Intestinal fortitude

In 1932, JAMA: The Journal of the American Medical Association published “Regional Ileitis: A Pathologic and Clinical Entity,” which described 14 patients who had been treated at New York’s Mount Sinai Hospital for fever, abdominal pain, diarrhea and emaciation. Despite its rather understated title, the article was soon recognized as a classic, and its first author, Burrill B. Crohn, M.D., has been immortalized by that honor peculiar to medicine, his name forever conjoined to an illness.

Today, Crohn’s disease and ulcerative colitis fall under the broader clinical umbrella of inflammatory bowel disease, or IBD. According to Judy H. Cho, M.D., associate professor of medicine and one of the world’s leading experts on the genetics of IBD, both diseases are chronic autoimmune conditions with similar symptoms, primarily distinguished by the regions of the gastrointestinal tract on which they wreak their havoc.

When Cho entered medical school at The Ohio State University in her hometown of Columbus, she planned to become a surgeon. But “when I saw the neurosurgeons standing in the OR for twelve hours,” she says with a laugh, “I decided it wasn’t for me.” Instead, after her residency at Northwestern University, Cho completed a fellowship in gastroenterology in 1991 at the University of Chicago.She got great satisfaction caring for IBD patients, she says, because the disorder’s chronic nature allowed her to build close relationships that approached those enjoyed by a primary care physician. Some cases of IBD can be successfully managed with immunosuppressant drugs, but up to two-thirds of patients require hospitalization or surgical treatment at some point in their lives.

But 60 years after Crohn’s JAMA paper, the causes of IBD remained a scientific mystery. “In about 1993,” says Cho, “I was sitting in a lab flipping through Science and saw a paper from Bert Vogelstein’s lab [at Johns Hopkins] which ultimately led to the identification of a whole new class of genes that, when mutated, cause a hereditary form of colon cancer.” Because IBD is also a familial disease, Cho recalls, “it clicked in my mind at that moment that genetic research was a perfect melding of clinical relevance and basic science.”

Soon after, Cho collected her first DNA samples from her patients. In 2001, before moving to Yale, Cho and colleagues at the University of Michigan were the first to establish a genetic vulnerability, in a gene known as NOD2, for Crohn’s disease.

Now, in addition to directing Yale’s Inflammatory Bowel Disease Program, an interdisciplinary group of gastroenterologists, radiologists, surgeons and pathologists, Cho chairs the steering committee of the IBD Genetics Consortium, a group of seven academic centers devoted to unraveling causes of the disease. This January, Cho and other members of the consortium linked regions on two chromosomes with ulcerative colitis.

But the successes in IBD genetics thus far are “low-hanging fruit,” Cho says, adding that further progress will require careful classification of IBD patients, whose symptoms and clinical course can vary wildly from case to case.

“The major reason to do genetics is to develop new therapeutic targets and to refine our understanding of the disease” she says. “We’re not lacking for potential targets, but we’re lacking an understanding of how the immune mediators associated with IBD combine to cause disease. Part of this means figuring out how to follow patients better over long periods of time, which our present research system doesn’t do very well.”

With an eye to the future, Cho acts as a mentor to young physician–scientists through the Yale Center for Clinical Investigation. “Human translational work is much more complex than classic basic science,” she says, largely because the lives of human patients don’t unfold in the tightly controlled confines of the lab. So Cho sets her sights with a wide range. “It will be very challenging to develop a novel therapy,” she says, “ but the intermediate goal is to somehow classify people a little bit better.”