The Second Annual Children's Discovery Institute Symposium

Investors and investigators gather to share, discuss progress

(St. Louis, The Eric P. Newman Education Center) Could a child with heart failure benefit from a drug that controls blood sugar? Can we find a treatment for muscular dystrophy targeted to the genetics of the disease?

Those were just some of the questions discussed when scientists, investors, and friends of the Children’s Discovery Institute gathered on September 30th for this year’s investor symposium. The symposium showcased the work of Institute investigators, who presented posters of their research or gave talks during breakout sessions.

Investigators described how advances in “bench” research—basic lab studies in cells or in mice—could be harnessed to improve pediatric medicine, and how the Institute helps make this possible. In the the words of Lee Fetter, President of St. Louis Children’s Hospital, who addressed one of the breakout sessions, “many applications of basic research to childhood illness just wouldn’t be happening without funding from the Children’s Discovery Institute.”

The Heart of the Matter

The connection between “the bench and the bedside” emerged clearly in the presentations of one group of investigators—Drs. Charles Canter and Patrick Jay, cardiologists at St. Louis Children’s Hospital. These scientists have forged a link between heart failure in children and metabolism of glucose (blood sugar).

“Today,” noted Dr. Jay, “medical advances allow many children born with congenital heart defects to survive, but these survivors often face the threat of heart failure.” Dr. Canter echoed this concern, and added, “helping children recover from heart failure, without the need for a heart transplant, is a very worthy goal.”

By conducting research in mice, Dr. Jay and his colleague Dr. Paul 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. 

Drs. Jay and Canter are now studying insulin sensitivity and myocardial glucose uptake in pediatric heart failure patients. Their preliminary results suggest that the metabolic abnormalities discovered in the lab likely occurs in their patients as well.

In the short-term, they 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.  In the long-term, they hope that this work will lead to clinical trials of diabetes drugs with the goal of improving the lives of children with heart failure.

Next-Generation Genetics

Many of the serious diseases of children have a basis in genetics. Dr. Rob Mitra, 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.

RDS is the most common cause of death in babies under 1 month old. These babies’ lungs do not produce enough of a substance called pulmonary surfactant, so they cannot get enough oxygen when they breathe. Studies in twins show that 50% to 80% of RDS cases can be explained by heredity.

Dr. Mitra’s goal is to find out which genes, when mutated, cause or predispose to RDS. In today’s medicine, knowing the genetics of a disease is the first step to prevention and treatment.

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.The plan is to sequence 2000 genes expressed in lung cells of RDS infants, then compare them to genesequences in healthy babies. Collaborating with Dr. Mitra is a team of physicians from the department of pediatrics:  Drs. F. Sessions Cole, Aaron Hamvas, and Todd Druley.

 Birch Mullins, Ray Van de Riet, Laurie Van de Riet 
The sequencing will enable Dr. Mitra to correlate genetic mutations with RDS. “Right now,” said Dr. Mitra, “we’re sequencing the first 50 genes as a pilot project. We will complete the remaining genes by next summer, and we expect to find a number of genes that predispose to RDS.”

Genetics also determines 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. According to Dr. Robert Baloh—a neurologist at St. Louis Children’s Hospital and one of the Institute’s Faculty Scholars—NMDs are relatively common, affecting about 1 in 1500 people.

“These diseases,” Dr. Baloh noted in his symposium presentation, “lead to severe disability and premature death. And unfortunately, there are no effective, disease-altering therapies we can give to patients with most NMDs.”

One limitation in caring for patients with NMDs is that, in many cases, we are not able to make an exact, genetic diagnosis. If we could reliably identify the genetic mutations in patients’ NMDs, we could begin to test different therapies that might specifically target the genetically determined pathways of disease. For that reason, Dr. Baloh is leading two major projects: the Neuromuscular Genetics Project and the Fibroblast and Induced Stem-Cell Project.

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 derived from a patient’s own tissue (taken from a small piece of skin) to study the pathways of NMD and the treatments that might alter those pathways.

Clocks and Cancer

Circadian rhythms are the biological clocks that control our bodies. In his symposium presentation, Dr. Erik Herzog, an associate professor of biology at Washington University, described the discovery that brain cancer cells and their response to treatment show circadian variations.

 Dr. Erik Herzog, during a breakout session 
“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 Dr. Joshua Rubin, an oncologist at St. Louis Children’s Hospital, and biologist Dr. Luciano Marpegan, 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.

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

Children First

The presentations and posters at the symposium show the breadth and range of Institute-funded research. As diverse as the research is, all projects share one ultimate goal: to improve the health of children.

Children’s Discovery Institute Executive Director, Dr. Alan Schwartz, summed it up. “Every investigator,” he said, “in partnership with every supporter of the Children’s Discovery Institute, strives to help those children who suffer from serious, sometimes deadly, diseases.”


Keith Harbison, Birch Mullins

Clarence Dula, Dr. Alison Nash

Listening to a breakout session. Top row:  Debbie Tarlow and Rich Alotta.  Middle row:  Karen Hueseman.  Bottom row: Susie and Joe Sivewright.