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James To Direct NIDDK's Division of Digestive Diseases and Nutrition

Dr. Stephen P. James has been named director of the Division of Digestive Diseases and Nutrition (DDN) at NIDDK. He had been head of the division of gastroenterology for 10 years and held the Moses and Helen Paulson chair in gastroenterology at the University of Maryland School of Medicine when he decided to return to NIH research and an NIDDK administrative role in 2001; he has been DDN deputy director for the past 2 years.

A Phi Beta Kappa graduate of Cornell University, Dr. Stephen James got his M.D. from Johns Hopkins School of Medicine in 1973. His research projects have received substantial support from both NIH and the Crohn's and Colitis Foundation in the last decade. He is a section editor of Inflammatory Bowel Disease, a past member of the editorial board of Gastroenterology and the author of multiple articles and book chapters.

A leader in the field of inflammatory bowel disease (IBD) research, James has seen several major shifts in the study of complex, immune-mediated GI disorders such as Crohn's disease and ulcerative colitis since he became interested in the field as a medical student during the early 1970s. After a gastroenterology fellowship at the University of Maryland, James first came to NIH in 1977 as a medical staff fellow in the liver diseases section of NIDDK and began studies on the immunology of liver disease. He furthered his training in immunology at NCI in the early 1980s and subsequently was a senior investigator in NIAID's Laboratory of Clinical Investigation until 1991, focusing on the immunological features of IBD.

In the early days, James recalls, immunology researchers focused on aspects of the "innate" immune system such as macrophages, and the structure and function of antibody molecules. When the role of T cells and B cells came to light, interest shifted to the biological workings of the "adaptive" immune system and how it programs its weaponry. With the recent discovery of the card15 gene mutation, which appears to increase a person's risk of developing Crohn's disease, research interest has shifted back to the innate immune system. Researchers hypothesize that it's possible that some cells may be deficient in sensing bacteria, which might result in an exaggerated inflammatory response.

"This is typical of how things recycle in science," says James, whose current mission as director of DDN is to better understand the perplexing biological mechanisms behind complex diseases, knowledge that would make new diagnostics and treatments possible.

Despite incremental discoveries, the mechanism behind Crohn's disease, an inflammatory disease of the small bowel, remains something of a mystery. Crohn's afflicts an estimated 400,000 to 600,000 Americans. "We still have a lot to learn," says James. One important recent advance was the discovery that tumor necrosis factor (TNF) is an inflammatory cytokine. This finding led to the development of infliximab, an anti-TNF monoclonal antibody, which has been effective in relieving symptoms in two-thirds of patients. "This is an example of the kind of bench to bedside progress we would hope to bring to other digestive diseases," James adds.

IBD comprises two of the complex digestive diseases needing more effective diagnostic tests and interventions. "The average person goes many years before being diagnosed," says James. "In Crohn's and ulcerative colitis, our long-term goal is to figure out who's at risk early enough to modify environmental risk factors and to intervene before complications and morbidity become an issue."

Celiac disease is another chronic inflammatory disease with interesting research potential, James points out. In this case, medical science knows a bit more: the body reacts to environmental triggers — proteins in wheat, rye and barley. "We also know there's a genetic link," he adds. "The question is: How do the controlling genes interact with the protein triggers to cause disease?"

Celiac disease is easily treated by eliminating these foods from the diet, James notes, but it remains widely underdiagnosed because symptoms are difficult to recognize and a biopsy is necessary to confirm diagnosis. "Celiac is a good research model," he says, "because once we know more about how genes and the environment conspire, we may be able to apply that information to other complex diseases. If we can develop better diagnostic tests, it will be possible to prevent complications and morbidity at low cost."

Digestive diseases such as IBD, esophageal reflux, celiac disease and chronic liver diseases such as hepatitis B and C all cause chronic inflammation and are associated with an increased risk of cancer. "Right now," James says, "we're collaborating with NCI in studying Barrett's esophagus as a precursor to esophageal cancer. We also are cooperating with the NIAID in hepatitis C studies."

In motility disorders such as gastroesophageal reflux disease (GERD) and irritable bowel syndrome (IBS), there are great opportunities for advances through neuroscience, James says, particularly in understanding the complex activities that connect the brain to the nerves in the gut. This has become "an exciting new area for patient-based research."

In addition, researchers are interested in how stress, depression and anxiety disorders affect motility. "We need to integrate neuroscience approaches with studies of diseases of the gut, and we have a number of interesting programs in this area," says James. One research center supported by NIDDK and the Office of Research on Women's Health is now using brain imaging and other novel technologies to study functional bowel disease.

The only way to tackle these little-understood disorders is through an interdisciplinary approach and basic science, according to James. "Fundamental research is our bedrock," he says.

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