2017 Report to CDI Investors

THE SCIENCE & THE STORIES 2017 Report to CDI Investors

THE SCIENCE & THE STORIES

Every patient family we treat at St. Louis Children’s Hospital has a unique and special story. Many end in triumph, others in tragedy.

We have scientific discovery, passion and courage to thank for the triumphs. The tragic outcomes drive our pediatric researchers to change future narratives and put more stories in the triumphant column.

Photo: Fluorescence microscopic view of cancer cells

A MESSAGE FROM CDI LEADERSHIP

We are proud to present the 2017 Children’s Discovery Institute (CDI) Investor Report. This year we are sharing stories of courage, hope and inspiration generated by the patients we treat and the physician scientists who work at both the bedside and the bench, turning clinical challenges into research inquiries.

The CDI has come a long way in a relatively short amount of time. Since 2006, this unprecedented partnership between St. Louis Children’s Hospital and Washington University School of Medicine has inspired researchers of all disciplines to think about what they can do to transform child health worldwide.

The promise of a CDI grant sparks innovation that makes us think about childhood disease in new ways.

Over the past 11 years, CDI studies have advanced the field of genomics-based, personalized treatments for children with common diseases, such as asthma and childhood infections, as well as those with rare and neglected diseases, birth defects, or metabolic and immunological disorders.

Your support of pediatric research is like a tsunami.

The research it enables gains strength quietly out of sight, surfacing first as a published study that causes ripples through the scientific community. When those ripples come together they gain momentum and soon become a force that changes the landscape of pediatric disease as we have known it.

The research studies we present in this report all hold the promise of great change in the way we diagnose, treat and think about childhood disease. These are great adventures that propel us to keep asking, keep reaching and keep fighting as long as there are childhoods being threatened by illness. Thank you for joining us. The best is yet to come.

Mary C. Dinauer, MD, PhD Scientific Director Children’s Discovery Institute Fred M. Saigh Distinguished Chair in Pediatric Research St. Louis Children’s Hospital

Gary A. Silverman, MD, PhD Executive Director Children’s Discovery Institute The Harriet B. Spoehrer, Professor and Chairman of the Department of Pediatrics Pediatrician-in-Chief, St. Louis Children’s Hospital

Joan Magruder President St. Louis Children’s Hospital

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THE GENETICS OF BIRTH DEFECTS

PROTECTING OUR MOST VULNERABLE Nearly 120,000 babies are affected by birth defects each year.

For some, the causes are unknown. Those are the focus of a CDI-funded research team determined to help families by providing them with a diagnosis. Meanwhile, other CDI-funded researchers are working to protect vulnerable premature infants from a dangerous infection that plagues babies in neonatal intensive care units worldwide.

Birth defects are a major cause of infant death in the United States. Despite their prevalence, researchers know little about their causes. To address this knowledge gap, next-generation genomics analyses of patients with birth defects and their family members permit discovery of possible gene variants that can be tested for function in model systems, such as worms or zebrafish.

Watching how these models develop will help CDI researchers understand how birth defects develop in children.

Photo: Heart cells taken from newborns who received a surgical operation for correction of congenital heart defects shortly after birth (Source: Massimo Caputo, MD; Paolo Madeddu, MD; Elisa Avolio, PhD)

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THE SCIENCE

F. Sessions Cole, MD; Jennifer Wambach, MD; Dustin Baldridge, MD; Dan Wegner

GENOMICS OF BIRTH DEFECTS In 2014, CDI funding enabled a collaboration between Washington University School of Medicine experts in newborn medicine, genetics, genomics, pediatric cardiology, critical care medicine, computational biology and developmental biology. Their focus has been to identify genetic problems in babies and young children who otherwise would not have a diagnosis.

“Once we confirm a birth defect of currently unknown origin and enroll the family in our study, we collect the DNA from the affected baby, siblings and both parents.

Then we look across the entire genome to see if we can identify the gene code anomaly that has caused the problem,” says co-principal investigator and the Park J. White, MD, Professor of Pediatrics, F. Sessions Cole, MD. The study also involves, on a day-to-day basis, co-principal investigator Jennifer Wambach, MD, newborn medicine; Dustin Baldridge, MD, newborn medicine; and Dan Wegner, laboratory manager.

It sounds fairly straightforward, but Dr. Cole says because all humans carry millions of gene code differences, trying to sort through them to find which one created the defect can seem like an insurmountable challenge. In fact, it takes the high level of computational firepower at the McDonnell Genome Institute at Washington University to make that type of needle-in-a-haystack work possible.

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The Genomics of Birth Defects project has enrolled more than 100 infants and children with structural birth defects, along with their families. So far, the study has provided diagnoses for around 25 percent of these families. Most of these infants and children have birth defects involving a single organ system, such as the heart, lung or brain, but 30 percent have birth defects involving multiple organ systems.

“We are one of the first research projects in the country using whole genome sequencing — a deep dive into more than three billion DNA base pairs —as opposed to exome sequencing, which only looks at the genetic code inside genes,” says Dr. Baldridge, who has been able to pursue a research career in genetics with the CDI funding of this project. “That means we’ve been able to expand our search of gene code problems from one percent to 100 percent of the base pairs that make up the human genome.”

Once a candidate gene code problem is identified, the team turns to a model system, such as mice or zebrafish, to confirm that it is what has caused the defect. “The CDI has allowed us to build a bridge between patients in the genetics clinic, the McDonnell Genome Institute and basic science investigators throughout the School of Medicine to help families solve their medical mysteries,” Dr. Baldridge says.

PROTECTING OUR MOST VULNERABLE The Genetics Of Birth Defects

THE STORY

gabby’s hope During a routine sonogram, Mike and Leslie Macari were told something was wrong. Their baby was too small. Her skull was shaped abnormally, and there was evidence of potential heart problems.

An amniocentesis procedure performed to rule out chromosomal abnormalities revealed nothing.

Other tests were also inconclusive.

So the Macaris waited, and on June 23, 2016, their daughter Gabrielle was born. At only 3 lbs., 12 oz., she was transported to Children’s, where the neonatal intensive care team would be tasked with helping little Gabby gain weight and begin to thrive.

As Gabby struggled, an array of specialists visited to see if they could offer their expertise and help provide a diagnosis.

“We were told that, with all the different things going on with Gabby, we were probably looking at some sort of syndrome,” says Mike. “However, Gabby’s symptoms didn’t match up with any known disease.

As a parent, not knowing what is wrong with your child is very difficult.“ The genetics team eventually gave Gabby a clinical diagnosis of neonatal progeroid syndrome (WiedemannRautenstrauch syndrome), a very rare disease that has been found in only 40 documented cases throughout the world. Among other things, this rare genetic syndrome is characterized by an aged appearance at birth, severe growth restrictions and a shortened life span. Most infants don’t live longer than 7 months.

to peel back the onion of a family’s genome to provide them with long-sought answers. Sequencing revealed that Gabby had variants in the POLR3A gene. Deeper digging uncovered other families throughout the world who had children with the same diagnosis, and the CDI’s genetic testing of these other children verified their gene variants were similar to Gabby’s. One of these families had a 16-year-old with this syndrome.

“The Genomics of Birth Defects study by the CDI has allowed us to find answers we have sought for a very, very long time about our daughter,” Mike says. “It has allowed us to have hope and find other families who share in our extraordinary journey. It has given them hope as well.”

“Plus,” Mike adds, “Gabby now has the opportunity to leave a lasting legacy of making the world a better place for children. She has already made an important and inspiring contribution to science. Suddenly, Gabby’s prognosis went from 7 months to the sky’s the limit.”

“The Genomics of Birth Defects study by the CDI has allowed us to find answers we have sought for a very, very long time about our daughter.”

For now, the Macaris are busy enjoying a happy little girl, who celebrated her first birthday with a taste of pink frosting from a cupcake she shared with her mom, dad and 4-year-old brother.

Looking for hope, Mike and Leslie decided to participate in a CDI-supported study designed 5

STOPPING NEC & REVERSING SHORT BOWEL SYNDROME

PROTECTING OUR MOST VULNERABLE

Necrotizing enterocolitis (NEC) is the most common and lethal gastrointestinal disease in preterm infants. It happens when bacteria invades the small intestine, causing infection and inflammation that ultimately destroys the wall of the bowel. Because its origins are unknown, no preventive strategy has meaningfully reduced its frequency. Once the disease takes hold, surgery to remove the dead tissue is the only treatment option currently available. This measure leaves the infant with insufficient intestine to absorb nutrients for growth, known as short bowel syndrome, and sentences them to the lifelimiting fate of receiving the nutrition they need through a feeding tube.

Photo: The human intestine at 17 weeks (Source: Misty Good, MD)

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THE SCIENCE

Brigida Rusconi, PhD

METABOLOMIC AND EXPERIMENTAL INVESTIGATION OF HOST LIPIDS IN NECROTIZING ENTEROCOLITIS ONSET Brigida Rusconi, PhD, pediatrics, applied for and received a CDI fellowship to join in the work of Phillip Tarr, MD, the Melvin E. Carnahan Professor in Pediatrics at the School of Medicine. His lab works to identify and quantify differences between microbial communities in the guts of infants who develop NEC and those who don’t. Now, with CDI funding of her own, Dr. Rusconi will employ the bank of fecal samples collected with support from prior CDI funding granted to Dr. Tarr and Barbara Warner, MD, pediatrics, to look for markers that could be used to alert clinicians that an infant is at risk for developing NEC. Dr. Rusconi is most interested in describing the role a certain type of lipid plays in that development.

Now, with CDI funding of her own, Dr. Rusconi will employ the bank of fecal samples collected with support from prior CDI funding granted to Dr. Tarr and Barbara Warner, MD, pediatrics, to look for markers that could be used to alert clinicians that an infant is at risk for developing NEC. “I have always been interested in this interface between host and pathogens,” Dr. Rusconi says. “How do such small bugs have such a big effect on us? To pursue that question, I’ve moved from classical microbiology to integrated translational research, looking at samples from the human population to investigate how they are influenced by bacteria. That’s why I came to Washington University.”

8 PROTECTING OUR MOST VULNERABLE Stopping NEC & Reversing Short Bowel Syndrome

Misty Good, MD

Clifford Luke, PhD; Stephen Pak, PhD

MODULATING THE INTESTINAL IMMUNE RESPONSE IN THE PATHOGENESIS OF NECROTIZING ENTEROCOLITIS

HIGH CONTENT DRUG SCREENS FOR THE PREVENTION OF NECROTIZING ENTEROCOLITIS

At the University of Pittsburgh School of Medicine, Misty Good, MD, pediatrics, and her team used a mouse model to show that a compound in amniotic fluid inhibits gut inflammation. Now a neonatologist at St. Louis Children’s, Dr. Good will use her CDI funding to explore the compounds in breast milk that offer the same protection and find out how to activate those compounds through nutritional supplementation.

She also is interested in understanding the signaling pathways that are involved in NEC development and predicting the infants at risk for NEC.

With their CDI funding, Clifford Luke, PhD, pediatrics; and Stephen Pak, PhD, pediatrics, are capitalizing on the translucence of a worm (C. elegans) to model intestinal cells under attack to develop and perform drug screens for compounds that could prevent NEC.

“Because we are saving younger and younger babies, we are seeing more vulnerability to NEC,” Dr. Good says. “Our goal is to protect them so they have a chance to lead healthy lives.”

Now a neonatologist at Children’s, Dr. Good will use her CDI funding to explore the compounds in breast milk that offer the same protection and find out how to activate those compounds through nutritional supplementation.

The investigators recently created a method to measure cell death and have conducted a pilot screen using a library of FDA-approved drugs.

The investigators recently created a method to measure cell death and have conducted a pilot screen using a library of FDA-approved drugs. After validation of potential protective compounds in worms, the researchers will test candidate drugs for efficacy in NEC mouse models. Ultimately, the investigators hope to find a drug that can protect babies from this life-threatening disease.

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THE SCIENCE

Kristen Seiler, MD

DEVELOPMENT OF PATIENT-DERIVED SMALL INTESTINE “ORGAN-ON-CHIP” MICROFLUIDIC DEVICES Like Dr. Rusconi, Kristen Seiler, MD, surgery, chose to pursue a surgical residency at the School of Medicine based on the strength of its resources and expertise in NEC. She works in the lab of Brad Warner, MD, the Jessie L. Ternberg, MD, PhD, Distinguished Professor of Pediatric Surgery and the Children’s Hospital surgeon-inchief, to explore small intestine regeneration. Her research seeks to understand the multilevel cellular interactions necessary to grow the human epithelium that lines the intestine. That knowledge could advance approaches for organ regeneration.

Her research seeks to understand the multilevel cellular interactions necessary to grow the human epithelium that lines the intestine. That knowledge could advance approaches for organ regeneration.

“My organ of interest has always been the small intestine, so when I was in medical school I did research on small intestine regeneration and was very interested in Dr. Warner’s work,” Dr. Seiler says. With her CDI funding, Dr. Seiler will line a microchip with living small intestine cells and watch how they develop the protective wrap that keeps toxins out and lets nutrients into the small intestine and the blood vessels that provide the oxygen the organ needs to live. “If we can understand what triggers gut growth, then maybe we could someday restore a child’s intestinal health and the ability to absorb nutrients.”

10 PROTECTING OUR MOST VULNERABLE Stopping NEC & Reversing Short Bowel Syndrome

THE STORY

veyda’s VICTORY She’s a 6-year-old fighter who makes going up against Fortunately, Veyda qualified for a bowel lengthening short bowel syndrome look like child’s play. Veyda procedure that pediatric surgeon Brad Warner, MD, was born with gastroschisis, a birth defect of the has in his collection of solutions to restore the abdominal wall that caused a small hole beside her intestines of children with short bowel syndrome. belly button through which her intestines protruded.

In the process, they became twisted, cutting off blood flow and causing them to die. This required immediate surgery to remove the dead tissue. Left with only about half the length of a normal intestine, she is unable to absorb necessary nutrients and fluids. She must be fed through an intravenous tube, making her prone to life-threatening infection. “We’ve been on antibiotics for years trying to get rid of the bad bacteria in her gut,” says Veyda’s mom, Elise. After years of being under siege, Veyda’s intestines had become dilated, causing “Dr. Warner is amazing. We feel so lucky to have him chronic diarrhea and a painfully distended tummy. in our corner,” Elise says. “In fact, we’re grateful for everything Children’s Hospital has done for us. It’s our “Earlier this year, we realized that we had to do second home.” That said, Elise and her husband, Adam, something,” Elise says. “She just didn’t want to live like are rooting for the researchers working to make short that anymore. She wants to be a normal kid who goes bowel syndrome a thing of the past. to school, plays with her friends, enjoys a sleepover.”

“Dr. Warner is amazing. We feel so lucky to have him in our corner,” Elise says.

“In fact, we’re grateful for everything Children’s Hospital has done for us.

It’s our second home.”

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PEDIATRIC CANCER RESEARCH

AS LONG AS THEY FIGHT, WE FIGHT On multiple fronts, CDI investigators fight for children who are battling disease and facing seemingly insurmountable odds.

At the same time, pediatric researchers compete for scarce public funding resources to fund studies in pediatric cancers, chronic respiratory diseases, congenital heart disease and disorders of the immune system. Despite the challenges, they are making gains by using seed money from the CDI to fund their urgent search for more targeted, more precise and more personalized treatments.

Cancer is the leading cause of disease-related death in children under 15 in the United States.

The incidence of pediatric cancer has risen about one percent annually for the past 35 years, yet, only four percent of National Cancer Institute funding is dedicated to pediatric cancer research.

That is partly why fewer than 10 drugs have been developed to treat pediatric cancer since 1990.

Researchers need philanthropic support to close that funding gap and save the lives of generations to come. And — because adult survivors of pediatric cancer are twice as likely as the general population to develop cancer — save those lives, too.

Photo: Pediatric brain tumor (Source: Victor Song, PhD)

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THE SCIENCE

Yongjian Liu, PhD; Hong Chen, PhD; Joshua Rubin, MD, PhD; Yuan-Chuan Tai, PhD

Rizwan Romee, MD; Todd Fehniger, MD, PhD; Jeffrey Bednarski, MD, PhD

IMAGE-GUIDED DRUG DELIVERY FOR IMPROVED TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA

MEMORY-LIKE NATURAL KILLER CELL IMMUNOTHERAPY FOR PEDIATRIC AND YOUNG ADULT LEUKEMIA PATIENTS

Washington University School of Medicine bioengineers Yongjian Liu, PhD, and Hong Chen, PhD, are using CDI funding to develop an innovative strategy to treat the single greatest cause of brain tumor–related deaths in children — diffuse intrinsic pontine glioma (DIPG).

Jeffrey Bednarski, MD, PhD, pediatrics; Todd Fehniger, MD, PhD, medicine; and Rizwan Romee, MD, medicine, have joined forces to create hope for children with acute myeloid leukemia (AML). This type of cancer has remained a challenge to treat, requiring many to undergo a bone marrow transplant. For patients who relapse after transplant, no viable options for treatment exist.

Traditionally, the location and scattered nature of DIPG prohibits surgery. Moreover, the disease does not respond to radiation and chemotherapy. Working to provide clinicians with more options, this research team will test the effectiveness and safety of using focused ultrasound to noninvasively, locally and temporally open the blood-brain barrier, which prevents most drugs from reaching the brain tissue. That would allow for ultra-small nanoclusters loaded with an imaging agent and chemotherapy drugs to reach the tumor.

Drs. Chen and Liu are testing this novel approach in collaboration with Children’s pediatric neuro-oncologist Joshua Rubin, MD, PhD, using brain tumor models based in mice.

Working to provide clinicians with more options, this research team will test the effectiveness and safety of using focused ultrasound to noninvasively, locally and temporally open the blood-brain barrier.

Their small, phase 1, “first-in-human” clinical trial provided evidence that the immune system’s “natural killer” (NK) cells can be dialed up in the laboratory, trained to recall that activation and then unleashed to destroy cancer cells in some patients.

This research team wants to develop an option by trying to mirror the success Drs. Fehniger and Romee had in showing promise for immunotherapy in treating adults with AML. Their small, phase 1, “first-in-human” clinical trial provided evidence that the immune system’s “natural killer” (NK) cells can be dialed up in the laboratory, trained to recall that activation and then unleashed to destroy cancer cells in some patients. Responses to the treatment were observed in five of the nine adult patients that could be evaluated.

To ensure they are hitting their targets, the researchers track the nanoclusters using PET imaging and modeling technologies developed by Dr. Liu’s colleague, Yuan-Chuan Tai, PhD, at Washington University’s Mallinckrodt Institute of Radiology.

14 AS LONG AS THEY FIGHT, WE FIGHT Pediatric Cancer Research

THE STORY

victoria’s ride December 2017 will mark the 11th year Victoria Drier has been battling brain cancer. She was 16 when terrible headaches led her to Children’s Hospital after an MRI at a separate facility revealed a tumor the size of two golf balls. Victoria went through a full craniotomy with pediatric neurosurgeon Matthew Smyth, MD, to remove the tumor and then had radiation therapy at Siteman Cancer Center.

and pediatric cancer research. Victoria was the inspiration for the cause’s Ride for a Child program, having served as Children’s Hospital’s first patient ambassador. David now serves as president of the Pedal the Cause board of directors. Its goal is to make sure 100 percent of all donations stay in St. Louis to fund the work of cancer researchers at Siteman Cancer Center and the McDonnell Pediatric Cancer Center of the CDI.

Victoria went on to graduate from high school.

Then, during her freshman year of college, another tumor emerged in the same place. Once again, Dr. Smyth removed it. He has since performed four more surgeries on Victoria. The most recent one was in May 2017, a less-invasive image-guided ablation.

She also has been to two other children’s hospitals to take part in clinical trials of experimental radiation and chemotherapy. Along the way, Victoria and her family have been contributing to scientific discovery here at home.

Thanks to funding from the CDI, each of her tumors has been stored in a tumor bank first overseen by pediatric oncologist Joshua Rubin, MD, PhD, pediatrics.

Thanks to funding from the CDI, each of her tumors has been stored in a tumor bank first overseen by pediatric oncologist Joshua Rubin, MD, PhD, pediatrics. Victoria is now undergoing an innovative personalized treatment involving a vaccine made from her most recent tumor’s DNA. Leaving nothing to chance, Victoria’s parents, Julie and David Drier, became involved in Pedal the Cause, an annual cycling event that raises money for adult

After so many years and so many interruptions of her adolescence, her education and her young adulthood, one might expect Victoria to be bitter. To that she says, “What good would that do? This was no one’s fault.”

Instead, Victoria remains upbeat and grateful for the care she has received. “All my doctors have been the best, and my family could not be more supportive.

We are a great team.” With all the advancements in cancer research, Victoria says, “I am more hopeful than ever that I will continue to live a high quality of life while effectively managing my cancer, and maybe even contribute to finding a cure.”

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THE SCIENCE donor as a reagent or “living drug” without risk of lifethreatening donor toxicity, called graft vs. host disease (GvHD). The research team will use its CDI funding to further optimize multiplex gene edited CAR-T to treat T-cell malignancies in children and adults. Additionally, they will develop strategies to overcome life-threatening cytokine release syndrome (CRS), a major limitation of adoptive T-cell immunotherapies in general. Finally, the DiPersio team incorporated a novel “suicide gene” in the CAR-T that will allow for their elimination, if needed, as well as to track these genetically manipulated T-cells in humans using a unique form of PET scanning.

Shalini Shenoy, MD; Robert Fulton; John F. DiPersio, MD, PhD

CLINICAL DEVELOPMENT OF CRISPR/CAS9 GENE EDITED CAR-T FOR THE TREATMENT OF T-CELL MALIGNANCIES Children who develop T-cell acute lymphoblastic leukemia (T-ALL) face a difficult road. Even after aggressive combination chemotherapy, the disease frequently returns, requiring allogeneic stem cell transplantation. In spite of these aggressive measures, the outcome for children with relapsed T-ALL is very poor.

But there is new hope based on recent advances made in the treatment of another form of leukemia, B-cell leukemia (B-ALL) and lymphoma (B-NHL).

Research breakthroughs have shown a novel form of immunotherapy using chimeric antigen receptor T-cells (CAR-T) to be extremely effective in the treatment of relapsed B-ALL and B-NHL. However, using CAR-T cells for the treatment of T-cell malignancies presents several significant challenges that so far have prevented the use of CAR-T or other targeted immune therapies to treat these devastating diseases. A group of Washington University School of Medicine researchers will work to overcome those obstacles.

The team is led by internationally known investigators John F. DiPersio, MD, PhD, medicine; and his colleague Matthew Cooper, PhD, medicine, along with pediatric hematologist/oncologist Shalini Shenoy, MD and Robert Fulton, a scientist at the Washington University McDonnell Genome Institute. They will use gene editing to develop an “off-the-shelf” CAR-T product that prevents CAR-T cells from attacking either each other or non-cancer cells in the patient. In addition, by also editing part of the T-cell receptor itself, these “multiplex gene edited” CAR-T cells can be used from any

Their studies will potentially yield the “first-in-human” CAR-T therapy for children and adults with relapsed T-ALL and T-NHL. The next step will be to test this approach in clinical trials. In addition, successful identification of new genetic and/or pharmacologic approaches to mitigate cytokine release syndrome will expand the clinical use and safety of CAR-T and advance the fields of CAR-T for both T- and B-cell malignancies in the future.

Gavin Dunn, MD, PhD; Karen Gauvain, MD

A PILOT STUDY OF A PERSONALIZED VACCINE APPROACH IN PATIENTS WITH RECURRENT PEDIATRIC BRAIN TUMORS In another newly funded clinical trial in pediatric cancer research, Karen Gauvain, MD, pediatrics; and Gavin Dunn, MD, PhD, neurosurgery, hope their study will lead to more effective treatments for children with recurrent brain tumors. Currently, very few options are available. This project is the first-ever clinical trial to treat pediatric patients experiencing relapsed or recurrent brain tumors with a personalized vaccine — referred to as a peptide vaccine — developed by targeting genetic abnormalities unique to each individual tumor. The researchers will benefit from the School of Medicine’s emergence as a world leader in developing personalized vaccines to fight cancer.

16 AS LONG AS THEY FIGHT, WE FIGHT Pediatric Cancer Research

THE STORY

simeon’s comeback As 10-year-olds go, Simeon Schlaggar was on a trajectory to success in every aspect of his life. Whether it was hockey, baseball or his studies at school, Simeon, whose dad is Bradley Schlaggar, MD, PhD, neurologistin-chief at Children’s Hospital, excelled. But a diagnosis of T-cell leukemia interrupted Simeon’s progress and promise.

For eight months in 2016, Simeon went through body blow after body blow of chemotherapy, in what Dr. Schlaggar calls a scorched-earth strategy designed to destroy tumor cells but that also injured his kidneys, liver and intestines. “My wife, Christina, who had gone through her own battle with breast cancer, said his treatment made hers seem like a walk in the park.”

Now, with the CDI - funded research to bring along the same type of immunotherapy used successfully in B- cell leukemia, Dr. Schlaggar sees a day when future T- cell treatments will be less toxic and more personalized.

Now in the three-year maintenance stage of treatment, Simeon is quickly returning to himself, even while enduring daily meds, monthly infusions, periodic lumbar punctures and bursts of steroids. “He has had chemotherapy and pitched later that day,” Dr. Schlaggar says. “That’s just how resilient he is.”

His doctors fought back with a treatment protocol that Dr. Schlaggar says is more complicated than the U.S. tax code. Every stage —induction, intensification, consolidation, delayed intensification and maintenance— presents its own set of challenges. “We watched Simi go from being a strong, healthy kid to someone who didn’t have the strength to stand up from a seated position or walk up a flight of stairs,” Dr. Schlaggar says.

Now, with the CDI-funded research to bring along the same type of immunotherapy used successfully in B-cell leukemia, Dr. Schlaggar sees a day when future T-cell treatments will be less toxic and more personalized.

“Our family has learned a lot from this whole process about what’s really important for life,” Dr. Schlaggar says. “And, in my own work delivering prognoses to my patients, I’ve learned that, while 85 percent survival may sound like a good prognosis to the person delivering it, it’s not nearly as reassuring as it might sound to the families who have to face so much uncertainty.”

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MAKING PEDIATRIC TRANSPLANTS LAST

AS LONG AS THEY FIGHT, WE FIGHT

Most pediatric lung transplant recipients develop chronic rejection within five years of transplant. Transplant patients undergo an immunosuppressive drug regimen, which helps prevent acute rejection but can lead to infections that may impact longer-term transplant outcomes. Rejection medication can impact the entire body, giving rise to high blood pressure, high cholesterol, arthritis and diabetes. In other words, the bodies of children with transplanted organs age quickly and never have a chance to bounce back. The next frontier of pediatric transplant research is already taking shape, thanks to funding from the CDI and the drive of its investigators to make life better for these children.

Photo: Fluorescence microscopic view of human lung fibroblasts

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THE SCIENCE

Joshua Blatter, MD, MPH

IDENTIFYING BIOMARKERS IN PEDIATRIC LUNG TRANSPLANTATION USING A COMPLETE MICROBIOME No lung transplant study has simultaneously examined the bacteria, fungi and viruses in transplanted lungs in order to identify associations between the microbiome and transplant outcomes.

The research team is investigating the utility of a particular class of viruses, called anelloviruses, in helping predict which patients are more or less likely to have bad outcomes following transplant.

To the researchers, it appears that having more anellovirus after transplant is actually a good thing.

That is until 2016, when Joshua Blatter, MD, MPH, pediatrics; and David Wang, PhD, molecular microbiology, embarked on a CDI-funded study to leverage knowledge from the largest group of pediatric lung transplant recipients in the world to identify early microbial biomarkers of disease associated with shorter transplanted lung survival. This is a multi-center effort led by these Washington University School of Medicine researchers.

The research team is investigating the utility of a particular class of viruses, called anelloviruses, in helping predict which patients are more or less likely to have bad outcomes following transplant. To the researchers, it appears that having more anellovirus after transplant is actually a good thing. Their best guess now is that when patients are more immunosuppressed, they develop higher levels of this virus.

And patients who are more immunosuppressed are, of course, less likely to reject their new lungs. So, because of this research, it may be possible for doctors to use this virus to gauge whether patients are receiving the right doses of immunosuppressants.

20 AS LONG AS THEY FIGHT, WE FIGHT Making Pediatric Transplants Last

THE STORY

kylie’s FIGHT Kylie is 13, and so far her life has been about beating back the symptoms that make cystic fibrosis such a challenging disease. It progressively debilitates two organ systems — the lungs and the pancreas — and often leads to the need for a lung transplant.

Kylie, who is from St. Joseph, Missouri, receives most of her care from doctors at Children’s Mercy in Kansas City. But when it came time for her to be put on a transplant list, those doctors sent Kylie to St. Louis.

Plus, Kylie no longer needs a wheelchair or an oxygen tank. Instead of fighting so hard to breathe, she can race her 9-year-old brother and have tickle fights.

“We tried to maintain her lung function to put off a transplant until she was at least 16,” says Kylie’s mom, Ramona. “But it just wasn’t working. She was on oxygen 24 hours a day and could barely walk across the living room. It was time.”

Kylie received her new lungs on May 21, 2017, and will have to work the rest of her life to keep them healthy and away from chronic rejection. “But,” Ramona says, “that’s easier than cystic fibrosis treatments.” Plus, Kylie no longer needs a wheelchair or an oxygen tank. Instead of fighting so hard to breathe, she can race her 9-year-old brother and have tickle fights. Homebound for so long, she can now go to school this fall.

After her transplant, one of Kylie’s first requests was to have her hair dyed magenta. So, now she’s just a girl with fun, pink hair, breathing in life.

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SOLVING FOR PRIMARY IMMUNODEFICIENCY

PERSONALIZED MEDICINE At the genetic level, any two people are more than 99.9 percent alike. With philanthropic support, Washington University School of Medicine and St. Louis Children’s Hospital have invested in the infrastructure necessary to understand the role of genetics in pediatric disease development.

The body’s immune system is there to protect.

Yet, mutations in the genes of immune cells can cause a great deal of harm. The CDI funds impassioned researchers on the forefront of understanding the biology of the immune system and the molecular and biochemical underpinnings of the system’s complex interactions and functions.

Photo: Neural tissue

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THE SCIENCE

Megan Cooper, MD, PhD

INVESTIGATION OF SOMATIC DEFECTS IN PATIENTS WITH AUTOIMMUNE DISEASES Megan Cooper, MD, PhD, pediatrics and pathology and immunology, leads a laboratory of scientists interested in the origins of pediatric autoimmune disease.

Specifically, they are interested in whether genetic defects lead to altered immune cell tolerance and the development of autoimmunity in childhood.

Pediatric autoimmune diseases are often difficult to diagnose and can have devastating long-term effects on health, including chronic arthritis, organ damage and cardiovascular disease. Since her original funding from the CDI, beginning in 2010, Dr. Cooper’s lab has identified abnormal immune cells in patients with pediatric-onset autoimmune disease. She evaluates the function of these immune cells and uses next-generation DNA sequencing to investigate whether genetic defects are the cause of the abnormalities. This research could lead to promising new approaches for the diagnosis, monitoring and treatment of pediatric autoimmune diseases within the next 10 years.

Pediatric autoimmune diseases are often difficult to diagnose and can have devastating long-term effects on health, including chronic arthritis, organ damage and cardiovascular disease.

24 PERSONALIZED MEDICINE Solving for Primary Immunodeficiency

THE STORY

chase’s CHANCE Chase woke up one morning when he was 9 years old unable to stretch out his left arm. “My sister thought I was joking, but when she tried to straighten it, I freaked out,” says the 19-year-old.

Little by little, all of Chase’s limbs and joints began betraying him. Although physical therapy at Children’s Hospital helped, Chase felt his life shrinking, and he couldn’t do anything about it. He started having what felt like electric shocks streak through the nerves of his body. “At some point, I started walking on my knees.

It was the only thing I could do to avoid a wheelchair.”

“That’s okay, though, because I’m sure Dr. Cooper is going to find a treatment that will make me healthy again.”

It wasn’t until Chase started having frequent infections that his doctors began to wonder if the source of Chase’s condition was his immune system. And that’s when Chase met Dr. Megan Cooper. “She told me about a study she wanted to do with me that sounded pretty cool.”

With Chase’s permission, Dr. Cooper performed whole exome sequencing of his genes. Studying the raw data, Dr. Cooper found a mutation in SGPL1, a gene that encodes a protein called sphingosine 1 phosphate lyase (S1P lyase). The gene was discovered by Dr. Julie Saba, using experiments on yeast cells in her Children’s Hospital Oakland Research Institute lab in 1997. Since that time, Dr. Saba’s lab has focused on how S1P lyase works, and how problems with it might cause disease.

She and Dr. Cooper formed a collaboration to continue studying the disease. Dr. Cooper’s lab is interested in learning how a deficiency in S1P lyase changes the immune system. Dr. Saba’s team is working with cells from patients and mouse models to uncover potential treatments.

Meanwhile, Chase is undergoing kidney dialysis until a kidney transplant undoes the damage the disease has caused. And he’s working hard to learn to walk again for the fourth time.

“That’s okay, though, because I’m sure Dr. Cooper is going to find a treatment that will make me healthy again.”

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PEDIATRIC CARDIOMYOPATHY

PERSONALIZED MEDICINE

New CDI research proves that therapies used to treat adults with heart failure do not work for children. This finding opens the door to opportunities to seek new strategies to help children avoid the need for heart transplantation and years of immunosuppression that come with it.

Photo: Heart macrophages and cardiomyocytes (Source: Kory Lavine, MD, PhD)

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THE SCIENCE

Kory Lavine, MD, PhD

OPPOSING ROLES FOR EMBRYONIC AND BONE MARROW-DERIVED MACROPHAGES IN PEDIATRIC DILATED CARDIOMYOPATHY New research by CDI-funded researcher Kory Lavine, MD, PhD, and his collaborators, just published in the Journal of Clinical Investigation, identified the underlying reason why children with heart failure do not respond to therapies typically used in adult patients. Heart failure medications currently used in adults target a process called adverse remodeling, a common mechanism by which the adult heart responds to injury. Typical drugs such as beta blockers and ACE inhibitors function to halt or slow down the remodeling process, reducing scar deposition and maladaptive remodeling of cardiac tissue. Dr. Lavine’s lab proved that adverse remodeling does not happen in children with heart failure. These findings provide a framework to understand why current treatments for heart failure do not work for children and signal that new approaches are needed.

“We hope to get to the day when a patient gets diagnosed with heart failure and undergoes routine genetic screening. For children who carry a heart failure mutation, we hope to either have identified drugs that target their mutation or engineer a zebrafish line to better understand their disease and identify drugs with the potential to reverse the course of their illness,” Dr. Lavine says.

Working with zebrafish through a recently funded CDI grant, Dr. Lavine’s lab is beginning to develop new strategies for pediatric heart failure. They are inserting genetic mutations identified in children with heart failure into the translucent zebrafish.

Then they employ advanced imaging techniques to understand why each pediatric heart failure mutation results in cardiac dysfunction and screen for drugs that may serve as precision therapies to treat an individual child’s mutation. “We hope to get to the day when a patient gets diagnosed with heart failure and undergoes routine genetic screening. For children who carry a heart failure mutation, we hope to either have identified drugs that target their mutation or engineer a zebrafish line to better understand their disease and identify drugs with the potential to reverse the course of their illness,” Dr. Lavine says.

28 PERSONALIZED MEDICINE Pediatric Cardiomyopathy

THE STORY

layla’s LEGACY In 2010, just two days before Christmas, Colleen and Mike learned that their 6-month-old daughter, Layla, suffered from dilated cardiomyopathy. As a registered nurse with cardiac care experience, Colleen knew her family’s life would never be the same from that day forward.

“When the diagnosis was cardiomyopathy, we felt like we were given a death sentence,” Colleen says.

“More than half of all children diagnosed don’t live past age 5. If they do survive, it is a fluke or due to a heart transplant, and that is not a cure, since the life span of a new heart is only around 10 to 15 years.”

Layla spent her first Christmas in the cardiac intensive care unit at St. Louis Children’s Hospital, and she had many more hospitalizations, tests and medical and surgical procedures after that. The Millers’ lives became filled with doctors’ appointments, medication schedules and worry, knowing the whole time that a transplant loomed in their future. That time came in August of 2014.

The chair has a plaque with Layla’s name and a quote that has sustained the Millers through it all. It reads: “There is no foot too small that it can’t leave an imprint on this world.”

“We have always had an idea of where the dilated cardiomyopathy road would lead,” Colleen wrote in her Caring Bridge blog after learning they were out of options. “We prayed and worked and gave meds, faithfully went to doctor’s appointments and spent many nights in the hospital and cardiac ICU. All of this was done to keep the worst at bay … knowing full well it was out of our control.”

Unfortunately, Layla passed away after going into cardiac arrest during a cardiac catheterization that was meant to determine the readiness of her lungs to handle a new heart. Since that devastating day, the Millers have channeled their grief into acts of kindness, such as installing a buddy bench at Layla’s school and purchasing a rocking chair for the cardiac ICU, where they spent so much time. The chair has a plaque with Layla’s name and a quote that has sustained the Millers through it all. It reads: “There is no foot too small that it can’t leave an imprint on this world.”

To help make that imprint, the Millers also never shy away from opportunities to raise awareness of pediatric cardiomyopathy.

“We are thrilled to do anything we can do to keep Layla’s story going,” Colleen says. “Raising awareness for a condition that has no cure, limited treatment, high mortality and needs more funding to find a cure is a goal of ours.”

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CURRENT RESEARCH GRANTS

Since 2006, the Children’s Discovery Institute has been the engine that drives the focus on pediatric research, promotes collaboration between clinicians and investigators, and leverages new intellectual resources into the effort through funding specific programs and projects.

Photo: Striated cardiac muscle cells myocytes

CONGENITAL HEART DISEASE CENTER

F. Sessions Cole, MD, Park J. White, MD, Professor of Pediatrics; Jennifer Wambach, MD, pediatrics Genomics of Birth Defects Kory Lavine, MD, PhD, medicine; Christopher Sturgeon, PhD, medicine Pluripotent Stem Cell-derived Macrophages as a Therapeutic for Pediatric Dilated Cardiomyopathy Colin Nichols, PhD, cell biology and physiology Cantu Syndrome: A Translational Approach to Mechanisms and Treatment Cynthia Ortinau, MD, pediatrics Underlying Mechanisms of Impaired Brain Development in Congenital Heart Disease Michael Shoykhet, MD, PhD, pediatrics Effect of Elastin Insufficiency on Brain Development and Cognition Jennifer Silva, MD, pediatrics; Jonathan Silva, PhD, biomedical engineering Improving Outcomes in the Pediatric Cardiac Catheterization Lab Using Augmented Reality

MCDONNELL PEDIATRIC CANCER CENTER

Jeffrey Bednarski, MD, PhD, pediatrics; Todd Fehniger, MD, PhD, medicine; Rizwan Romee, MD, medicine Memory-like Natural Killer Cell Immunotherapy in Pediatric and Young Adult Leukemia Patients Hong Chen, PhD, biomedical engineering; Yongjian Liu, PhD, radiology Image-guided Drug Delivery for Improved Treatment of Diffuse Intrinsic Pontine Glioma John F. DiPersio, MD, PhD, medicine, pathology and immunology, pediatrics Clinical Development of CRISPR/Cas9 Gene-Edited CAR-T for the Treatment of T-cell Malignancies 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; Gavin Dunn, MD, PhD, neurosurgery A Pilot Study of a Personalized Vaccine Approach in Patients with Recurrent Pediatric Brain Tumors Karen Gauvain, MD, pediatrics; David Limbrick, MD, PhD, neurology MRI-guided Laser Heat Ablation to Induce Blood Brain Barrier Breakdown in Pediatric Brain Tumors

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CURRENT RESEARCH GRANTS

MCDONNELL PEDIATRIC CANCER CENTER (CONTINUED)

Jeffrey Magee, MD, PhD, pediatrics Developmental Changes in Stem Cell Self-renewal Mechanisms and Their Role in Leukemogenesis

Laura Schuettpelz, MD, PhD, pediatrics Elucidating the Role of KLF7 in T-cell Development

Rob D. Mitra, PhD, genetics Sex-specific Super Enhancer Activity in Glioblastoma

Shalini Shenoy, MD, pediatrics A Phase-one Trial of Familial Haploidentical Nonmyeloablative Bone Marrow Transplantation in Children

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

Qin Yang, MD, PhD, radiation oncology; Dennis Hallahan, MD, radiation oncology Developing a Novel Reprogramming Strategy for Pediatric Brain Tumor Treatment

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

32 RESEARCH GRANTS

When Bella was 4 years old, a lump found near her right ear led to a diagnosis of rhabdomyosarcoma (RMS). She was still fighting three years later when her pediatric oncologist, Dr. Fred Huang , orchestrated a cast of pediatric and adult surgical specialists in a 12-hour surgery on her head and neck, a complex region of the body. Now, at age 10, Bella’s scans are as clean as those of any healthy 10-year-old girl poised to take on the world.

CENTER FOR METABOLISM AND IMMUNITY

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

Clifford Luke, PhD, pediatrics; Stephen Pak, PhD, pediatrics High Content Drug Screens for the Prevention of Necrotizing Enterocolitis

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

Mark Manary, MD, pediatrics Understanding and Ameliorating Environmental Enteropathy

Regina Clemens, MD, PhD, pediatrics The Molecular Regulation of Neutrophil Calcium Signaling in Acute Lung Injury

Jonathan Miner, MD, PhD, medicine; Robyn Klein, MD, PhD, medicine Neurodevelopmental Implications of Congenital Zika Virus Infection

Brian DeBosch, MD, PhD, pediatrics Role of Enterocyte GLUT9 in Intestinal Urate Handling and Energy Homeostasis Brian DeBosch, MD, PhD, pediatrics; Paul Hruz, MD, PhD, pediatrics Prevention and Treatment of Hepatic Steatosis Through Selective Targeting of GLUT8 Abhinav Diwan, MD, medicine Metabolomics-guided Therapies for Lysosome Storage Disease Misty Good, MD, pediatrics Modulating the Intestinal Immune Response in Pathogenesis of Necrotizing Enterocolitis

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 Environmental Exposures in Early Life and the Risk for Food Allergy in Children David Rudnick, MD, PhD, pediatrics; Stephen Pak, PhD, pediatrics Discovering Novel Therapeutic Interventions for Alpha-1-antirypsin Deficiency Liver Disease

Lori Holtz, MD, pediatrics Defining the Role of Viruses in Environmental Enteropathy

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CURRENT RESEARCH GRANTS

CENTER FOR METABOLISM AND IMMUNITY (CONTINUED)

Brigida Rusconi, PhD, pediatrics Metabolomic and Experimental Investigation of Host Lipids in Necrotizing Enterocolitis Onset

CENTER FOR PEDIATRIC PULMONARY DISEASE

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

Kristen Seiler, MD, surgery Development of Patient-derived Small Intestine “Organ-on-Chip” Microfluidic Devices 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

Under the guidance of Dr. Leonard Bacharier, St. Louis Children’s Hospital and Washington University School of Medicine have been international leaders in clinical asthma research and care for decades. They have been central to two pediatric asthma care networks supported by the National Institutes of Health and are lead sites for two other studies involving prevention and treatment of severe asthma. That’s good news for Isaiah and Dina Huddleston, who receive asthma treatments from a donor-funded Healthy Kids Express mobile health program that visits their school.

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

34 RESEARCH GRANTS

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

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

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

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

ALL-CENTER GRANTS F. Sessions Cole, MD, Park J. White, MD, Professor of Pediatrics Comprehensive Genome Analysis for Discovery of Missing Heritability in Infants with Birth Defects Todd Druley, MD, PhD, pediatrics; Rob Mitra, PhD, genetics Genome Technologies Core

Lilianna Solnica-Krezel, PhD, developmental biology; Jeffrey Milbrandt, MD, PhD, James S. McDonnell Professor and Head, Department of Genetics, Professor of Pathology and 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

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)

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FINANCIAL HIGHLIGHTS CENTER AWARD TOTALS (2006 – 2017)

173 CDI grants Awarded since inception

$279 million Extramural grant funding obtained as a result of CDI awards

771 published research papers As a result of their CDI awards

BY THE NUMBERS CDI (All Centers)

Center for Pediatric Pulmonary Disease

$9.3 million

$8.3 million

$56 million

McDonnell Pediatric Cancer Center

Awarded to date

$10.7 million Congenital Heart Disease Center

Center for Metabolism and Immunity

$11 million

$16.7 million

GRANTS HELD BY DEPARTMENT (2006 – 2017)*

6

Biology

7

Developmental Biology

5

Molecular Microbiology

10

Pathology & Immunology

2

Biomedical Engineering

8

Genetics

5

Neurology

84

Pediatrics

5

Cell Biology & Physiology

2

Neurosurgery

1

1

Chemistry

3

Obstetrics & Genecology

Radiation Oncology

1

Mechanical, Aerospace & Structural Engineering

1

Radiology

1

Computer Science & Engineering

Medicine

5

Orthopedic Surgery

1

Surgery-Pediatric

25

*T he 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.

36

CHILDREN’S DISCOVERY INSTITUTE LEADERSHIP BOARD OF MANAGERS Chair: Raymond R. Van de Riet Jr.

Richard J. Mahoney

President, Aero Charter Inc.

Retired Chairman and Chief Executive Officer, Monsanto Company

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

Distinguished Executive in Residence, Weidenbaum Center on the Economy, Government and Public Policy, Washington University in St. Louis

Lee F. Fetter

Richard H. McClure

Group President, BJC Healthcare

Former President, UniGroup, Inc.

Daniel Getman, PhD

James S. McDonnell III

Retired President, Kansas City Area Life Sciences Institute

Retired Corporate Vice President, McDonnell Douglas Corp.

Former Vice President, Pfizer R&D, Director, St. Louis Laboratories

Jeffrey Milbrandt, MD, PhD

Jeffrey I. Gordon, MD

The James S. McDonnell Professor of Genetics, Washington University School of Medicine

Dr. Robert J. Glaser Distinguished University Professor

Andrew E. Newman

Director, Center for Genome Science and Systems Biology, Washington University School of Medicine Keith S. Harbison Managing Partner, Alitus Partners, LLC

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

Jennifer K. Lodge, PhD

Executive Director, Children’s Discovery Institute

Professor, Molecular Microbiology

Chairman, Department of Pediatrics

Associate Dean for Research, Washington University School of Medicine

The Harriet B. Spoehrer Professor of Pediatrics, 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

Joan Magruder (Ex-officio) President, St. Louis Children’s Hospital

President and Chief Executive Officer, KRW Advisors, LLC

NONPROFIT ORGANIZATION U.S. POSTAGE

PAID

ST. LOUIS, MO PERMIT NO. 858

St. Louis Children’s Hospital Foundation One Children’s Place, St. Louis, MO 63110 888.559.9699 or 314.286.0988 childrensdiscovery.org

The Children’s Discovery Institute is a multidisciplinary, innovation-based research partnership between St. Louis Children’s Hospital and Washington University School of Medicine. Launched in 2006, the Institute is focused on accelerating discoveries in pediatric research to ultimately find cures for the most devastating childhood diseases and disorders. We 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