Learning from Patients: Inspiration and Insights
By Karen Hopkin

For oncologist Bert Vogelstein, it was Melissa. For neurologist Huda Zoghbi, it was Ashley. These young patients—a four-year-old with leukemia and a two-year-old with Rett syndrome—led Vogelstein and Zoghbi to devote their energies to combating human disease. But patients do more than inspire researchers. They provide scientists with insights that guide them toward new methods for diagnosing, preventing, and treating these disorders. And by cooperating with researchers like Zoghbi and Vogelstein, patients advance our understanding of fundamental human biology.

"Mutations and the diseases they cause are nature's most ancient experiment," says Zoghbi, "and they provide great clues about biology." Her studies of Rett syndrome and of the neuromuscular disorder spinocerebellar ataxia type 1 have yielded insights into the maturation and interaction of neurons, the regulation of gene activity, and the operation of the molecular machinery that clears damaged proteins from cells. In addition, Zoghbi's investigations provide scientists and physicians with new ways of thinking about more common neurological disorders, including autism, mental retardation, and Parkinson disease.

Of course, she had no way of knowing that when she started out. "I pursued these disorders because of intrinsic rewards," says Zoghbi. "I got to know the patients, and I wanted to help them in some way. I was also simply curious about these diseases and how they destroy the nervous system."

That curiosity led her to discover the genes that drive both of these diseases. Along with those genes came a broader appreciation of the molecular underpinnings of the disorders, as well as new strategies for diagnosis and treatment. For example, development of a mouse model of Rett syndrome led to the discovery that mutations in the responsible gene cause animals to display anxious behaviors, such as avoiding elevated spaces. The finding suggests that antianxiety medications might alleviate symptoms in children with Rett syndrome. In this way, researchers hope that obtaining a better understanding of basic biology will ultimately benefit their patients.

This synergy between medicine and research requires that people in the clinic keep in touch with people in the lab and vice versa. "The journeys you take as physicians and basic investigators will be quite different," Zoghbi told the graduates of the Baylor College of Medicine at their commencement ceremony in 2001. "But there will be times when your paths might cross. Stop and talk to each other."

To fuel that dialogue, she says, clinicians should "keep their eyes open" and take time to think about their unusual cases. Most patients have common problems that can be easily handled, Zoghbi notes. "But occasionally you'll encounter a patient who will have unique features that leave you and your colleagues at a loss." Pay attention to these special patients she says. "This will not only help your patient, but it might lead you to a path of discovery that you would have never imagined."

When it comes to stimulating scientific exploration, says Zoghbi, "sometimes a single patient can make a difference."

Such patients have, at times, also kept Vogelstein on track. In late 1980s and early 1990s, he and his colleagues were searching for a gene for a form of colon cancer dubbed HNPCC. The problem, says Vogelstein, is that the researchers weren't positive that the disease was hereditary. Colon cancer is so common that several people in the same family can develop the disease by chance alone. If this were true for HNPCC, combing families for the culprit gene would be fruitless. The scientists searched for years and were on the verge of giving up when a man in the Newfoundland family they were studying got colon cancer at the age of 28. "We knew that wasn't likely a chance occurrence," Vogelstein says. The man was too young to develop the disease without inheriting a predisposition. So the team redoubled its efforts and eventually turned up the gene for HNPCC. The young man and his family, says Vogelstein, "pushed the research forward."

Vogelstein and his colleagues have spent the better part of two decades trying to understand the genetics and biology of cancer. "Now we are trying to take that knowledge and apply it to treating the disease," says Harith Rajagopalan, an M.D.-Ph.D. student who works with Vogelstein. Many of the research projects in the lab are aimed at identifying genes and proteins that can serve as drug targets, devising more efficient and less invasive ways to diagnose cancer early, and discovering compounds or therapeutic approaches that can be tested in clinical trials.

Here, too, the investigators are often motivated by personal experience. Shibin Zhou, a junior faculty member in Vogelstein's group, joined the lab in part, he says, "because it's so hard to watch patients dying of cancer." One of Zhou's patients was a smoker in his early 30s who had advanced lung cancer. "He would kneel down in front of my office and beg me for painkillers," says Zhou. "I was holding his hand when he died. It was so painful. That's the major reason I study cancer—so that I can use what we learn from basic research to benefit cancer patients directly."

Although the work is noble, says Rajagopalan, "it takes a lot of vision and guts. Projects we do tend to be risky." Someone in the lab might spend years preparing a molecule or developing a cell line, he says, "and you don't know whether, in the end, it will be interesting or useful." And to be of any value, particularly to patients, experiments not only have to work, they also have to yield the desired result. "The tumors have to shrink. It's the only answer that is useful," says Rajagopalan. "And that answer can be hard to come by." But the potential rewards are tremendous.

"The best part about doing science, for me at least, is discovering completely new ways to help patients. Even one patient," says Vogelstein. "But it's also incredibly difficult to get to those moments. Diseases do not give up their secrets easily."

But researchers like Vogelstein and Zoghbi will continue to pry—because they are curious and because their patients depend on them. "I used to pass through the radiation unit to get to my lab," says Vogelstein. "It was filled with patients with incurable cancer. You can’t just walk through there every day and see these people and not want to do something—not want to find ways to help."

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