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Protecting childhood with precision medicine 2016 Report to CDI Investors

Protecting childhood with precision medicine Precision medicine – or what some call personalized medicine – focuses on custom treatments for each individual, taking into account the variability in genes, environment and lifestyle. CDI investigators are working to discover the causes of and better treatments for a variety of pediatric diseases — represented by the pattern of dots throughout this report. Just as one dot is highlighted, each researcher is using precision medicine to protect childhood.

A Message from CDI Leadership Whether you are an investor in science or a scientific investigator, it is an incredibly exciting time to be engaged in pediatric research. Between genomics, proteomics, computa-

Your support of the CDI through its first decade has

tional biology, systems biology and bioinformatics, we

makes you a Guardian of Childhood.

meant the world to us, to our talented investigators, to the Children’s Hospital physicians, to the families who count on us to know the answers and is what

have more tools at our disposal than we have ever had to understand the basic science of pediatric disease. We also face challenges. Chief among these is the

Mary C. Dinauer, MD, PhD

shrinking number of pediatricians going into research.

Scientific Director

The stakes are just too high, especially for young

Children’s Discovery Institute

physician/scientists just launching their careers.

Fred M. Saigh Distinguished Chair in Pediatric Research St. Louis Children’s Hospital

This makes institutions like the Children’s Discovery Institute (CDI) critical. Over the past 10 years, the CDI has engaged some of the brightest minds at St. Louis Children’s Hospital and Washington University School of Medicine in the pursuit of understanding the mechanisms and biology of diseases that plague so many childhoods. Generating

Gary A. Silverman, MD, PhD Executive Director

nearly $222 million in extramural grant funding — a 400

Children’s Discovery Institute

percent return on investment — CDI supporters have

The Harriet B. Spoehrer Professor of Pediatrics

put in motion a precision medicine revolution that will continue to spark innovation and deepen our knowledge for decades to come.

Pediatrician-in-Chief St. Louis Children’s Hospital

This report reflects on some of the advances CDI investigators have made in understanding the origins of childhood cancers, pulmonary disease, heart defects and diseases of metabolism and immunity. We also highlight tools and technologies put in place that can move us closer to the practice of pediatric precision medicine. This emerging form of disease diagnosis

Joan Magruder President St. Louis Children’s Hospital

and prevention will use genetic and other individualized information to deliver personalized treatments that strike at the heart of a child’s illness.


Donation to discoveries: a look back Fueled by the investment of impassioned donors, CDI researchers tirelessly pursue better treatments for the most serious childhood diseases. Discoveries do not always happen in a linear fashion. But without research, no knowledge is gained, no progress made. The stalwart support of CDI investors has made the following milestones possible.


“The promise of personalized medicine is that we can become more sophisticated in our understanding of each disease, identify personal variations and tailor therapy to those variations in a way that is likely to be more effective.” ••• D  avid H. Perlmutter, MD, executive vice chancellor for medical affairs and dean of the School of Medicine


From hypothesis to working on the international stage In 2006, Todd Druley, MD, PhD, pediatrics and genetics; and Rob Mitra, PhD, genetics (see page 14), teamed up to find better ways to search for rare genetic variants that could be implicated in infant leukemia. As a pediatric oncologist, Dr. Druley knows that more often than not this disease is too fierce for its tiny victims to fight. The result of this partnership was breakthrough research which showed that babies with leukemia have a genetic predisposition that makes them highly susceptible to the disease. Specifically, the published research showed that every infant with acute myeloid leukemia inherits two damaged copies of the gene MLL3. Today, Dr. Druley’s lab is working to determine the biological impact of MLL3 variants. To do this, he and his colleagues have developed a unique, non-invasive system to study the genetics of every infant St. Louis Children’s Hospital treats for leukemia. “We catch urine, which contains enough cells to grow in the lab, reprogram them to their pluripotent (not-yet differentiated) stem cells and then differentiate them into blood. These cellular


Blood smear showing large acute myeloid leukemia (AML) cells with the smaller red blood cells

models have the exact genetic composition of the children from which they came.” Using this method, Dr. Druley’s lab has shown that MLL3 controls blood development during pregnancy, which leads to the conversion of normal blood to leukemia by mechanisms currently unknown. This finding will not only improve clinicians’ ability to treat the disease but also will expand the world’s collective knowledge about normal human blood development.

The result of this partnership was breakthrough research which showed that babies with leukemia have a genetic predisposition that makes them highly susceptible to the disease.


From banking brain tumors to a brain trust of insight In 2007, the CDI funded the Pediatric Brain Tumor Bank to overcome the difficulty in obtaining and culturing brain tumor cells. With that grant, Joshua Rubin, MD, PhD, pediatrics, and Jeffrey Leonard, MD, neurosurgery, created a repository of brain tumor tissue connected to individual patient data that is updated as the patient’s treatment progresses. This continuously monitored specimen-patient linked data has been enormously valuable as the understanding of brain tumors in children evolves. Since that time, Dr. Rubin has acted as principal or co-principal investigator for five other CDI grants. Through his work on the role a child’s sex plays in tumor development, Dr. Rubin’s lab is amassing a substantial body of evidence to suggest that even the more common therapeutics used now for treating brain tumors have different levels of effectiveness in male and female cells. Early on, his research discovered that a molecule called cyclic AMP, which is important in the development of brain tumors, is regulated in different ways in the brain cells of males vs. females. Knowledge generated from his work on sex differences in brain tumor development will inform the design of clinical trials. Dr. Rubin is currently working with Rob Mitra, PhD, genetics, on a study of the link between cellular identity

and the activity of super enhancers, the roughly 300 regions in DNA that regulate cell type-specific gene expression. Read more about this ground-breaking work on page 14. Moving forward, Dr. Rubin will lend his expertise to a new CDI-funded study designed to identify the biomarkers of cognitive deficits in survivors of pediatric brain tumors. Dr. Rubin and co-principal investigator Brad Schlaggar, MD, PhD, the A. Ernest and Jane G. Stein Professor of Neurology and neurologist-in-chief at St. Louis Children’s Hospital, will apply advanced neuroimaging and computational analysis to identify reliable biomarkers of risk for cognitive deficits in children treated for brain tumors. Cognitive deficits are the single greatest detractor from the quality of life for these patients. This study aims to develop the necessary tools to enhance cognitive recovery. “For years now, we have monitored and measured the damage that occurs in the brains of children after treatment for tumors,” Dr. Rubin says. “Sometimes that damage is minimal. Sometimes it’s devastating. The CDI recognizes that with the imaging and computational capabilities we have at the Washington University School of Medicine, we are uniquely positioned to assess how the treatment of the tumors and the tumors themselves contribute to cognitive deficits.”



From repairing heart defects to new reasons to exercise The heart is the first embryonic organ to develop, just a mere 10 weeks post-conception. And its early emergence has always stymied researchers looking for ways to prevent heart defects. “The damage is done before we even know it has started,” Patrick Jay, MD, PhD, pediatrics, told the New York Times in April of 2015. The Times was covering Dr. Jay’s research published in Nature a week earlier. That research had its genesis in a 2013 CDI grant enabling Dr. Jay, co-principal investigator Gary Patti, PhD, chemistry, and colleagues to explore innovative ways to lower the risk of congenital heart disease. When Dr. Jay established his School of Medicine laboratory 12 years ago, he wanted to learn why the same genetic mutation can cause a mild heart defect in one mouse and a severe form of the same defect in another. Since it was already known that women over 35 are more likely to have babies with heart defects, he thought he’d start by asking a simple question: Does a heart defect develop in a baby because of maternal age or because of the age of the mother’s eggs? Dr. Jay knew that if it turned out to be latter, the genetic mutation would be there from the beginning of the female’s embryonic development, and therefore next to impossible to prevent. But if the genesis of the disease came from the environment the mother 6

provided the fetus, maybe the mother could do something to alter that environment. To find the answer, Dr. Jay’s team conducted a first-of-its-kind experiment. Using both young and old mice bred to have a genetically high risk of delivering pups with heart defects, they conducted an ovary/ egg swap. The young ovaries with the young eggs were transplanted into the older mice and vice-versa. The results showed that older mothers had a higher incidence of pups with heart defects, regardless of the age of their eggs. So what was it about those older mothers that put their babies at risk? Was it diet? Further experiments showed that being fed a high-fat or low-fat diet had nothing to do with the risk of heart defects. But, what about exercise? After installing exercise wheels in half the genetically modified mice, young and old, what the researchers found made pregnant women take notice. For reasons yet to be tested, such as how exercise alters the workings of some genes, older mice who were given the chance to exercise had far fewer young with heart problems than did older sedentary mice. While Dr. Jay cautions that more research needs to be done to see if those results hold true in humans, it’s a step in the right direction toward an end to congenital heart defects.


From dangerous disease to hope for premature infants In 2009, with funding from the Children’s Discovery Institute, Barbara Warner, MD, pediatrics, along with Phil Tarr, MD, the Melvin E. Carnahan Professor of Pediatrics at Washington University School of Medicine, launched the St. Louis Neonatal Gut Microbiome Initiative. Their goal was to follow a cohort of healthy infant twins over their first year of life to examine the role early microbial colonization has on a child’s health and well-being. Dr. Warner hoped to use the knowledge gained from this undertaking to understand how that process might go awry in premature babies. During her career as a neonatologist, she’d seen too many of these tiny infants fall victim to a lifethreatening intestinal infection, called necrotizing enterocolitis (NEC). Thanks to Dr. Warner’s and Dr. Tarr’s efforts, the pediatric community now knows that the population of bacteria in babies’ gastrointestinal tracts may depend more on their biological makeup and gestational age at birth than environmental factors. Their research showed that bacterial communities assemble in an

“The Holy Grail is prevention, and if so much of what happens in the gut depends on the host, this research may help us identify just what increases an infant’s risk for developing NEC and help us target therapies.” ••• Dr. Barbara Warner orderly, choreographed progression, with the pace of that assembly slowest in infants born most prematurely. That’s important because, according to the researchers, early colonies of gut microbes make the most impact on long-term health. “The Holy Grail is prevention, and if so much of what happens in the gut depends on the host, this research may help us identify just what increases an infant’s risk for developing NEC and help us target therapies,” Dr. Warner says.

3D representation of gut bacteria microbiome



From curiosity to breakthroughs in understanding malaria Malaria causes a tremendous amount of global suffering. More than 500 million people become ill with malaria every year and more than one million die. Most of these deaths are in young children under the age of 5. Most severe malaria is caused by a parasite called Plasmodium falciparum. Because the parasite has become resistant to commonly used drugs, such as chloroquine, new drugs need to be added to the development pipeline. Audrey Odom, MD, PhD, pediatrics, received a CDI faculty scholar award in 2009 to examine the route by which the malaria parasite generates isoprenoids. This group of compounds has many important jobs within the cell, and disruption of this pathway will kill the parasite. Soon, Dr. Odom and her colleagues found one way the malaria parasite becomes resistant to fosmidomycin, an antimalarial drug in clinical trials. The lab has received multiple NIH grants stemming from this work. Her work quickly caught the attention of the Doris Duke Foundation, which awarded her their


Most severe malaria is caused by a parasite called Plasmodium falciparum. Because the parasite has become resistant to commonly used drugs, such as chloroquine, new drugs need to be added to the development pipeline.

prestigious Clinical Scientist Development Award. The award came with $486,000 to continue her discoveries. Additional breakthroughs have followed. Dr. Odom and her colleagues recently found that when Plasmodium falciparum infects red blood cells, it produces lemon-scented chemicals that may lure mosquitos to their host. It remains to be determined whether that makes a difference in the success of the parasite. Fortunately, a new five-year $500,000 award from the prestigious Burroughs Wellcome Fund will help her find out.


Rendering of the release of malaria parasites from a red blood cell


From gene discovery to better diagnostics of a rare lung disease It all began with a single child who had a “bad cold.” Tom Ferkol, MD, the Alexis Hartmann Professor of Pediatrics, was asked to see a young infant from an Amish community who had persistent nasal congestion and a cough. She was later found to have primary ciliary dyskinesia (PCD). This rare inherited disease, characterized by an inability of motile cilia — tiny hair-like structures that line the airways — to do their job of sweeping mucus and trapped bacteria from the lungs. Cilia are a primary defense of the lung and upper airway, and children with PCD frequently have persistent infections of the lung, middle ear, and paranasal sinuses. When Dr. Ferkol learned that the child was not unique and others from the community also had features consistent with PCD, he recognized that there was an opportunity to uncover the genetics of the disease. A CDI grant in 2008 gave Dr. Ferkol and a team of collaborators from across the Washington University Danforth and School of Medicine campuses the resources necessary to better understand PCD. From the beginning, Dr. Ferkol worked closely with investigator Steven Brody, MD, medicine, who received CDI funding to head up the institute’s Airway Epithelial Cell Core. Established in 2007, this resource provides CDI researchers with valuable models for the

study of lung disease. Through Dr. Brody, Dr. Ferkol met Susan Dutcher, PhD, genetics and current director of the McDonnell Genome Institute, who has spent most of her career trying to understand how algae swim. Under an electron microscope, the flagella in algae look like human cilia. In fact, according to Dr. Ferkol, 30 of the 32 genes that have been linked with PCD to date in humans have ortholgues in algae. The focused exploration of Amjad Horani, MD, pediatrics — and past Martin K. and Jill F. Sneider Endowed Fellow, working with Dr. Ferkol — identified a genetic error in HEATR2, a previously unknown gene. The defect could be reproduced in algae. The finding gave clinicians the culprit they needed to provide accurate diagnoses for this Amish community and other children who have PCD. The HEATR2 discovery led to Dr. Horani’s CDI-funded exploration of how mutations in that gene alter the structure of cilia and affect the motors that power them to beat. “Ultimately, we want to identify all the genes associated with PCD,” Dr. Ferkol says. “That will be a huge step toward improving diagnosis and allowing us to better connect genotype with the child’s clinical phenotype.”


Centers of research at the core of discovery Big data and advances in technology make precision medicine possible. The core facilities at Washington University provide CDI researchers with the resources needed to maximize efficiency and an optimum environment to achieve breakthrough discoveries.


“The human genome is a history book — a narrative of the journey of our species through time. It’s a shop manual, with an incredibly detailed blueprint for building every human cell.” ••• Dr. Francis Collins, director, National Human Genome Research Institute


Meet the Future: New Models, New Methods Zebrafish Facility As the Alan A. and Edith L. Wolff Distinguished Professor of Developmental Biology and head of the Department of Developmental Biology at Washington University School of Medicine, Lilianna Solnica-Krezel, PhD, is in a unique position in what she calls a unique time in science. She says the knowledge and technology are in place to gain a deep understanding of what goes on inside embryos at many stages of human development using animal model systems and human pluripotent stem cells. Her research is focused on uncovering the signals that determine the fate of cells in the early embryo and how those signals guide cells down paths that ultimately help shape, for example, the brain, the heart or blood. Toward that goal, she played an important role in studies that established zebrafish as a major organism in science. Under Dr. Solnica-Krezel’s leadership, the School of Medicine has built one of the largest and most automated zebrafish facilities in the world, which she oversees along with Kelly Monk, PhD, developmental biology, and other researchers employing the zebrafish model. Dr. Monk’s own research is focused on myelin, the layered tissue that forms a protective sheath around nerve cells. “When I was a university student in my native Poland, the first genes that controlled embryonic development were being identified in the fruit fly,”


Dr. Solnica-Krezel says. “Now, 30 years down the road, we know of thousands of genes that are driving development in model systems. Moreover, sequencing genomes of pediatric patients and their families identifies an avalanche of candidate disease genes. Zebrafish emerged as a very useful model in which to identify new genes involved in human development, but also to validate candidate disease genes from human genetic studies and to screen for candidate therapeutics.” Why zebrafish? As vertebrates, the genetic similarity to humans makes zebrafish excellent for observing disease processes. Compared to rodents, zebrafish produce a larger number of offspring in each generation. Plus, zebrafish offspring also grow and develop very quickly. Innovative robotic feeding at the School of Medicine’s facility fuels that growth rate. Zebrafish are transparent and develop outside their mothers, which makes following genetic mutations much less invasive. And, with recent developments in genetics, it is easy to introduce changes to their genes. CDI funding in 2016 has helped support the use of the zebrafish facility by CDI researchers to study pediatric disease. With the rise and affordability of genetic sequencing, a CDI researcher seeking to understand the development of disease, can sequence the genome of patients with that disease. That work often leads to the discovery of several gene changes. To narrow down the candidates, researchers can


efficiently and inexpensively disrupt those specific genes and even introduce the same specific gene changes in the zebrafish model and watch what unfolds. For example, Children’s Discovery Intstitute funded researcher Todd Druley, MD, PhD, pediatrics, has been analyzing the sequencing data in infants born with leukemia, a blood cancer that is often fatal in these vulnerable new lives. His lab has uncovered several gene variants he suspects cause blood cells to develop incorrectly. Zebrafish models will enable Dr. Druley’s lab to screen each of these gene variants and gain more answers about how they influence development.

Center of Regenerative Medicine Dr. Solnica-Krezel also serves as co-director of Washington University’s Center of Regenerative Medicine, which she helped found. The goal of the center is to develop new medical treatments that one day might allow doctors to regrow or replace a damaged organ or severed nerves, or restore lost vision or hearing. “The fact that this kind of research is possible at the Center of Regenerative Medicine has attracted some amazing young talent here,” Dr. Solnica says. For example, Jeff Millman, PhD, internal medicine, has been differentiating pluripotent cells into pancreatic β-cells that secrete insulin, and could be used to treat diabetes. In the School of Medicine’s department of

developmental biology, Andrew Yoo, PhD, and his colleagues are devising reprogramming strategies to generate human neurons by directly converting human skin cells. Samantha Morris, PhD, developmental biology, moved to St. Louis from Boston to pursue her research in cell fate engineering. With a CDI grant, Dr. Morris is working with pediatric surgeon Brad Warner, MD, to tackle the clinically vexing problem of short bowel syndrome. Dr. Warner has had to perform all-too-many surgeries on infants born prematurely who, for one reason or another, must have parts of their intestines removed, to seek something better. CDI seed funding has allowed Dr. Morris to explore the possibility of taking skin cells and turning it into intestinal cells. It’s a daunting challenge that few in the world have explored.

The researchers at the Center for Regenerative Medicine believe that knowledge gained from such experiments will transform the way we study and apply developmental biology and regenerative medicine to solving clinical problems.



Meet the Future: Genome Technology Brings Precision Medicine into Focus Center for Genome Sciences and Systems Biology Rob Mitra, PhD, genetics, didn’t take a biology class until his second year of graduate school, while focusing on achieving a doctorate in electrical engineering at the Massachusetts Institute of Technology. What he learned about the state of biological sciences from that biology class greatly influenced his career trajectory that now finds him as the Alvin Goldfarb Distinguished Professor of Computational Biology. Dr. Mitra also is a member of the Center for Genome Sciences and Systems Biology at the School of Medicine and was part of the founding team of the university’s Genomics and Pathology Services Initiative, which offers genetic testing for cancer and other diseases. Dr. Mitra is clearly on the leading edge of the science of precision medicine. “I got really excited about biology in the mid1990s because I saw the field was in a similar place as physics was in the early 1900s,” he explains. “The genome had not yet been sequenced, so I realized that biology was about to go through a really magical time of discovery. And it’s still there today. Now that we’ve mapped the human genome, it’s all about trying to understand what the genes that have been discovered do and what their mutations do. These are still fundamental mysteries that bring up many interesting questions.” Currently Dr. Mitra’s lab is focused on developing new genomic methods and using them to understand how master switch proteins, called transcription


“With the CDI, we are able to take full advantage of a collaborative culture. And because we find ourselves at the forefront of biology, we are positioned to really make impactful discoveries in pediatric cancers.” ••• Dr. Joshua Rubin factors, determine which genes are turned on and which are turned off, at what times and in what locations during the development of an organism. Dr. Mitra’s lab also is developing ways to study the epigenome, often described as the “software” that governs how the DNA “hardware” of a cell is processed and expressed. “In many ways, physicians at Washington University are routinely practicing precision medicine right now,” he says. “I can think of several cases around the School of Medicine where cancer patients are being given different drugs based on the specific mutations that occur in their tumor. One of my lab’s goals is to identify genes that could serve as novel drug targets, thereby expanding the toolbox used in precision medicine.” This interest sparked one of many conversations Dr. Mitra has had with CDI-funded pediatric cancer researcher Joshua Rubin, MD, PhD, pediatrics.


Dr. Rubin has been trying to understand why males and females respond so differently to treatment for glioblastoma, a brain tumor that has been very difficult to treat in children. Males have a higher incidence of glioblastomas than females and die at a much higher rate from the tumor (see page 9).

Structure of the Bromodomain 1 of the human Brd4 protein. Based on PyMOL rendering of PDB 2oss.

The two scientists were discussing Brd4, a transcription factor implicated in glioblastoma development. They decided it would be interesting to see if there was a difference in the Brd4 binding sites of male and female cancer cells. Preliminary experiments showed there was a difference.

So, together, they wrote a grant to the CDI, and once awarded funding, began testing a drug they knew that targets Brd4. The results surprised them. It turns out this drug works on male cells but not on female cells. In fact, female cells tend to grow faster and more likely to form tumors with the drug. “This was completely unexpected,” Dr. Mitra says. “Heretofore, Brd4 had never been implicated in the sex differences of cancer treatment disparities between males and females. But now, because of a conversation and a subsequent grant from the CDI, we know that Brd4 is at the heart of that disparity. Now we have a handle on what the differences are at a molecular level. So we can begin to trace the pathway we revealed and understand what is actually happening.” And, adds Dr. Rubin, without the willingness of the CDI to grant the resources necessary to make this basic-science discovery, they never would have uncovered this important finding. “Conceptually, we are on the frontier of the origins of cell identity. And it couldn’t happen anywhere else,” Dr. Rubin says. “Thanks to scientists like Dr. Mitra, genomic technology is one of the School of Medicine’s greatest strengths. With the CDI, we are able to take full advantage of a collaborative culture. And because we find ourselves at the forefront of biology, we are positioned to really make impactful discoveries in pediatric cancers.”



Meet the Future: State-of-the-Art Cellular Imaging Technologies WUCCI With the October 2015 opening of the Washington University Center for Cellular Imaging (WUCCI), researchers throughout the Washington University School of Medicine campus, including those funded by the Children’s Discovery Institute (CDI), have access to a shared technology resource center where the sole focus is the advancement of imaging technologies in support of their pediatric research studies. Since receiving CDI funds last fall to support pilot imaging studies, WUCCI has helped 18 CDI center members and six currently funded CDI investigators take advantage of its new and illuminating resource. Here are a few examples: Steven Brody, MD, medicine, pulmonary and critical care, is using the center as part of his lab’s investigation of the assembly of cilia for ciliary function, and how the assembly is affected in genetic and acquired disease. The aim is to identify the function of known and novel lung disease proteins in cilia and identify their role in the assembly of cilia and, in turn, how that function is disrupted in disease. Cilia are the microscopic, hair-like structures that extend outward from the surface of many animal cells. In the lung, their function is to sweep airways clean of mucus.


Children’s Discovery Institute researchers now have access to a shared technology resource center where the sole focus is the advancement of imaging technologies in support of their pediatric research studies.

Abdinav Diwan, MD, medicine, cardiology, studies lysosomes, ubiquitous organelles that play a role in the breakdown of lipids, proteins and carbohydrates. Dr. Diwan is using CDI funding to study how exactly lysosome dysfunction impairs metabolism, causing reduced fat stores and resulting in significant energy deficit. He brought a unique C. elegans (roundworm) system of lysosome storage disease to the WUCCI to help expose how lysosome dysfunction causes a deficiency in lipid metabolism.

WUCCI STAFF Above: Matt Joens, staff scientist; James Fitzpatrick, PhD, WUCCI scientific director; Robyn Roth, staff scientist; Daniel Geanon, undergraduate research assistant; Dennis Oakley, staff scientist

Phyllis Hanson, MD, PhD, cell biology and physiology, looks at lysosome storage disease, as well as other pediatric diseases, from another angle. She takes advantage of the WUCCI’s electron microscopy and confocal and super-resolution imaging to study a variety of fixed and live cell models depleted of some essential proteins that run the operation of lipid degradation. Kory Lavine, MD, PhD, medicine, cardiology, is using the center’s transmission and scanning electron microscopy to study a zebrafish model of pediatric cardiomyopathy (heart failure). In addition, three-dimensional electron microscopy will be used to precisely quantify abnormalities in the size and geometric structure of mechanistic elements that contribute to the disease.

S. Celeste Morley, MD, PhD, pediatrics, infectious diseases, uses the WUCCI’s live cell imaging to help identify molecular pathways that control immune response to pneumococcal respiratory infection, a major cause of pediatric illness and mortality worldwide. Rodney Newberry, MD, medicine, gastroenterology, studies the rising incidence of food allergies. He is using WUCCI technology to gain insight into how dietary antigens are crossing the stomach lining to be delivered into the immune system. Dr. Newberry hopes to identify alterations in feeding practices and the gut microbiota in infancy that predispose to food allergies.


Innovation that fuels curiosity, now and tomorrow Through grants and research projects, CDI investigators are advancing our understanding of serious pediatric diseases and protecting childhood.


“Many rare and old pediatric diseases will be redefined by their genetic underpinnings, thereby leading to dramatic new therapies that could not have been imagined a few years ago.” ••• D  r. Gary Silverman, executive director, Children’s Discovery Institute

Current CDI Research Grants


F. Sessions Cole, MD, the Park J. White, MD, Professor of Pediatrics; Jennifer Wambach, MD, pediatrics Genomics of Birth Defects

Abhinav Diwan, MD, medicine Metabolomics-guided Therapies for Lysosome Storage Disease

Kory Lavine, MD, PhD, medicine Opposing Roles for Embryonic and Bone Marrow-Derived Macrophages in Pediatric Dilated Cardiomyopathy

Colin Nichols, PhD, cell biology and physiology Cantu Syndrome: A Translational Approach to Mechanisms and Treatment

Michael Shoykhet, MD, PhD, pediatrics Effect of Elastin Insufficiency on Brain Development and Cognition

Whether you are an investor in science or a scientific investigator, it is an incredibly exciting time to be engaged in pediatric research.



Vikas Dharnidharka, MD, MPH, pediatrics Next-generation Deep Sequencing of Rare Congenital Variation in Infantile Leukemia

Todd Druley, MD, PhD, pediatrics Functional Characterization of Rare Congenital Variation in Infantile Leukemia Improving Minimal Residual Disease Surveillance of Pediatric AML Via Error-corrected Sequencing

Karen Gauvain, MD, pediatrics; David Limbrick, MD, PhD, neurology

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

Joshua B. Rubin, MD, PhD, pediatrics; Bradley Schlaggar, MD, PhD, neurology Survivors of Pediatric Brain Tumor: Biomarkers of Cognitive Dysfunction

Laura Schuettpelz, MD, PhD, pediatrics

MRI-guided Laser Heat Ablation to Induce Blood Brain Barrier Breakdown in Pediatric Brain Tumors

Elucidating the Role of KLF7 in T-cell Development

Jeffrey Magee, MD, PhD, pediatrics

A Phase-one Trial of Familial Haploidentical Nonmyeloablative Bone Marrow Transplantation in Children

Developmental Changes in Stem Cell Self-renewal Mechanisms and Their Role in Leukemogenesis

Shalini Shenoy, MD, pediatrics

Rob D. Mitra, PhD, genetic

Qin Yang, MD, PhD, radiation oncology; Dennis Hallahan, MD, radiation oncology

Sex-specific Super Enhancer Activity in Glioblastoma

Developing a Novel Reprogramming Strategy for Pediatric Brain Tumor Treatment

Suman Mondal, PhD, radiology Intraoperative Real-time Fluorescence Imageguided Resection of Pediatric Brain Tumors

Nima Mosammaparast, MD, PhD, pathology and immunology Understanding Mechanisms of Alkylation Chemoresistance in Pediatric Glioblastoma



Ana Maria Arbelaez, MD, pediatrics; Christopher Smyser, MD, neurology, pediatrics Effects of Childhood Malnutrition on Brain Development

Ying (Maggie) Chen, MD, PhD, medicine Podocyte Endoplasmic Reticulum Stress in Hereditary Nephrotic Syndromes

Brian DeBosch, MD, PhD, pediatrics

Environmental Exposures in Early Life and the Risk for Food Allergy in Children

Audrey Odom, MD, PhD, pediatrics; Baranidharan Raman, PhD, MS, biomedical engineering

Role of Enterocyte Glut9 in Intestinal Urate Handling and Energy Homeostasis

Towards Noninvasive Diagnosis of Malaria Infection Through Exhaled Breath Analysis

Dennis Dietzen, PhD, pediatrics

Scott Saunders, MD, PhD, pediatrics; David Ornitz, MD, PhD, developmental biology; Brad Warner, MD, the Jessie L. Ternberg, MD, PhD Distinguished Professor of Pediatric Surgery

Integration of the Ketogenic-ketolytic Axis with Metabolic Homeostasis in Newborn Period and Beyond

Abhinav Diwan, MD, medicine Metabolomics-guided Therapies for Lysosome Storage Disease

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

Samantha Morris, PhD, developmental biology Reprogramming Colon to Small Bowel as a Therapy for Short Bowel Syndrome


Rodney Newberry, MD, medicine; Avraham Beigelman, MD, pediatrics; Phillip Tarr, MD, Melvin E. Carnahan Professor of Pediatrics; Barbara Warner, MD, pediatrics

Growth Factor Signaling Pathways Regulating Development of the Small Intestine

Sudhir Singh, PhD, medicine Podocyte Endoplasmic Reticulum Stress as a Therapeutic Target in Hereditary Nephrotic Syndrome

Indi Trehan, MD, MPH, DTM&H, pediatrics Innovative Interventions for Improving Childhood Growth and Environmental Enteropathy

Indi Trehan, MD, MPH, DTM&H, pediatrics; Mark Manary, MD, pediatrics Optimizing Therapeutic Foods for Neurocognitive Development in Malnourished Children

Barbara Warner, MD, pediatrics Impact of Childhood Intestinal Microbial Maturity on Nutritional Status and Immunity


Leonard Bacharier, MD, pediatrics; Avraham Beigelman, MD, pediatrics Upper Respiratory Tract and Fecal Microbiomes and Recurrent Wheezing Following RSV Bronchiolitis

Joshua Blatter, MD, MPH, pediatrics; David Wang, PhD, molecular microbiology Identifying Biomarkers in Pediatric Lung Transplantation Using a Complete Microbiome

Jeffrey Haspel, MD, PhD, medicine Impact of the Circadian Clock and Age on Anti-viral Responses that Contribute to Asthma

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

Jessica Pittman, MD, MPH, pediatrics; Dmitriy Yablonskiy, PhD, radiology Determinants of Change in Lung Function During Pulmonary Exacerbation and Recovery in Cystic Fibrosis

Generating $222 million in extramural grant funding — a 400 percent return on investment — CDI supporters have put in motion a precision medicine revolution that will continue to spark innovation and deepen our knowledge for decades to come.

MULTI-CENTER GRANTS F. Sessions Cole, MD, pediatrics Comprehensive Genome Analysis for Discovery of Missing Heritability in Infants with Birth Defects

Todd Druley, MD, PhD, pediatrics; Robi Mitra, PhD, genetics Genome Technologies Core

Phyllis Hanson, MD, PhD, cell biology and physiology; Paul Taghert, PhD, anatomy and neurobiology Washington University Center for Cellular Imaging Collaboration with The Children’s Discovery Institute

Ericka Hayes, MD, pediatrics Summer Pediatric Research in Global Health Translation (SPRIGHT)

Kathryn Miller, PhD, biology CDI Summer Undergraduate Research Fellowship Program

Lilianna Solnica-Krezel, PhD, developmental biology; Kelly Monk, PhD, developmental biology Zebrafish Models of Human Disease — Zebrafish Research Services Cooperative

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 Human Pluripotent Stem Cell Core

Philip Spinella, MD, pediatrics; Katherine Steffen, MD, pediatrics Implementation of Science Principles to Develop Blood Management Guidelines for Critically Ill Children 23

Financial Highlights By the Numbers

$50.8 million

invested in research to date

158 research grants awarded since inception

$222 million

Center Award Totals 2006 – 2016 CDI (All Centers)

$9.3 million Congenital Heart Disease Center

$9.8 million

Center for Pediatric Pulmonary Disease

extramural grant funding obtained as a result of CDI awards

$8.1 million

671 published research papers

Center for Metabolism and Immunity

from Children’s Discovery Institute investigators

$14.6 million

McDonnell Pediatric Cancer Center

$9.0 million

Grants Held by Department (2006 – 2016)* Biology – 6

Molecular Microbiology – 5

Biomedical Engineering – 1

Neurology – 5

Cell Biology & Physiology – 5

Neurosurgery – 2

Chemistry – 1

Obstetrics and Genecology – 3

Computer Science and Engineering – 1

Orthopedic Surgery – 5

Developmental Biology – 7

Pathology and Immunology – 10

Genetics – 8

Pediatrics – 75

Mechanical, Aerospace and Structural Engineering – 1

Radiation Oncology – 1 Radiology – 1

Medicine – 21 * 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

Joan Magruder (Ex-officio)

President, Aero Charter Inc.

President, St. Louis Children’s Hospital

Dale L. Cammon

Richard J. Mahoney

Chairman and Co-Chief Executive Director, Bryant Group, Inc.

Retired Chairman and Chief Executive Officer, Monsanto Company

Lee F. Fetter Group President, BJC Healthcare President, St. Louis Children’s Hospital Foundation

Daniel Getman, PhD Retired President, Kansas City Area Life Sciences Institute Former Vice President, Pfizer R&D, Director, St. Louis Laboratories

Jeffrey I. Gordon, MD Dr. Robert J. Glaser Distinguished University Professor Director, Center for Genome Science and Systems Biology, Washington University School of Medicine

Keith S. Harbison

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 Chairman, Hackett Security, Inc.

David H. Permutter, MD (Ex-officio) Executive Vice Chancellor for Medical Affairs and Dean, Washington University School of Medicine

Gary A. Silverman, MD, PhD Executive Director, Children’s Discovery Institute

Managing Partner, Alitus Partners, LLC

Chairman, Department of Pediatrics

Jennifer K. Lodge, PhD

The Harriet B. Spoehrer Professor of Pediatrics, Washington University School of Medicine

Professor, Molecular Microbiology Associate Dean for Research, Washington University School of Medicine Vice Chancellor for Research, Washington University in St. Louis

Pediatrician-in-Chief, St. Louis Children’s Hospital

Kelvin R. Westbrook President and Chief Executive Officer, KRW Advisors, LLC





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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 depend on the generosity of our CDI investors. Thank you for the support that makes you a Guardian of Childhood. Learn more at childrensdiscovery.org.

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Children's Discovery Institute / Investor Report 2016  

Children's Discovery Institute / Investor Report 2016