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
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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
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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.
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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.
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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.
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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.”
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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.
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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.
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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.
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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
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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?
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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.
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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
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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.
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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
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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.
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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.
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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.
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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
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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
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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 CantĂş 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
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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.
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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
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* 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
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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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