Two-Way Translation
Researchers and Caregivers Trade Expertise to Bring Innovative Treaments to Kids

BY MARK SHWARTZ

WINTER 2005 -- It was early July 1998, and while most kids were preoccupied with fireworks and parades, 14-year-old twins Mike and Josh Rubin had more pressing things on their minds. Doctors at Packard Children's Hospital had just discovered that both boys had a deadly cardiac disease, and that Josh, at least, would need a new heart to live.

Cardiologist Dan Bernstein, M.D., at Josh's bedside after the boy's heart transplant seven years ago.

A team of Packard cardiologists led by Daniel Bernstein, MD, had diagnosed the twins with cardiomyopathy— an abnormal enlargement of the heart muscle (myocardium) that reduces the ability of the heart to pump blood and often results in heart failure. Each year in the United States, one in 100,000 children under the age of 18 is diagnosed with cardiomyopathy, a largely hereditary disease.

The twins' father, Scott Rubin, had been diagnosed with the disease years earlier and had even undergone a heart transplant in 1985 when the boys were just a year old. Then, in 1998, during Fourth of July weekend, Josh was brought to Packard in a weakened condition with flu-like symptoms, which Bernstein diagnosed as advanced cardiomyopathy. Josh was told that he would need a transplant to survive. His identical twin, Mike, appeared to be in good health, but given the family history, Bernstein decided to have Mike tested as well. The results confirmed that, like his father and brother, Mike also had the disease.

The Rubin twins were fortunate to have come under the care of Bernstein, an expert in pediatric cardiomyopathy. As co-director of the Children's Heart Center at Packard, Bernstein exemplifies the growing trend in medicine toward translational research—clinicians developing new treatments and diagnostic tools at the laboratory bench and translating them directly to the patient's bedside. Of particular interest to Bernstein is designing new therapies for children that will alleviate the need for transplants and finding the underlying genetic causes of cardiomyopathy.

Bernstein's lab studies certain neurohormones, including adrenaline, which are activated when the heart begins to fail. "At first the hormones are beneficial because they increase the strength and rate of cardiac contraction, but in the long term they can cause damage to the heart muscle and lead to worsening heart failure, arrhythmias, and death," explains Bernstein, the Alfred Woodley Salter and Mabel Smith Salter Endowed Professor in Pediatrics and chief of the Division of Pediatric Cardiology.

Bernstein is especially interested in the role of drugs, known as beta blockers, which interfere with these hormones. "Although it was initially thought counterintuitive to give beta blockers to patients with heart failure, it turns out that these drugs have substantial beneficial effects because of their ability to inhibit chronic hormone stimulation," he says.

Mike, who was diagnosed with the same potentially fatal heart condition, wheels his brother to the car on the day of Josh's discharge from Packard.

Rather than let Mike's symptoms worsen over time, Bernstein suggested that he join a clinical trial to test a new type of beta blocker—an experimental drug designed to improve the heart's pumping ability. "Mike was one of the first patients to participate in a pediatric trial of this particular beta blocker, which has since become a standard therapy for adults and children with the disease," Bernstein says.

Now, seven years later, the Rubin twins are finishing college and thinking about future careers. Mike continues taking the beta blocker, now available by prescription, and has yet to undergo a heart transplant. "In some ways I was lucky because they caught it at the beginning stages," the 21- year-old math major recalls.

"It's likely that the beta blocker has kept Mike from requiring the transplant that his brother needed seven years ago," Bernstein adds.

This kind of bench-to-bedside medicine is what Packard is all about, says Harvey Cohen, MD, PhD, the Adalyn Jay Chief of Staff of the Hospital and the Arline and Pete Harman Chair of Stanford's Department of Pediatrics. "Often you think about translating as going in one direction -- from English to French, for example, or from one discipline to another," Cohen says. "But I look at it as a bidirectional phenomenon -- from bedside to bench and back to bedside."

A strong advocate of pediatric translational research, Cohen says the whole process begins with the patient. "It starts with a clinically significant problem for which you need some answers," he explains. "That's why it's so important to have a place like Packard Children's Hospital, which attracts children and families because of the comprehensive care we provide. Without patients, we wouldn't even know what the problems are."

According to Cohen, a successful program in translational medicine also requires the kind of expertise and entrepreneurship for which Stanford and its surrounding communities are famous. A good example is the university's celebrated Bio-X Program, which Cohen has been involved with since 1999. Bio-X brings together scientists and engineers from a wide range of disciplines to tackle significant problems in biology and biomedicine, including pediatrics. "If we were not part of a great university with medicine, engineering, and the basic sciences, and if we were not sitting in Silicon Valley, we wouldn't have the technologies around to try to answer key questions and bring the solutions back to the patients," he adds.

"Concentric Circles" of Care

"I like to think of translational research as concentric circles," Cohen explains. "At the center is a child with an illness. You surround that child with a comprehensive care team of doctors, nurses, therapists, psychologists, social workers and chaplains, and others. Surrounding them are clinical investigators who observe the course of the disease and suggest new treatment protocols. Surrounding the investigators are the basic scientists who research the disease and design new therapies in the laboratory.

"Information flows both ways," he says, "from the child to the caregivers and clinical investigators, to the researcher, so we find out what works and what doesn't, and then back through the investigators and care team to the patient to see how new technologies and knowledge can be applied to care."

Cohen believes that translational medicine is still in its infancy and that the greatest discoveries are yet to come. "We ain't seen nothin' yet," he says, pointing to the success of the Human Genome Project in mapping and sequencing all of the genes in human DNA. "With these results, we're going to be able to predict which kids are susceptible to certain diseases, what tumor cell abnormalities are specific to an individual child, and then design specific treatments to take care of them. I think Packard is going to be a leading force, because all the stars are lined up: We have great people, support from the community, and a terrific hospital on the campus of a leading research medical center and university sitting in the middle of Silicon Valley."

It's a sentiment echoed by former Packard patient Mike Rubin: "I know that experimental technologies aren't cheap, but these are our lives. I hope people continue to support more research."

Mike and Josh Rubin, today.