Xavier Lab

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

Abdulrahman Basabrain
Research Technologist
Leigh Baxt
Research Associate, MGH; Associated Scientist, Broad Institute
Jason Bishai
Associate Computational Biologist
Zhifang Cao
Instructor in Medicine, HMS; Assistant in Biochemistry, MGH
Sarah Carden
Research Fellow
Elizabeth Creasey
Project Manager
A. Nicole Desch
Research Fellow
Stacie Dodgson
Research Fellow
Gautam Goel
Research Fellow
Daniel Graham
Research Scientist; Instructor, HMS
Motohiko Kadoki
Research Fellow
Lingjia Kong
Research Fellow
Kai Liu
Research Fellow
Vishnu Mohanan
Research Fellow
Toru Nakata
Research Fellow
Abdifatah Omar
Research Associate
Geraldine Paulus
Research Fellow
Christine Petersen
Research Fellow
Souad Rahmouni
Research Staff
Theresa Reimels
Medical Science Writer
Dmitry Shungin
Research Fellow
Thomas Sundberg
Research Scientist
Jinjin Xu
Research Fellow
Wenting Xu
Research Scholar
Junmei Yao
Research Lab Manager
Moran Yassour
Research Fellow
Niko Andre
Head Global Medical Affairs, Roche, Basel, Switzerland
Christine Becker
Staff Scientist, Mt. Sinai Hospital, New York, NY
Jakob Begun
Senior Research Fellow, Mater Health Services, Translational Research Institute, Brisbane, Australia
Yair Benita
Head Computational Research & Discovery, Compugen, Holon, Israel
Julio Bernabe-Ortize
Professor, Dept of Biochemistry, Catholic University of Santa María, Arequipa, Peru
Adam Castoreno
Senior Scientist, Alnylam Pharmaceuticals, Cambridge, MA
Ashish Chawla
West Chester Gastrointestinal Group, West Chester, PA
Michael Choi
Assistant Professor in Medicine, MGH/Harvard Medical School
Elisabeth Cole
Resident, Pediatrics, Children’s Hospital of Pittsburgh, Pittsburgh, PA
Kara Conway
Assistant Professor of Biology at Jacksonville University
Aivi Doan
Medical Student, University of Connecticut, Farmington, CT
Jason Eisenberg
Massachusetts Institute of Technology
John Gagnon
Graduate Student at UCSF, San Francisco, CA
Kevin Gao
MD/PhD Student, University of Massachusetts Medical School, Worcester, MA
Agnes Gardet
Scientist, Biogen Idec, Cambridge, MA
Cosmas Giallourakis
Assistant Professor in Medicine, MGH
Robert Heath
CEO, ThinkBiome LLC
Alan Huett
Assistant Professor, Faculty of Medicine & Health Sciences, University of Nottingham, UK
Kazuhiro Ishiguro
Associate Professor, Dept of Therapeutic Medicine and Gastroenterology, Nagoya University, Nagoya, Aichi, Japan
Humberto Jijon
Clinical Assistant Professor; Division of Gastroenterology, Department of Medicine; University of Calgary
Liv Johannessen
Scientist, Syros Pharmaceuticals, Cambridge MA
Bernard Khor
Assistant Member, Benaroya Research Institute at Virginia Mason
Dan Knights
Assistant Professor, Department of Computer Science and Engineering and the Biotechnology Institute at the University of Minnesota, Minneapolis, MN
Raivo Kolde
Scientist, Philips Research, Cambridge MA
Aleksandar Kostic
Assistant Professor, Harvard Medical School and Joslin Diabetes Center, Boston MA
Petric Kuballa
Senior Manager Vector Generation, Taconic Biosciences GmbH, Cologne, Germany
Szu-Yu (Meredith) Kuo
Postdoctoral Researcher UCSF
Aimee Landry
Scientist, Genocea Biosciences
Kara Lassen
Principal Scientist, Roche, Basel Switzerland
Isabel Latorre
Scientific Program Manager, Harvard Program in Therapeutic Science at Harvard Medical School
Chun Li
Resident Physician, Department of Surgery, Beth Israel Deaconess Medical Center
Amanda Mok
Graduate Student, UC Berkeley, Berkeley, CA
Tatsuro Murano
Clinical Fellow, Tokyo Medical and Dental University, Tokyo, Japan
Kavitha Narayan
Scientific Editor, Immunity, Cambridge, MA
Daniel O'Connell
Senior Scientist, Intellia Therapeutics Inc., Cambridge MA
Joanna Peloquin
Assistant Professor, Johns Hopkins Hospital, Baltimore, MD
Shan Qin
Children's Hospital, Boston, MA
Oren Shibolet
Director, Liver Disease Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Harry Sokol
Associate Professor, Marie Curie University, Paris, France
Jaeyun Sung
Assistant Professor and Senior Associate Consultant, Department of Surgery, Mayo Clinic (Rochester, MN)
Eduardo Villablanca
Assistant Professor, Karolinska Institutet, Stockholm, Sweden
Heather Wachtel
Surgical Resident, University of Pennsylvania, Philadelphia, PA
Shuchen Wei
Associate Professor, National University of Taiwan, Taipei, Taiwan

Xavier Lab Research

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.

Human biology

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

PRISM
RISK
SHARE
DIABIMMUNE
LifeLines DEEP
500 FG
Framingham Heart Study

Recent products of cohort studies

Rivas et al.,

Nat Genet

Ananthakrishnan et al.,

Am J Gastroenterol

Jostins et al.,

Nature

Knights et al.,

Genome Med

Kleinnijenhuis et al.,

PNAS

IBD

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.

Khor et al.,

Nature

Rivas et al.,

Nat Genet

McCarroll et al.,

Nat Genet

Lassen et al.,

PNAS

Graham et al.,

Nat Commun

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).

Lassen et al.,

PNAS

Graham et al.,

Nat Commun

Begun et al.,

Cell Rep

Smeekens et al.,

Nat Commun

Huett et al.,

Cell Host Microbe

Conway et al.,

Gastroenterology












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).

Sundberg et al.,

PNAS

Kuo et al.,

PNAS

Aldrich et al.,

JACS

Khor et al.,

eLife

Shaw et al.,

ACS Chem Bio

Computational biology

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.

Goel et al.,

Nucleic Acids Res

Ng et al.,

PNAS

Cheng et al.,

Science

Tannahill et al.,

Nature

Krishnan et al.,

Nature

Doench et al.,

Nat Biotech

Giallourakis et al.,

J Immunol

Microbiome

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.

Flagship programs

Phase 2 of the Human Microbiome Project: HMP2
The Center for Microbiome Informatics and Therapeutics at MIT: CMIT
CCFA Microbiome Initiative
JDRF/DIABIMMUNE

Recent progress

Gevers et al.,

Cell Host Microbe

Kostic et al.,

Cell Host Microbe

Wlodarska et al.,

Cell Host Microbe

Huttenhower et al.,

Immunity