New funds support physicians in research

By Ann Barnard
Printed with permission from the Globe

Todd Golub, M.D.

May 28, 2002--Dr. Todd R. Golub noticed that some children he treated at the Dana-Farber Cancer Institute fought off leukemia unusually well, an insight that led him to discover genetic differences that can predict patients' responses to chemotherapy and allow some to avoid the harshest doses. Dr. Bruce D. Walker sat up and listened when a Somerville man named Robert Massie told him he had carried the HIV virus for two decades without getting sick. Studies of Massie's blood helped show that the immune system can be stimulated to fend off AIDS. Dr. Christopher A. Walsh spent five years studying a family in which six out of about 20 close relatives had either mental retardation or epilepsy. In the process, he discovered a genetic mutation that hampers the movement of brain cells during early development. The three Harvard-affiliated researchers are among 12 physician-scientists selected by the Howard Hughes Medical Institute to receive up to $1 million a year in research funding as part of a new initiative announced yesterday to reward the increasingly rare investigators who treat patients while also working in the lab to understand the biology of diseases.

Scientists say that balancing act is becoming harder and harder to achieve as both medical practice and science become more complicated and specialized - yet it is more and more necessary in order to harvest the potential benefits from the exploding study of the human genome.

''We're talking about people who derive the inspiration for their science from the patients that they see, and then they go into the lab and discover the basis of the disease process on the level of the genes and proteins that are involved,'' said the institute's president, Thomas R. Cech. ''Then they turn back to the clinic to find ways to intervene.''

The institute chose the winners from among 160 applicants and would have chosen more than 12 if it could have found more meeting its standards, Cech said. ''The good news is that we were able to find 12 of these people. The bad news is there were not hundreds.''

Only about 5 percent of physicians choose a research-oriented career, said Dr. David G. Nathan, president emeritus of Dana-Farber and a medical adviser to the Hughes institute, and among them many end up focused exclusively on the lab.

Doctors who want to both treat patients and do serious laboratory work face increasing obstacles, partly because research is not that lucrative. To begin with, only around 20 percent of grant applications to the National Institutes of Health get funded. It can be hard to find mentors outside major research centers like Boston. The average debt of a medical school graduate has climbed to around $100,000.

Dr. Leonard Zon, professor of pediatrics at Harvard, who is a Hughes researcher and vice president of the American Society of Clinical Investigators, said many young doctors interested in research would like to see the creation of debt forgiveness programs. He said one young doctor told him at a recent conference on research careers, ''If you have significant debt at the end of medical school, you've got to be crazy to go into research.''

Dana-Farber's Nathan said another obstacle was the increasing public suspicion of clinical trials following a few scandals where researchers had conflicts of interest. ''Patients feel they're going to be used,'' he said. ''The whole thing is built on trust. Bob Massie trusts Bruce Walker. He knows that Bruce would never do anything that wasn't in his interest.''

But by far the biggest problem, Nathan said, is that the volume of knowledge now needed to excel in any clinical or research area is so great that only a few top doctors can manage both. In the long run, he said, science will have to shift its focus from individual star researchers to teams that include both clinicians and lab scientists, working together and sharing credit and blame.

Walker, director of the Partners AIDS Research Center, said he was grateful to two patients in particular for his discoveries: First, Massie's blood showed that he had an immune response that was thought to be absent from HIV-infected patients. Then, Walker and his team were able to foster that same response in another man, a newly infected AIDS patient. The work helped pave the way for the three-drug cocktails that patients diagnosed early with HIV now take to control virus levels.

The Hughes money will allow Walker to expand clinical trials to patients with more advanced disease, as well as detailed laboratory studies to look more closely at how the body controls the virus at the molecular level and how that process can fail.

Golub, who pioneered the dividing of acute lymphocytic leukemia into subsets according to genetic characteristics, plans to use the new funding to expand that work to adult solid tumors, a more complicated enterprise.

Walsh, who is based at Beth Israel Deaconess Medical Center, says he will use the funding to expand his outreach work to physicians around the world, from India and the Middle East to Australia. He helps doctors come up with more specific diagnoses for children with mental retardation or neurological disease, in order to offer more tailored treatment or family counseling. In return he tries to recruit families for further genetic studies, particularly from places where there are large families living in relative isolation, giving him the homogeneous populations he needs to trace and single out the genes involved.

This story ran on page B1 of the Boston Globe on 5/28/2002. Click here for the original.

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