The primary research goal of the Xavier Laboratory at Massachusetts General Hospital and the Broad Institute is to discover and understand the function of important mediators and effectors involved in both the innate and adaptive immune systems. Of particular interest are the cellular components and regulatory networks that interact dynamically within temporal, spatial, and patho-physiological contexts of innate immunity. A second area of focus is to examine the pathway defects associated with genetic variants in inflammatory bowel disease and identify novel small molecules that interrupt signal transduction pathways associated with disease risk. We are pursuing integrative systems approaches that closely couple genome-wide experimentation with high-throughput assays and computational methods. Furthermore, we are pursuing studies of the microbiome in autoimmunity and inflammatory bowel disease.
Xavier Lab Team
Ramnik Xavier is the Kurt Isselbacher Professor of Medicine at Harvard Medical School and Chief of Gastroenterology at Massachusetts General Hospital. He is board certified in Medicine and Gastroenterology. Ramnik is also the Director of the Center for the Study of Inflammatory Bowel Disease, an Institute Member of the Broad Institute of MIT and Harvard, and Co-Director of the Center for Microbiome Informatics and Therapeutics at MIT. Ramnik is clinically active, teaching medical students, residents in medicine, and gastroenterology fellows rotating through MGH.
Massachusetts General Hospital and its collaborating institutions are important destinations for world-class care for patients with IBD, allergic disease of the gut and autoimmunity. As part of the initiative to link bench and bedside, we invite patients to participate in research efforts by providing clinical samples to both basic and translational researchers. The Xavier lab participates in many such cohort-building efforts, such as PRISM, SHARE, 500FG, and others. Insights from patient samples have led to advances in our understanding of both genetic and environmental risk factors for IBD and autoimmune disorders, responses to treatment, and the role of the microbiome in IBD and autoimmunity.
Examples of ongoing clinical cohort studies
Recent products of cohort studies
The immune system is implicated in a vast array of diseases along a spectrum of hyperinflammatory, hyperimmune, and autoimmune states. Among these diseases, inflammatory bowel diseases (IBDs), comprising Crohn’s disease and ulcerative colitis, are of particular interest in our lab. More than a million individuals in the United States have a form of IBD. These diseases have no known cause, but significant progress is underway in understanding the underlying mechanisms of these disorders. Our current model of IBD is based on a combination of increased genetic risk and an immune system that overreacts to environmental and microbial stresses.
To uncover basic mechanisms of IBD that can be used to develop treatment, our research takes three general and complementary approaches: using insights from human genetics to understand the biological mechanisms underlying disease, using genetic and chemical screens to identify the function of genes implicated in IBD risk, and gathering primary data from patients themselves. These approaches are guided by the lab’s central philosophy, which is to understand compelling biological and clinical questions, and drive innovation through development, optimization, and adaptation of new technologies.
Dr. Xavier is also a leader in the Broad Institute’s efforts to sequence thousands of exomes of IBD patients and healthy individuals in a project funded by the Helmsley Trust.
Genetics and pathways
Among complex diseases, genetics has been particularly successful in the identification of genes/genetic loci associated with risk of IBD. With this rapid progress, however, it has become clear that a major challenge in the study of complex genetic traits is to determine how disease genes and their corresponding alleles exert their influence on the biology of health and disease. Our working model is that alleles associated with predisposition to IBD — and more importantly, protection from IBD — will identify key pathways in the pathogenesis of IBD. We propose that defining these pathways will provide new insights into each disease state.
Innate and adaptive immunity
In research driven by insights from human genetics, we use functional genomics to discover and understand the function of important mediators and effectors involved in innate and adaptive immunity.
To this end, we are pursuing integrative systems approaches that closely couple genome-wide experimentation with high-throughput assays, chemical biology, and computational methods. Using these techniques, we are interested in understanding the role of regulatory circuits in mucosal immunity, in particular using (1) insights from human genetics and whole-genome sequencing to understand regulatory mechanisms in innate and adaptive immunity, (2) chemical approaches to controlling cellular disease phenotypes suggested by human genetics, and (3) harnessing computational approaches to uncover both broad and precise patterns of pathway activation in the context of disease and treatment.
Genes and Pathways
One approach to discovering the key mediators of innate and adaptive immunity focuses on defining immune-related genes and placing them in their proper pathways. Current areas of focus using this approach are studies of (1) autophagy (Lassen et al., 2014), (2) host defense and the inflammatory response (Conway et al., 2012), and (3) tolerance and regulatory cells (Khor et al., 2015, recently highlighted in Nature Immunology and selected as an “Editors’ Choice” by Science Translational Medicine).
Chemical approaches to controlling cellular disease phenotypes suggested by human genetics
Using chemical (e.g., small molecule) screening approaches, we can gain insight into disease gene function and place risk genes into signal transduction pathways. Chemical screens have the additional potential to identify small molecule probes and early therapeutic leads, as recently demonstrated by Kuo et al. (paper; press release).
We use the power of computational biology to uncover patterns in complex pathway analysis, as well as to integrate multiple ’omics data types to decipher human disease.
The goal of the microbiome program in the Xavier lab is to use informatics to understand the function of the human microbiome in health and disease. We are particularly interested in identifying microbial small molecules with immunomodulatory activities and to characterize their mechanisms of immune modulation.
Commensal gut microbiota are both ecologically and functionally perturbed during immune-mediated diseases such as inflammatory bowel diseases (IBD) and type 1 diabetes (T1D). Using these diseases as models for understanding the human microbiome’s role in complex inflammatory disease, our recent studies have characterized the microbiome of treatment-naïve Crohn’s disease, and identified trends in the development of the human infant gut microbiome along with specific alterations that precede T1D onset and distinguish T1D progressors from nonprogressors.
Xavier Lab Resources
Functional Genomics Workshop, King’s College London, UK
February 6-8, 2013
GIGA Seminar Series: Medical Genomics, University of Liege, Belgium
16th International Congress of Mucosal Immunology, Vancouver, Canada
July 17-20, 2013