Five questions for Ramnik Xavier

Ramnik Xavier calls it “learning from human genetics.” That’s how the senior associate member of the Broad Institute describes his research building on the soaring number of genes now known to be implicated in two common disorders, Crohn’s disease and type 1 diabetes.

Working on a project funded by The Leona M. And Harry B. Helmsley Charitable Trust, Ramnik is seeking a better understanding of the two immune-related diseases based on genetic discoveries that Broad senior associate member Mark Daly and others around the world have made in the last three years. As head of gastroenterology at Massachusetts General Hospital (MGH), Ramnik has learned from his patients how difficult it is to live with Crohn’s disease, an inflammatory intestinal disorder whose genetic risk factors he is dedicated to unraveling.

Along with Mark Daly, co-director of the Program in Medical and Population Genetics at the Broad and chief of the Analytic and Translational Genetics Unit at MGH, Ramnik hopes to bring lessons from genetics to bear on both Crohn’s and type 1 diabetes, another disorder in which a combination of genetic risk factors, faulty regulation in the immune system, and a triggering event such as an infection are believed to result in lifelong disease. Ramnik reflected recently on one of the two diseases -- Crohn’s -- and the past 10 years, in which genetic research has revealed some likely causes for the disease and accelerated progress toward potential therapies. More detail about the Broad's Crohn’s and type 1 diabetes research can be found in this year’s Annual Report online.

Q1: What can medicine offer Crohn’s patients today?

RX: I have been a gastroenterologist for more than 10 years and the outlook for patients with Crohn’s disease has only marginally improved. The disease commonly affects the small bowel but any part of the gastrointestinal tract may be affected. The intestinal disease is often complicated by extra-intestinal manifestations that can affect joints, the skin, eyes and the bile ducts; and patients with Crohn’s are at an increased risk for small bowel and colon cancer. There are flares and they get progressively worse. Right now the big drugs are steroids, as well as biological agents, such as anti-TNF, which can affect the immune system globally. What we would like to find are drugs that affect the immune system in selective ways.

Q2: What has been learned about Crohn’s in the same 10 years?

RX: The NOD2 gene was discovered in 2001 and in the last nine years we have only begun to understand the function of NOD2 polymorphisms [different forms of the gene] associated with risk of disease. We have learned about genes that increase the risk of disease, genes that decrease risk of disease, and we have also begun to understand how the innate immune system may function as the gatekeeper of disease initiation. The next challenge is to find what genes do. In early studies, we have stumbled on new pathways such as autophagy.

Q3: What is autophagy and why does it look promising?

RX: Autophagy is a cellular process that digests and recycles proteins. It’s conserved all the way from yeast to humans, but in humans it has taken on a high-order function. In addition to working in the starvation or nutrient recovery program, it fights infection and it helps clear protein aggregates, so it has a role in both innate and adaptive immunity. Patients with changes in two genes associated with autophagy -- one called ATG16L1 and the second gene called IRGM -- are at increased risk for Crohn’s. There are a number of genes that are required for this program, but ATG16L1 is a key gene in that program. We are trying to find ways to modulate the autophagy program, asking if we can use already identified drugs that might correct the defect in patients.

Q4: What’s your approach?

RX: The goal is to identify novel small molecules with the potential to offer breakthrough therapy in type 1 diabetes and Crohn’s disease. By identifying the genetics and the genes that are altered in patients with these diseases, one could also try to design preventive approaches. We’ve already got some clues. For example, we know that programs that potentially correct autophagy or programs that correct the function of regulatory T cell in type 1 diabetes might be beneficial, so now the challenge is to find a small molecule, or drug-like molecule, that is safe to get into a patient.

Q5: You are also director of the Center for the Study of Inflammatory Bowel Disease and chief of Gastroenterology at MGH. How do you combine the clinical and research sides of your work?

RX: The goal is to bring patients in, make a clinical diagnosis, offer them the best available therapy but then also have access to patient-derived biological samples that we can bring to the Broad. We do high-end experimentation with state-of-the-art technologies to try to identify the genes that are abnormal in these patients and look to see what this genetic variation might do to the cells in patients vs. healthy controls. Our goal is to understand the signal transduction pathways that are altered, the gene expression changes that are brought about, and then try to use small molecules to get a better understanding of these pathways and, more important, see if we could correct it.