“The NIH won’t support research until the idea is proven valid—the Children’s Discovery Institute funds the studies that provide the proof.”— Dr. Patrick Jay

Highlights of Our Second Annual Symposium

“The Children’s Discovery Institute catalyzes ideas among scientists, who might never have been able to work together without this funding.” 

So said Patrick Jay, MD, PhD, an Institute investigator and cardiologist at St. Louis Children’s Hospital and Washington University School of Medicine. Dr. Jay echoed a sentiment heard over and over at the Institute’s Second Annual Symposium. As noted by Lee Fetter, President of Children’s Hospital, speaking at the symposium, “many applications of basic research to childhood illness just wouldn’t be happening without funding from the Children’s Discovery Institute.” 

The annual symposium showcases cutting-edge research and its implications for children’s health. The symposium brings together investors, investigators, and friends of the Institute—a diverse group of people who, in the words of the Institute’s Executive Director, Alan Schwartz, MD, PhD, “are united in their dedication to children who suffer from serious, sometimes deadly diseases.” 

“From bench to bedside” in children with heart failure

All of the Institute’s research projects ultimately aim to improve pediatric diagnosis and treatment—to translate findings at the laboratory “bench” to better care at the patient’s bedside. So when investigators begin to study potential therapies for young patients, it’s a cause for celebration. 

One research team presenting its work at the symposium—Dr. Jay and his fellow cardiologist, Charles Canter, MD—has embarked on studies to show how abnormalities of insulin and glucose (blood sugar) metabolism develop in children with heart failure. Today, medical advances allow many children born with congenital heart defects to survive, but these survivors often face the threat of heart failure. By understanding the nature of insulin resistance in their patients, Drs. Jay and Canter hope that its treatment could improve their quality of life and outcomes.

The research began at the laboratory bench, when Dr. Jay teamed up with Paul Hruz, MD, PhD, a pediatric endocrinologist also at Washington University. By conducting research in mice, Dr. Jay and Dr. Hruz learned that heart failure is associated with systemic resistance to insulin and abnormal uptake of glucose in the heart muscle (the myocardium). They wondered whether correcting these abnormalities with a drug prescribed for diabetes would help. In fact, when insulin sensitivity and myocardial glucose uptake improves, so does the function of the heart and survival in the animals. 

As a result of this basic research, Drs. Jay and Canter are now studying insulin sensitivity and myocardial glucose uptake in children with heart failure. Their preliminary findings suggest that the abnormalities discovered in the lab likely occur in their patients as well. “I’m encouraged by what we see,” said Dr. Canter. “If there is a relationship between glucose and heart failure, it may give us the key to helping children recover from heart failure, without recourse to a heart transplant.” 

Winning NIH sponsorship 

In the short-term, Drs. Canter and Jay plan to collect additional data at St. Louis Children’s Hospital as well as with other pediatric heart failure centers, in a study sponsored by the National Institutes of Health (NIH). They have been aided in their work by nuclear medicine expert Robert Gropler, MD. Dr. Gropler conducts imaging studies that measure the uptake of glucose by a child’s heart. 

In the long-term, these investigators hope their work will lead to clinical trials that answer a question posed by Dr. Jay: “Can diabetes drugs, which affect the uptake of glucose, improve the lives of children with heart failure?” 

Dr. Canter stressed that Institute-funded research has led to “a real opportunity in children with heart failure. It’s possible that therapy targeting blood sugar or insulin metabolism might help these children.” 

Dr. Jay agreed, and noted that today, “our team wouldn’t be involved in the NIH study without the initial funding of the Children’s Discovery Institute.” He added that “a large organization like NIH won’t support research until a scientist has strong data to prove an idea is valid. That’s where the Institute comes in—it funds the studies that provide the proof.” 

Genetic and cellular research presentations

Several other investigators presented important findings at the symposium. 

• Genetics of respiratory distress. Many of the serious diseases of children have a basis in genetics. At the symposium, Rob Mitra, PhD, an assistant professor of genetics at Washington University, presented genetic research on one of the most devastating events a family can endure—respiratory distress syndrome (RDS) in a newborn. 

The lungs of babies with RDS do not produce enough of a substance called pulmonary surfactant, so they cannot get enough oxygen when they breathe. Dr. Mitra’s goal is to find out which genes, when mutated, cause or predispose to RDS. To achieve his goal, Dr. Mitra is using cost-efficient, next-generation technology to conduct gene sequencing—a method to determine the order of the components in a DNA molecule. Collaborating with Dr. Mitra is a team of physicians from the department of pediatrics: F. Sessions Cole, MD, Aaron Hamvas, MD and Todd Druley, MD, PhD. 

• Neuromuscular diseases. Genetics also determine another group of serious illnesses that begin in childhood—the inherited neuromuscular diseases (NMDs). NMDs include muscular dystrophy, spinal muscular atrophy, and a host of other syndromes that progressively weaken muscles and nerves. 

During his symposium presentation, Robert Baloh, MD, PhD—a neurologist at St. Louis Children’s Hospital and Washington University School of Medicine and one of the Institute’s Faculty Scholars—noted that NMDs “lead to severe disability and premature death. And unfortunately, there are no effective, disease-altering therapies we can give to patients with most of these diseases.” 

Dr. Baloh is leading two major projects. The Neuromuscular Genetic Project will maintain a centralized database of DNA samples from patients with NMDs. Since 2006, over 750 DNA samples have been collected for use in research. The project will also examine how to use next-generation gene sequencing technology to make genetic diagnoses of NMDs. Simultaneously, the Fibroblast and Induced Stem-Cell Project will use adult stem cells— which are derived from a small piece of each patient’s own skin—to study the pathways of NMD and the treatments that might alter those pathways.

• Cancer and circadian rhythms. Erik Herzog, PhD, an associate professor of biology at Washington University, presented findings on the link between brain cancer and circadian rhythms—the biological clocks that control our bodies. “There are certain times of day” Dr. Herzog said, “when children’s cancers may be more susceptible to treatment and when side effects of anticancer drugs could be minimized.” 

Working with a team that includes Joshua Rubin, MD, an oncologist at St. Louis Children’s Hospital and Washington University School of Medicine, and Washington University biologist Luciano Marpegan, PhD, Dr. Herzog has found that the cells of one type of pediatric brain tumor, the astrocytoma, express daily rhythms in their “clock genes.” When these cells aggregate, as in a tumor, it alters the activity of the clock genes. Exposing the cells to cancer chemotherapy can, depending on the drugs chosen, synchronize or desynchronize the daily rhythms. 

“My hope,” said Dr. Herzog, is that “we can learn to deliver cancer treatments in synch with a child’s body rhythms, to improve clinical outcomes.” 

That kind of hope—a better life for gravely ill children—is what drives and inspires everyone involved in the Children’s Discovery Institute.