A Magic Formula
Blend of Science and Medicine Entices Outstanding Young Faculty to Packard

BY KRISTA CONGER

SPRING 2003 - Call it translational medicine. Or bench-to-bedside. Whatever the term, Lucile Packard Children's Hospital is at the forefront of a drive to interweave research and medicine to bring new scientific discoveries quickly to a child's bedside.

The Hospital's young patients benefit greatly from this strong collaboration between the physicians who care for them and the researchers who seek better treatments and cures for their illnesses. But there is another plus: This kind of interdisciplinary work makes Packard very attractive to junior faculty.

"Some of the best young people in pediatrics come here to establish their careers," says Harvey Cohen, M.D., Ph.D., chief of staff at the Hospital. "They believe in Packard's combination of comprehensive clinical care and academic work to improve the future health of children. They are dedicated not only to taking care of children but also to finding solutions to the diseases that affect them. It's a magic formula that will continue to attract the best and the brightest."

So what are these rising stars up to? Here's a sampling of three of the many Packard physicians and researchers devoted to caring for, and curing seriously ill children.

Tina Cowan, Ph.D.
Predicting Metabolic Disorders

Tina Cowan, Ph.D., might seem like a modern day fortune teller -- parlaying drops of blood into predictions about a child's future. But she and her colleagues in Packard Children's Hospital's newly established Biochemical Genetics Laboratory are looking for something very serious: metabolic glitches caused by defective or missing proteins, which can cause brain damage or death in children if not treated immediately.

"Many of these diseases are treatable, but only if you know exactly what you're dealing with," says Cowan, director of the laboratory. Prior to the lab's opening last July, that knowledge required shipping blood or plasma samples to facilities scattered across the country. Results could take up to a week, with little or no interaction between those who analyzed the data and those who treated the patient.

Using sophisticated testing and analysis, Tina Cowan, Ph.D., and her team in the new Biochemical Genetics Lab at Packard help diagnose and monitor the treatment of patients, like Joshua Aragon, with inborn errors of metabolism. Joshua has cobalamin C disease, a rare inherited disorder that causes neurological and vision problems as a result of abnormal processing of vitamin B12.

The lab -- the only one of its kind in Northern California -- exists in part due to a gift from the Pavlov family, who endured the anxious wait for results of tests on their newborn daughter, Madeline, in early 2000. Support also came from former colleagues of Madeline's father, George, at the Mayfield Fund and his current colleagues at Tallwood Venture Capital. The lab analyzes samples from infants like Madeline, who tested positive on an expanded newborn screening test, and from older children exhibiting suspicious symptoms such as vomiting, seizures, and lethargy.Most samples are from Packard patients, but the lab also serves local hospitals.

Although many of the hundreds of possible metabolic problems are very rare, some, like phenylketonuria (PKU) are much more common. Babies with PKU -- about one in every 12,000 infants -- face progressively worsening mental retardation and developmental delays unless the common amino acid phenylalanine, found in meat, fish, and dairy products, is severely restricted from their diet.

Cowan and her colleagues are able to offer quick and personalized results using a variety of sophisticated equipment, including a tandem mass spectrometer -- a large machine adept at cataloging and quantifying the hundreds of biochemical compounds found in a single drop of blood. Cowan envisions one day expanding the lab's capabilities to include prenatal testing for metabolic deficiencies, and to researching why some children with identical mutations experience different symptoms.

"At a lab like this at an academic medical center," she says, "each patient has a story."

Karl Sylvester, M.D.
Coaching Fat Into Tissue

If Tina Cowan is a fortune teller, then Karl Sylvester, M.D., is an alchemist. Sylvester is studying chameleon-like cells found in fat that appear to be able to form many different types of tissue -- at least in the laboratory. He and his colleagues want to know if these cells can one day be used in children to repair or even regenerate damaged organs, or to deliver missing genes.

"We're tying to understand if it's a true design of nature that cells from two locations are able to become the same thing when exposed to the same signals," says Sylvester. If so, it may be possible, for example, to isolate the cells from the fat of a child with diabetes and tutor them in the laboratory with the specific biochemical signals usually heard by insulin-producing cells in the pancreas. The cells would then be returned to the patient, and if all goes well, the newly indoctrinated cells would lodge in the pancreas and begin churning out insulin.

Karl Sylvester, M.D., and his colleagues at Packard and Stanford are at the forefront of regenerative medicine. Their work focuses on ways a child's own cells can be used to replace defective or diseased tissue. Sylvester's preliminary data suggest that fat cells can be turned into different types of tissue, such as bone, cartilage, or endothermal cells that make up the liver or pancreas.

The technique also may make it possible to train the cells to replace liver, kidney, or other types of cells in children whose organs have been damaged by diseases like cancer or by traumatic injury.

Although this type of regenerative medicine is not yet possible, it holds some very concrete potential benefits: the cells from fat are easily obtained and, because they are not foreign, they will not be rejected by the patient's immune system. Even if the cells are transplanted from one person to another, perhaps to supply a critical gene missing in a patient's cells, they are less likely than other types of cells to be rejected.

Sylvester and his colleagues are comparing cells from fat with another versatile type of cell from the bone marrow. They'd like to learn exactly how to direct the cells to specialize, or differentiate, into various types of tissues, beginning with bone, cartilage, and perhaps muscle. After working out the kinks in the laboratory, the researchers plan to try using the now specialized cells in mice with diseases that mimic those in people.

"Do the cells perform in vivo as they do in the laboratory?" says Sylvester. "That's the ultimate yardstick."

Eric Sibley,M.D., Ph.D.
Understanding Gut Reactions

Unlike Karl Sylvester, Eric Sibley, M.D., Ph.D., isn't interested in your fat; it's your gut that fascinates him. Sibley is trying to piece together how different proteins are produced in different places along the length of the intestine. By focusing on one particular protein, lactase, Sibley hopes one day to be able to toggle genes, and the proteins they make, on and off like light switches. His findings could help treat a wide range of gastrointestinal disorders, ranging from basic lactose intolerance to necrotizing enterocolitis -- a bowel inflammation common in premature babies that can kill parts of the intestine.

"The gut is normally thought of as just a big, long tube; it looks very similar at both ends," says Sibley. "But some genes are specifically expressed at the beginning, the middle, or the end of this tube.We'd like to understand how genes are turned on and off at different locations in development, and what the clinical implications are."

For the last five years, gastroenterologist Eric Sibley, M.D., Ph.D., has treated 18-year-old Chelsea Stock, who has Crohn's Disease, a chronic and severe inflammation of the lower intestine. By studying the mechanisms of gene expression in the intestine, Sibley's research may some day lead to new treatments for a variety of debilitating gastrointestinal diseases.

Lactose intolerance is caused by the loss of lactase enzyme activity. Understanding how the body stops making lactase has far-reaching implications. If Sibley can learn how to turn on the expression of critical digestive enzymes in regions of the gut where they are normally silent, his research could make the difference between eating normally and long-term intravenous nutrition for infants who have lost part of their bowel due to necrotizing enterocolitis.

"Many enzymes, like lactase, are expressed in the middle segment of the gut," says Sibley. "If we can identify a common mechanism of gene expression, we may be able to increase the expression of digestive enzymes in other parts of the gut and potentially treat these infants' bowel problems."

The intestine's large absorptive surface also makes it an attractive target for gene therapy that ultimately could be used to treat a variety of diseases. Theoretically, a patient could swallow a capsule containing a specially packaged piece of DNA that would set up residence in the lining of the intestine and deliver the missing protein directly into the blood supply.

"The more we know about intestinal-specific gene expression, the more helpful it is to eventual gene therapy in the bowel," says Sibley. "The bowel is an attractive target for gene transfer, but we need to understand how to turn the genes on and off to maximize the treatment's effectiveness."