study of the
human microbiome such a hot topic
for pediatric researchers?
Dr. Warner: I credit Dr. Jeffrey Gordon* for much of
the pioneering work and awakening our interest in the
microbiome and its far-reaching influence on human health.
In collaboration with the Gordon laboratory, Dr. Phil Tarr
and I initially submitted a grant to the CDI to fund the
St. Louis Neonatal Gut Microbiome Project to examine the
role the health of the intestinal microbiome in infancy affects
a child’s health throughout life. It eventually overlapped with
Dr. Gordon’s recent work with the Gates Foundation looking
at the role of microbial community maturation and its impact
on childhood malnutrition in the developing world. Through
this funding, we were able to create a rich collection of
microbial data from a cohort of healthy newborn twins to
begin to fully understand the nature and concentration of
microbes in an infant’s gut.
“Pre-term babies seem
to develop a very
different kind of gut
during early
life. It is packed with organisms that
are more inflammatory
This activity has formed the basis for additional studies
on this campus examining the role of early microbial
colonization and health. The CDI-funded healthy term baby
cohort now serves as a nice comparison group for a preterm
cohort we’ve been amassing. Using what we’ve found in
this group of pre-term babies, we are ready to take the next
step of studying potential interventions for the diseases that
threaten the health of these fragile infants.
How are the microbiomes of a preterm
and a full-term newborn different?
Dr. Dantas: I echo Dr. Warner in crediting Dr. Gordon
Dr. Warner: Typically, what you see in full-term infants
for beginning the world-leading microbiome research
conducted at the School of Medicine today. I also want to
emphasize the importance of the healthy term infant fecal
sample collection through the Neonatal Gut Microbiome
Project and the complementary core of samples from
preterm infants that followed. Building on these incredible
resources, I received a CDI grant in 2011 to study the impact
of antibiotic use on the microbiomes in these two infant
populations. In collaboration with Drs. Warner and Tarr,
my lab has already published two papers on CDI-funded
work on the healthy term cohort, and we have another
big paper under review on our CDI-funded work using the
preterm cohort.
are helpful bacteria. Preterm babies seem to develop a
very different kind of gut during early life. It is packed
with organisms that are more inflammatory in nature.
We have been following these babies after they leave
the NICU so we can determine whether they continue
to carry this aberrant mix of microbes through life, and
develop treatments for these kids that don’t cause
antibiotic resistance.
in nature.”
Dr. Dantas: The reason that’s important is that
early life is an exceptionally critical developmental time.
One week during the first few months of life may be
substantially more important than one week at any other
period of time in life, in terms of human health and disease.
* Jeffrey Gordon, MD, is the Dr. Robert J. Glaser Distinguished University Professor and director of the Center for
Genome Sciences & Systems Biology. His pioneering research on the genomic and metabolic foundations of the
mutually beneficial relationships between humans and their gut microbes has been instrumental in launching human
microbiome projects throughout the world. (Source: wustl.edu) Dr. Gordon also serves on the CDI Board of Managers.
13
Talk about some of the research
spawned from the neonatal gut
microbiome investment.
Dr. Warner: I am amazed by all the trans-disciplinary
research that has resulted. Just five years ago, I would never
have imagined the interest that cohort has received. But now
we have Drs. Rodney Newberry and Avraham Beigelman
using it to help them pinpoint early environmental exposures
that put children at risk for food allergies. And we have
Dr. Leonard Bacharier exploring the connection between
a common respiratory virus and asthma using CDI funding
and samples from that cohort.
Dr. Dantas: One of the newest studies in my lab involves
analyzing the fecal samples of children born to HIV positive
mothers in South Africa. In that country, and much of subSaharan Africa, children born to HIV-positive mothers are
automatically started on sustained antibiotics from birth
through the first year and a half of life. This is done to protect
the kids from potential infections, in case they contract HIV
from their mothers. But no one has ever studied whether
that practice has long-term negative health consequences
for these children.
It sounds like you and your colleagues
are making names for yourselves in this
area of pediatric research. Where do you
go from here?
Dr. Warner: Because of the CDI’s investment in
microbiome research, Dr. Dantas and I, in collaboration
with five other principal investigators, were able to write
a very persuasive grant request to the NIH to study the
systems biology of antibiotic resistance.
Dr. Dantas: In this case, the NIH sent out a request for
applications essentially describing much of the work that
the CDI has already enabled. For instance, we were able
to propose using the 70,000 fecal samples of the preterm
babies that Drs. Warner and Tarr have banked to understand
the short-term and long-term developmental ramifications
of giving nearly all preterm babies antibiotics during the first
24 to 48 hours of life, and a subset of babies many more
courses of drugs during their NICU stay. This builds directly
on our CDI-funded work on microbiome DNA sequencing
of this cohort, reported in our paper currently under review.
For the proposed new study, we now want to expand our
14
Drs. Warner and Dantas collaborate to find solutions to clinical
problems that stand in the way of a child’s good health.
analysis and work toward the goal of being able to advise
clinicians on which specific antibiotics to use with specific
patients based on targeted microbiome diagnostics, to
optimally treat their infections while minimizing negative
impacts on their gut microbiomes.
Dr. Warner: In this way, the CDI is directly responsible
for helping clinicians improve the risk/benefit ratio at
the bedside. It has been a reminder of the importance
of scientific inquiry, and certainly has encouraged
collaborations like ours, bringing clinicians and lab
investigators together to find solutions to clinical problems.
Dr. Dantas: When I started at Washington University,
I could never have envisioned bringing a clinician into my
“I can now envision a time when there’s not a
huge division in perspective between clinicians and basic
science researchers:
when a clinician won’t hesitate to bring a basic science question to me and I start to always consider the clinical translational potential of
our work.”
lab. But now, because of the CDI, I work regularly with
Dr. Aimee Moore, a neonatologist, who brings clinical
problems in for a closer look. Now, like the NIH grant
submission I just mentioned, Dr. Warner and I don’t have
to wonder what a collaboration of this nature would look
like because we’ve already done it many times. I can
now envision a time when there’s not a huge division
in perspective between clinicians and basic science
researchers: when a clinician won’t hesitate to bring a basic
science question to me and I start to always consider the
clinical translational potential of our work.
fighting
hunger
from the
frontlines
Indi Trehan, MD, MPH, DTM&H,
pediatrics, CDI Faculty Scholar;
Mark Manary, MD, the Helene B.
Roberson Professor of Pediatrics
A commitment to make a
difference in the world by
eradicating global diseases
of poverty, led Dr. Indi
Trehan to Washington
University School of
Medicine to work on the
research team of Dr. Mark
Manary, a Washington
University School of
Dr. Trehan in Malawi.
Medicine pediatric
emergency medicine
physician who is internationally known for his
research on malnutrition in children. Dr. Trehan
has spent the past three
years with Dr. Manary’s
team in southern Malawi.
With support from the CDI,
they have turned their
attention to environmental
enteropathy (EE). This
inflammatory condition
of the gut causes severe
Dr. Manary in his
malnutrition, stunted
School of Medicine lab.
physical growth and
cognitive development, frequent infections and
decreased response to vaccines. The CDI grant
supports their efforts to study whether something
as simple as introducing readily available legumes
and common beans to a baby’s diet could help
stem the tide of EE.
“We know that legumes have a palatable balance
of protein, dietary fiber, starch, minerals, vitamins
and antioxidants. The question is will they make
enough of a difference,” Dr. Trehan says.
15
The CDI has invested
$4.6 million in its
Faculty Scholar Program,
giving 16 young pediatric
researchers the funding
needed to test their
bold ideas.
we Wonder
16
Where do they go from here?
17
a conversation with
dr. beth kozel
As we approach the 10th anniversary of the CDI, we look back at
some of the accomplishments of our Faculty Scholars. A conversation
with Beth Kozel, MD, PhD, pediatrics, named a Faculty Scholar in 2011,
seemed like a good place to start.
18
The NIH recently chose you to become
a Lasker Clinical Research Scholar. What
does that mean for you and your career
as a clinician-researcher?
Dr. Kozel: First of all, I’m thrilled and honored to receive
this award, which was designed to nurture the next
generation of translational researchers. I’m very fortunate
in that the appointment gives me the flexibility to continue
to see patients in the Williams Syndrome Clinic at St. Louis
Children’s Hospital while allowing me to accelerate my
research into the vascular problems associated with Williams
syndrome. I was drawn to apply because the award gives
early-stage investigators a chance to develop into leaders of
translational research and builds on what I’ve already been
doing in my CDI-funded lab. For the next five to seven years,
I will apply what I’ve learned through animal models in my
lab here and apply that knowledge to clinical studies at the
NIH Clinical Center, the nation’s largest hospital devoted
entirely to clinical research. It attracts patients from all
over the world. That’s important for a researcher hoping
to perform translational research on a rare disease. The
idea behind the award is to return clinical researchers to
their former academic medical centers with the skills and
the extramural funding needed to continue their
translational research.
Is the overarching goal of the Lasker
program to have more people who can
go back and forth between the bench
and the bedside?
work and animal studies, and that ultimately is the type
of experience the NIH set out to find when it created this
award. Being a Faculty Scholar gave me the opportunity
to conduct the preliminary studies I needed, to gather
verifiable data and to publish a fair number of papers in a
short period of time.
But that’s far from all my CDI Faculty Scholar award has
spawned. Through my research I’ve been able to collect
DNA samples from more than 200 patients with Williams
syndrome. That’s a huge cohort for a rare disease. It’s
the infrastructure necessary to not only explore the
vascular aspects of the disease, which I’m interested in,
but to collaborate with a wide range of other Washington
University School of Medicine investigators. For example,
it gives investigators looking into the neurocognitive aspect
of the syndrome access to data they need to conduct their
own studies … and not just on Williams syndrome. Since
patients with Williams syndrome typically are hyper social,
studying their DNA and psychosocial features may serve
as a good counterpoint to those of patients on the autism
spectrum. So, we will be able to re-mine the same data to
answer questions that we haven’t even thought of asking
today. It’s all very exciting. And I’m so happy to contribute.
Dr. Kozel: Exactly. More translational researchers at more
institutions is a good thing for medical discovery. And, the
ability to keep seeing patients in the Williams Syndrome
Clinic here means that I can enlist some of those patients
into the NIH clinical research. The award’s funding will cover
their expenses to travel and stay at the clinical center while
I perform the imaging or other studies I need to advance the
research. It’s creates some great synergy.
How big of a role did your CDI Faculty
Scholar award play in you receiving this
honor from the NIH?
Dr. Kozel: Oh, it wouldn’t have happened otherwise.
The CDI has supported everything we’ve done in terms of
helping me establish my lab and the Williams Syndrome
Clinic. Through the CDI, I’ve been able to pursue clinical
“I was drawn to apply because the award gives
early-stage investigators a chance to develop into leaders of translational research and builds on what I’ve already been doing
in my CDI-funded lab.”
19
more faculty scholar
achievements
After kick-starting their research endeavors as Faculty Scholars,
the CDI celebrates their success and contributions to pediatric
medicine over the past nine years.
Ying (Maggie) Chen, MD,
PhD, medicine, is using her 2013
Faculty Scholar Award to pursue
studies on genetic forms of nephrotic
syndrome. This condition results from
inherited defects in certain proteins
that cause endoplasmic reticulum
(ER) stress in kidney podocyte cells,
which damages kidney function. Her overarching goal is to
develop biomarkers for the early detection of podocyte ER
stress and drugs that reduce that stress. Dr. Chen recently
received multiple career development awards from the
Doris Duke Charitable Foundation, Nephrotic Syndrome
Study Network (NEPTUNE) and Central Society for Clinical
and Translational Research (CSCTR). She was also awarded
grants from the American Society of Nephrology/Halpin
Foundation and the National Institutes of Health (NIH).
Megan Cooper, MD,
PhD, pediatrics,
received a Faculty Scholar
Award in 2010 to study
the natural killer cell — a
major cell in human innate
immune response — and
find ways to enhance its
20
immunologic memory. Today, her overall research goals
are to explore this critical component of the immune system
and to identify defects of the immune system of children
with autoimmune disease and immune deficiencies. Her
work has contributed to medical journals, including Blood
and the Journal of Clinical Immunology.
Brian DeBosch, MD, PhD,
pediatrics, a 2014 Faculty Scholar,
studies the role of enderocytes, the
cells lining the gastrointestinal tract,
in metabolism and controlling levels
of a metabolite called uric acid. If
not regulated properly, uric acid
may cause childhood pre-diabetes.
His recent work has been published in
Nature Communications and other top
medical journals.
Todd Druley, MD, PhD,
pediatrics, was named a 2010
Faculty Scholar to better understand
how rare genetic variation influences
the onset and treatment of complex
diseases, particularly childhood
leukemia. Results from that study
propelled Dr. Druley on to garner
extramural funding from the American
Cancer Society, the Doris Duke Charitable Foundation
(Clinical Scientist Development Award) and Hyundai Hope
on Wheels.
Jennifer Duncan, MD,
pediatrics, earned her Faculty
Scholar Award in 2008 to research the
origins of congenital heart disease.
Her focus has been on metabolic
regulation of the heart and how a
mother’s nutritional status might affect
fetal heart development. Since her CDI
award, Dr. Duncan’s studies have been
published in PPAR Research, Journal
of Lipid Research, Circulation and Journal of Molecular and
Cellular Cardiology.
Stephanie Fritz, MD,
pediatrics, earned a 2012
Faculty Scholar Award to define how
methicillin-resistant Staphylococcus
aureus (MRSA) is spread within
households of children infected with
this aggressive organism. The goal is
to identify new methods to interrupt
that spread and prevent future
infections. Findings from her study
were published in JAMA Pediatrics
and generated extramural grants
from the Agency for Healthcare Research and Quality
and the NIH.
Christina Gurnett,
MD, PhD, neurology,
a 2007 Faculty Scholar,
used the award to study the
causes of musculoskeletal
birth defects, such as
clubfoot and scoliosis.
Human Molecular Genetics published her research, which
identified genetic risk factors that predispose children to
scoliosis. Since then, she has been awarded funding from
the NIH, Mallinckrodt Institute of Radiology, March of Dimes,
Multiple Sclerosis Society, the Orthopaedic Research
Education Foundation, the University of Missouri Spinal
Cord Injury Research Program and Shriner’s Hospital. A
recently awarded NIH grant will allow her to identify genetic
variants that are associated with severe scoliosis.
Lori Holtz, MD, pediatrics,
is using her 2013 Faculty Scholar
Award to develop a translational
research laboratory to study virusassociated disorders of the developing
childhood gut using metagenomics,
virology and epidemiology techniques.
One such disorder is environmental
enteropathy (EE) associated with
inflammation and flattening of the lining of the small
bowel, leading to malnourishment and stunted growth.
Using advanced techniques to study known and unknown
viruses in stool samples from children with and without EE,
Dr. Holtz discovered that viruses are associated with the
development or maintenance of EE. Her findings on the
dynamics of gut virome early in life recently were reported
in Nature Medicine.
21
Jeffrey Magee, MD,
PhD, pediatrics,
is using his 2014 Faculty
Scholar Award to work
toward understanding
how and why certain
mutations have agedependent effects on stem cells and evolving leukemia
cells. Dr. Magee, who was a St. Baldrick’s Scholar Award
and Hyundai Scholar recipient in 2014, has been published
numerous times in journals such as Nature and Leukemia.
(See the conversation with Dr. Magee on page 6.)
Celeste Morley, MD, PhD,
pediatrics, used her 2010 Faculty
Scholar Award to expand work she
began as a medical student studying
lymphocytes and macrophages, white
blood cells that move through the body
to fight bacteria, viruses and cancer
cells. The award helped her focus on
understanding how the deficiency
of a protein, L-plastin, hampers children’s immunity to
pneumonia. Data from her study was published in journals,
including the Journal of Immunology and Infection and
Immunity. Since her Faculty Scholar Award, she has received
extramural funding from the American Heart Association,
the American Lung Association, March of Dimes, Pfizer, the
University Research Strategic Alliance and the NIH.
Audrey Odom, MD, PhD,
pediatrics, used her 2009 Faculty
Scholar Award to establish her lab
focused on enzymes and signaling
pathways in the malaria parasite,
Plasmodium falciparum. In seeking to
understand what the parasite needs
to make and why it needs to make
it, Dr. Odom has published multiple
papers on her lab’s findings. She
also has been awarded extramural
funding from the Doris Duke
22
Charitable Foundation (Clinical Scientist Development
Award), NIH, March of Dimes and Monsanto.
Laura Schuettpelz, MD, PhD,
pediatrics, received a 2013 Faculty
Scholar Award to pursue studies on
the effects of inflammation on blood
stem cells and leukemia. Her studies
resulted in high-profile publications
in Blood, the Journal of the American
Medical Association and other
journals. Dr. Schuettpelz also received
a Hyundai Scholar Hope Grant and
an Alex’s Lemonade Stand Young
Investigator Award.
Michael Shoykhet,
MD, PhD, pediatrics,
received a 2011 Faculty
Scholar Award to study the
impact of cardiac arrest
on a child’s brain using
innovative research tools.
Dr. Shoykhet’s long-term
goal is to design strategies
first responders and other caregivers can use to protect
a child’s brain during cardiac arrest and preserve quality
of life after recovery. Since his Faculty Scholar Award, Dr.
Shoykhet has been awarded funding from the NIH and The
Laerdal Foundation. His research has been published
in The Journal of Neuroscience, Pediatric Research and
other journals.
Indi Trehan, MD, MPH,
DTM&H, pediatrics, received
a Faculty Scholar Award in 2014 to
investigate whether including nutrientrich legumes in the diet of rural
Malawian children can improve their
growth and health, and reduce signs of
environmental enteropathy, a condition
believed to be caused by chronic intestinal infections and
leading to stunted growth and developmental delays.
These and related projects will enable Dr. Trehan to further
develop as a clinical investigator in global child health,
with an emphasis on nutrition, growth and resilience
against common infections. Dr. Trehan contributed to a
2015 published study in the Proceedings of the National
Academy of Science linking an unhealthy gut microbiome
to acute malnutrition.
23
NEW WONDERS | 2015 RESEARCH PROJECTS
we Wonder
Here are the pediatric research projects the CDI launched in 2015.
If successful, the new test will improve the ability to
assess how patients are responding to treatment and
use the information to optimize that treatment.
Leonard Bacharier, MD, pediatrics;
and Avraham Beigelman, MD, pediatrics
Interdisciplinary Research Initiative
Drs. Bacharier and Beigelman received a grant to
uncover how bacteria in the upper airway and in
the gastrointestinal tract influence the development
of asthma following RSV bronchiolitis. A greater
understanding of the link between the microbiome
and RSV may allow for the development of
microbiome-directed therapies to prevent asthma
and related diseases.
Todd Druley, MD, PhD,
pediatrics
Interdisciplinary
Research Initiative
Dr. Druley will use next-generation
sequencing technology to develop
a new and more sensitive diagnostic test to identify
surviving leukemia cells in chemotherapy-treated
AML patients. He then will compare the new test’s
performance with current methods, using samples
provided by national and international collaborations.
24
Phyllis Hanson, MD, PhD, cell biology
and physiology; Paul Taghert, PhD,
anatomy and neurobiology
Core Large Initiative
This grant opens the door for researchers to take
advantage of sophisticated cellular imaging available
at the new Washington University Center for
Cellular Imaging (WUCCI). Through the initiative, CDI
investigators and members will have the opportunity
to apply for micro-grants to subsidize the use of
WUCCI services. They also will be privy to training on
all instrumental platforms and receive consultation
on experimental design and support for digital image
processing and analysis. The WUCCI will enhance a
broad array of existing and future projects in which
cellular imaging is used to provide a new understanding
of childhood disease studied in all CDI centers.
How we can continue to advance
the understanding of diseases
that threaten childhood.
Kory Lavine, MD, PhD,
medicine
Interdisciplinary
Research Initiative
Ericka Hayes, MD, pediatrics; Philip
Spinella, MD, pediatrics; and Katherine
Steffen, MD, MHS, pediatrics
Educational Initiatives
The spring 2015 funding cycle saw the launch of two
new educational initiatives. The Summer Pediatric
Research in Global Health Translation (SPRIGHT), led
by Dr. Hayes, will support summer students doing
translational work related to global pediatric health.
The goal of the SPRIGHT initiative is to increase both
the number and success of researchers in the field.
Also funded was support for child-based blood
management guideline development, proposed by
Dr. Philip Spinella and Dr. Katherine Steffen. Patient
blood management is an evidence-based approach for
reducing inappropriate blood use to conserve a limited
resource and improve patient outcomes. Drs. Spinella
and Steffen will organize a conference series which
will develop and publish a multidisciplinary consensus
statement for blood management in critically ill children.
This statement will support the goals of the CDI by
improving outcomes and safety in all children needing
a transfusion.
In a study published last year, Dr.
Lavine, an adult cardiologist, found
that blocking inflammatory white blood cells from an
adult mouse’s heart muscle while allowing beneficial
white blood cells in can improve heart function and
promote cardiac recovery. With his CDI funding, he will
investigate if the same is true for young mice. This could
lead to better treatment for children who suffer from
dilated cardiomyopathy (DCM) and don’t respond well
to the heart failure medications prescribed for adults.
Nima Mosammaparast,
MD, PhD, pathology and
immunonology
Interdisciplinary
Research Initiative
Dr. Mosammaparast will work to
advance the understanding of the mechanisms involved
in the formation of pediatric glioblastoma, an aggressive
brain tumor with a very poor prognosis. In children,
these tumors are resistant to chemotherapy drugs that
are effective in treating the adult version of the disease.
Dr. Mosammaparast will focus his work in a newly
discovered enzyme that may enhance the tumor’s
ability to repair its own damaged DNA. Findings from
this research will have implications beyond pediatric
glioblastoma, including numerous other tumors that
are treated with similar drugs.
25
NEW WONDERS | 2015 RESEARCH PROJECTS
Dr. Nichols will work with co-investigators Dorothy
Grange, MD, pediatrics; Gautam Singh, MD, pediatrics;
and Maria Remedi, MD, medicine, to reach the goals of
this study, which is to develop novel treatment options
for this debilitating syndrome and related diseases.
Yi-Chieh Perng, PhD,
medicine
Postdoctoral Research
Fellowship
Rodney Newberry, MD, medicine;
Avraham Beigelman, MD, pediatrics;
Phillip Tarr, MD, the Melvin E. Carnahan
Professor of Pediatrics; and Barbara
Warner, MD, pediatrics
Dr. Perng will use animal models
to study a class of drugs being
developed for other diseases that may be effective
treatments for cytomegalovirus (CMV) infection. CMV
can cause serious illness in newborns and in bone
marrow stem cell transplant patients. If the drugs are
proven effective, more studies will be performed that
could lead to pilot studies in humans.
Interdisciplinary Research Initiative
Dr. Newberry and his co-principal investigators will
examine the development of food allergies and how
they can be prevented. They will look for environmental
factors contributing to food allergies and develop
recommendations for feeding babies, guidelines on
when known food allergens should be introduced and
if early introduction of antibiotics reduces the risk of
food allergies.
Colin Nichols, PhD, cell
biology and physiology
Interdisciplinary
Research Initiative
Dr. Nichols will use his CDI funding
to leverage the first multidisciplinary
clinic for patients with Cantŭ syndrome at St. Louis
Children’s Hospital to test whether drugs used to treat
congenital diabetes can be employed to treat the rare
genetic condition. Cantŭ syndrome is characterized
by excess hair growth, a distinctive facial appearance,
heart defects and skeletal abnormalities.
26
Jessica Pittman, MD, MPH, pediatrics;
and Dmitriy Yablonskiy, PhD, radiology
Interdisciplinary Research Initiative
These co-principal investigators are teaming up to use
sophisticated imaging technology to understand the
process of lung function decline in patients with cystic
fibrosis. They want to determine the impact of antibiotic
therapy on the respiratory microbiota and correlate
structural and functional measures of lung disease,
as well as investigate regional structural changes
associated with disease.
Michael Shoykhet, MD,
PhD, pediatrics
Interdisciplinary
Research Initiative
In collaboration with Dr. Beth Kozel,
Dr. Shoykhet seeks to uncover the
link between vascular stiffness, blood flow to the brain
and neurobehavioral deficits in patients with Williams
syndrome, a genetic condition that can put a child at
risk for stroke. With that knowledge, physicians who
treat Williams syndrome patients will be able to provide
more effective clinical management.
Barbara Warner, MD,
pediatrics
Interdisciplinary
Research Initiative
Dr. Warner will continue her
work toward gaining a greater
understanding of the infant biome. (See the
conversation with Dr. Warner on page 12.)
Josh Rubin, MD, PhD, pediatrics; Albert
Kim, MD, PhD, neurosurgery; Kristen
Kroll, PhD, developmental biology; and
Hiroko Yano, PhD, neurosurgery
Interdisciplinary Research Initiative
This research team will test an innovative hypothesis
that some pediatric brain tumors are associated not
only with genetic changes in tumors, but also with what
are called epigenetic changes. These are environmental
changes that occur on the proteins that regulate how
DNA works in tissue. This project uses the resources of
the CDI-funded Brain Tumor Bank and should enhance
our understanding of what triggers the development
of brain tumors and how best to treat them. (See the
conversation with Dr. Rubin on page 6.)
27
THE WONDER CONTINUES | CURRENT RESEARCH GRANTS
current
research
grants
CONGENITAL HEART
DISEASE CENTER
Carlos Bernal-Mizrachi, MD, medicine
Developmental Origins of Metabolic
Syndrome and Cardiovascular Disease
F. Sessions Cole, MD;
Park J. White MD, Professor of
Pediatrics; Jennifer Wambach, MD,
pediatrics
Genomics of Birth Defects
Patrick Jay, MD, PhD, pediatrics;
Gary Patti, PhD, chemistry
A Modifiable Pathway to Prevent
Congenital Heart Disease
Kory Lavine, MD, PhD, medicine
Opposing Roles for Embryonic and
Bone Marrow-Derived Macrophages
in Pediatric Dilated Cardiomyopathy
Michael Shoykhet, MD, PhD, pediatrics
Survival Strategies in Pediatric Cardiac
Arrest; Effect of Elastin Insufficiency on
Brain Development and Cognition
Christopher Smyser, MD, neurology
Neuroimaging in Infants with
Congenital Heart Disease and Relation
to Neurodevelopmental Outcome
28
McDONNELL PEDIATRIC
CANCER CENTER
Vikas Dharnidharka, MD, MPH,
pediatrics
Next-generation Deep Sequencing in
Post-transplant Lymphoproliferative Disorders
Todd Druley, MD, PhD, pediatrics
Improving Minimal Residual Disease
Surveillance of Pediatric AML Via
Error-corrected Sequencing; Functional
Characterization of Rare Congenital
Variation in Infantile Leukemia
Jeffrey Magee, MD, PhD, pediatrics
Developmental Changes in Stem Cell
Self-renewal Mechanisms and Their Role
in Leukemogenesis
Nima Mosammaparast, MD, PhD,
pathology and immunology
Understanding Mechanisms of Alkylation
Chemoresistance in Pediatric Glioblastoma
Joshua Rubin, MD, PhD, pediatrics;
Albert Kim, MD, PhD, neurosurgery;
Kristen Kroll, PhD, developmental
biology; Hiroko Yano, PhD, neurosurgery
Targeting the Abnormal Chromatin State
of Pediatric Brain Tumors
Laura Schuettpelz, MD, PhD, pediatrics
Elucidating the Role of KLF7
in T-cell Development
CENTER FOR METABOLISM
AND IMMUNITY
Ying (Maggie) Chen, MD, PhD, medicine
Podocyte Endoplasmic Reticulum Stress
in Hereditary Nephrotic Syndromes
Megan Cooper, MD, PhD, pediatrics
Investigation of Somatic Defects in Patients
with Autoimmune Diseases
Brian DeBosch, MD, PhD, pediatrics
Role of Enterocyte Glut9 in Intestinal Urate
Handling and Energy Homeostasis
Dennis Dietzen, PhD, pediatrics
Integration of the Ketogenic-ketolytic Axis
with Metabolic Homeostasis in Newborn
Period and Beyond
Joseph Dougherty, PhD, genetics
Building Tools for Regenerative Medicine
to Specify and Pattern Pluripotent Neural
Crest Cells
Stephanie Fritz, MD, pediatrics
Epidemiology and Prevention of
Staphylococcal Colonization, Infection
and Transmission
Lori Holtz, MD, pediatrics
Defining the Role of Viruses
in Environmental Enteropathy
Mark Manary, MD, pediatrics
Understanding and Ameliorating
Environmental Enteropathy
29
THE WONDER CONTINUES | CURRENT RESEARCH GRANTS
CENTER FOR METABOLISM
AND IMMUNITY (CONTINUED)
Rodney Newberry, MD, medicine;
Avraham Beigelman, MD, pediatrics;
Phillip Tarr, MD, Melvin E. Carnahan
Professor of Pediatrics; Barbara Warner,
MD, pediatrics
Leonard Bacharier, MD, pediatrics;
Avraham Beigelman, MD, pediatrics
Environmental Exposures in Early Life and
the Risk for Food Allergy in Children
Colin Nichols, PhD, cell biology and
physiology
Cantú Syndrome: A Translational Approach
to Mechanisms and Treatment
CENTER FOR PEDIATRIC PULMONARY DISEASE
Upper Respiratory Tract and Fecal
Microbiomes and Recurrent Wheezing
Following RSV Bronchiolitis
Susan Dutcher, PhD, genetics; Steven
Brody, MD, medicine
Novel Approaches for Understanding Ciliary
Assembly in Rare Childhood Diseases
Nicole Gilbert, PhD, molecular
microbiology
Audrey Odom, MD, PhD, pediatrics;
Baranidharan Raman, PhD, MS,
biomedical engineering
Probing Bacterial Vaginosis Sialidase
as a Risk Factor for GBS Colonization
and Fetal Transmission
Towards Noninvasive Diagnosis of Malaria
Infection Through Exhaled Breath Analysis
Amjad Horani, MD, pediatrics
Scott Saunders, MD, PhD, pediatrics;
David Ornitz, MD, PhD, developmental
biology; Brad Warner, MD, Jessie L.
Ternberg, MD., PhD Distinguished
Professor of Pediatric Surgery
Growth Factor Signaling Pathways Regulating
Development of the Small Intestine
Indi Trehan, MD, MPH, DTM&H,
pediatrics
Innovative Interventions for
Improving Childhood Growth and
Environmental Enteropathy
Barbara Warner, MD, pediatrics
Impact of Childhood Intestinal Microbial
Maturity on Nutritional Status and Immunity
30
Characterization of HEAT2 in Ciliogenesis
Amanda Lewis, PhD, molecular
microbiology; Warren Lewis, PhD,
medicine
GBS Hyaluronidase as a Determinant
of Invasion and an Indication of Risk for
Invasive Disease
Celeste Morley, MD, PhD, pediatrics
Defining Host Determinants of Severe
Childhood Pneumococcal Pneumonia
Yi-Chieh Perng, PhD, medicine
Development of Novel Treatment Against
Congenital Viral Infections
Phyllis Hanson, MD, PhD, cell biology
and physiology; Paul Taghert, PhD,
anatomy and neurobiology
Jessica Pittman, MD, MPH, pediatrics;
Dmitriy Yablonskiy, PhD, radiology
Washington University Center for Cellular
Imaging Collaboration with The Children’s
Discovery Institute
Determinants of Change in Lung Function
During Pulmonary Exacerbation and Recovery
in Cystic Fibrosis
Christina Stallings, PhD, molecular
microbiology
Ericka Hayes, MD, pediatrics
The Summer Pediatric Research in
Global Health Translation
Kathryn Miller, PhD, biology
Novel Treatments for Mycobacterial Infections
in Infants and Children
CDI Summer Undergraduate Research
Fellowship Program
Thaddeus Stappenbeck, MD, PhD,
pathology and immunology; Steven
Brody, MD, medicine
Lilianna Solnica-Krezel, PhD,
developmental biology; Jeffrey
Milbrandt, MD, PhD, James S.
McDonnell Professor and Head,
Department of Genetics, Professor of
Pathology & Immunology, Medicine and
Neurology
Isolation, Expansion and Characterization
of Lung Epithelial Stem Cells
MULTI-CENTER GRANTS
Human Pluripotent Stem Cell Core
Todd Druley, MD, PhD, pediatrics; Robi
Mitra, PhD, genetics
Philip Spinella, MD, pediatrics; Katherine
Steffen, MD, MHS pediatrics
Genome Technologies Core
Bradley Evanoff, MD, medicine
Implementation Science Principles to
Develop Blood Management Guidelines
for Critically Ill Children
Research Forum — Child Health
For a complete description of current and completed
research projects, please visit ChildrensDiscovery.org
and select the Research Center of interest.
31
BY THE NUMBERS
financial
highlights
$45 million
invested in research to date
$191.8 million
extramural grant funding obtained
as a result of CDI awards
142 research
grants
awarded since inception
576 published
research papers
Center Award Totals
2006 – 2015
CDI (All Centers)
$7.3 million
Congenital Heart Disease Center
$9.7 million
Center for Pediatric Pulmonary Disease
$7.2 million
Center for Metabolism and Immunity
$13.7 million
McDonnell Pediatric Cancer Center
$7.2 million
from Children’s Discovery Institute
investigators
Grants Held by Department (2006 – 2015)*
Biology — 5
Medicine — 18
Biomedical Engineering — 1
Molecular Microbiology — 5
Cell Biology & Physiology — 5
Neurology — 5
Chemistry — 1
Neurosurgery — 2
Computer Science and Engineering — 1
Obstetrics and Genecology — 3
Developmental Biology — 5
Orthopedic Surgery — 5
Genetics — 7
Pathology and Immunology — 10
Mechanical, Aerospace and
Structural Engineering — 1
Pediatrics — 68
32
* The chart above reflects the department of the primary principal
investigator. It does not include the many collaborators from
other departments who take part in the research grants.
CHILDREN’S DISCOVERY INSTITUTE LEADERSHIP
board of
managers
Raymond R. Van de Riet Jr. — CHAIR
President, Aero Charter Inc.
Dale L. Cammon
Chairman and Co-Chief Executive Director,
Bryant Group, Inc.
Lee F. Fetter
Group President, BJC Healthcare
Joan Magruder (Ex-officio)
President, St. Louis Children’s Hospital
Richard J. Mahoney
Retired Chairman and Chief Executive Officer,
Monsanto Company
Distinguished Executive in Residence,
Weidenbaum Center on the Economy,
Government and Public Policy, Washington
University in St. Louis
James S. McDonnell III
Retired Corporate Vice President,
McDonnell Douglas Corp.
Andrew E. Newman
President, St. Louis Children’s
Hospital Foundation
Chairman, Hackett Security, Inc.
Daniel Getman, PhD
Executive Director,
Children’s Discovery Institute
Retired President, Kansas City Area
Life Sciences Institute
Alan L. Schwartz, PhD, MD
Chairman, Department of Pediatrics
Former Vice President, Pfizer R&D,
Director, St. Louis Laboratories
The Harriet B. Spoehrer Professor
of Pediatrics, Washington University
School of Medicine
Jeffrey I. Gordon, MD
Pediatrician-in-Chief,
St. Louis Children’s Hospital
Dr. Robert J. Glaser Distinguished
University Professor
Director, Center for Genome Science
and Systems Biology
Washington University School of Medicine
Keith S. Harbison
Managing Partner, Alitus Partners, LLC
Jennifer K. Lodge, PhD
Larry J. Shapiro, MD (Ex-officio)
Executive Vice Chancellor
for Medical Affairs and Dean,
Washington University School of Medicine
Kelvin R. Westbrook
President and Chief Executive Officer,
KRW Advisors, LLC
Professor, Molecular Microbiology
Associate Dean for Research,
Washington University School of Medicine
Vice Chancellor for Research,
Washington University
33
NON-PROFIT
ORGANIZATION
U.S. POSTAGE
PAID
ST. LOUIS, MO
PERMIT NO. 858
St. Louis Children’s Hospital Foundation
One Children’s Place, St. Louis, MO 63110
888.559.9699 or 314.286.0988
childrensdiscovery.org
The Children’s Discovery Institute is a multidisciplinary,
innovation-based research partnership between St. Louis Children’s
Hospital and Washington University School of Medicine. Launched
in 2006, the Institute is focused on accelerating discoveries in
pediatric research to ultimately find cures for the most devastating
childhood diseases and disorders. We are entirely donor funded,
And, for that, we say thank you.
Learn more at childrensdiscovery.org.
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