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.


NEWS AND EVENTS

  • Congratulations! to Vishnu Mohanan in the Xavier lab on receiving an MGH ECOR Fund for Medical Discovery Postdoc Fellowship Award.

Eavesdropping on gut gossip. The gut's intestinal stem cells (ISCs) "talk" to other cell types to help maintain a robust and healthy cellular community. In this week's Cell, Moshe Biton, Adam Haber, Noga Rogel, Aviv Regev, Ramnik Xavier, and colleagues dive into one such conversation, between ISCs and T helper (Th) cells. They found that some ISCs express MCH II (a surface complex that activates Th cells), while Th cells produce cytokines (chemical messages) that influence ISCs’ behavior. The crosstalk may help maintain the right balance of immune activity in the gut, as well as a hardy stem cell pool. Read more in a Broad news story.

Like taking microbes from a baby.  In search of microbial triggers for type 1 diabetes (T1D), a team led by Tommi Vatanen, Curtis Huttenhower, and Ramnik Xavier analyzed nearly 11,000 metagenomes in stool samples from children at risk for T1D, collected monthly starting at three months of age. Known as The Environmental Determinants of Diabetes in the Young (TEDDY) study, it produced the most shotgun metagenomic microbiome profiles published for a single target population to date. Appearing in Nature, the work finds that the microbiome gains adult-like functions as early as one year of age, and suggests that short-chain fatty acids may protect against early-onset T1D.

Peptide presentation prognosticator produced. We don't fully understand the immune system's rules for determining whether a peptide from a bacterium and other source will 1) be presented to T cells, and 2) spark an immune response. To help bring new clarity, Dan Graham, Chengwei Luo, Ramnik Xavier, and colleagues profiled the "peptidome" of potential antigens bound to MHC class II (a protein complex that presents peptides to T cells) in mice. They used their data to build and train BOTA, a machine learning algorithm that predicts antigenic peptides based on bacterial whole genome data. Learn more in Nature Medicine and in a Broad news story. A comprehensive summary of the study can be found here.

  • Microbiome profiling reveals associations with ulcerative colitis severity, treatment. In a study published in Cell Host & Microbe, a multicenter team led by computational scientist Melanie Schirmer and Ramnik Xavier report on compositional and temporal changes in the gut microbiome of pediatric ulcerative colitis patients that are linked to disease course.  A comprehensive summary of the study can be found here.

Xavier Lab Team

Abdulrahman
Basabrain
Research Techni...
Jason
Bishai
Associate Compu...
Marta
Brandt
Research Fellow
Zhifang
Cao
Instructor in M...
Xiangjun
Chen
Research Fellow
Elizabeth
Creasey
Project Manager
Ianina
Ferder
Research Fellow
Daniel
Graham
Research Scient...
Xiebin (Ben)
Gu
Research Techni...
Motohiko
Kadoki
Research Fellow
Haroon
Kalam
Research Fellow
Lingjia
Kong
Research Fellow
Kai
Liu
Research Fellow
Vishnu
Mohanan
Research Fellow
Toru
Nakata
Research Fellow
Abdifatah
Omar
Research Associate
Vladislav
Pokatayev
Research Fellow
Theresa
Reimels
Medical Science...
Dmitry
Shungin
Research Fellow
Lingfei
Wang
Research Fellow
Jinjin
Xu
Research Fellow
Junmei
Yao
Lab Manager
Yun
Zhao
Research Scient...
Niko Andre
Head Global Medical Affairs, Roche, Basel, Switzerland
Leigh Baxt
Associate Director of Biology, Tri-Institutional Therapeutics Discovery Institute, New York, NY
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-Ortiz
Professor, Dept of Biochemistry, Catholic University of Santa María, Arequipa, Peru
Sarah Carden
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, Boston, MA
Elisabeth Cole
Resident, Pediatrics, Children’s Hospital of Pittsburgh, Pittsburgh, PA
Kara Conway
Assistant Professor of Biology at Jacksonville University, Jacksonville, FL
A. Nicole Desch
Senior Scientist at Janssen Pharmaceutical Companies of Johnson & Johnson, Cambridge, MA
Aivi Doan
Medical Student, University of Connecticut, Farmington, CT
Stacie Dodgson
Associate Editor, Cell, Cambridge, MA
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
Gautam Goel
ImmusanT, Director, Precision Medicine, Cambridge, MA
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, Canada
Liv Johannessen
Scientist, Syros Pharmaceuticals, Cambridge MA
Bernard Khor
Assistant Member, Benaroya Research Institute at Virginia Mason, Seattle, WA
Dan Knights
Associate 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, San Francisco, CA
Aimee Landry
Scientist, Genocea Biosciences
Kara Lassen
Principal Scientist, Roche, Basel Switzerland
Chun Li
Resident Physician, Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA
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
Geraldine Paulus
Associate, The Engine, Cambridge, MA
Joanna Peloquin
Assistant Professor, Johns Hopkins Hospital, Baltimore, MD
Shan Qin
Children's Hospital, Boston, MA
Souad Rahmouni
Principal investigator, University of Liege/GIGA Institute
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
Assistant Professor, University of Pennsylvania, Philadelphia, PA
Shuchen Wei
Associate Professor, National University of Taiwan, Taipei, Taiwan
Wenting Xu
Medical Resident, Internal Medicine

PI BIO

Director, Center for Computational and Integrative Biology

Ramnik Xavier is a core institute member of the Broad Institute of MIT and Harvard and co-director of the Broad’s Infectious Disease and Microbiome Program. He is the Kurt Isselbacher Professor of Medicine at Harvard Medical School; director of the Center for Computational and Integrative Biology and member of the Department of Molecular Biology at Massachusetts General Hospital (MGH); and co-director of the Center for Microbiome Informatics and Therapeutics at MIT.

Xavier Lab Areas of Interest

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