The Center for the Study of Inflammatory Bowel Disease (CSIBD) is a multidisciplinary program whose goal is to define fundamental mechanisms underlying Crohn’s disease and ulcerative colitis. Our center is sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases. The center encompasses one hundred and one investigators at the Massachusetts General Hospital, Beth Israel Deaconess Medical Center, Broad Institute, Harvard Medical School, Massachusetts Institute of Technology, Tufts University, and the Whitehead Institute, all pursuing research in a broad spectrum of basic science relevant to inflammatory bowel disease (IBD). Since its establishment in 1991, the CSIBD has advanced our understanding of IBD through the study of relevant basic biological processes and the directed study of the diseases themselves.
IBD is a general term that refers a family of diseases, the major forms of which are ulcerative colitis and Crohn’s disease. 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. We believe that IBD affects people who have inherited genetic risk factor(s) that makes them predisposed to get the disease. When a person with this predisposition is exposed to some environmental factor, the disease is triggered.
The overall goal of this Center is to promote research that will yield insights into the cause(s) and pathogenesis of IBD and lead to improved therapeutic approaches. The specific goals of the Center derive from the conviction that understanding the mechanisms of IBD will depend on progress in relevant areas of basic research and extension of these findings to explore their importance in the context of IBD. It is our further conviction that these goals can only be achieved through an increase in the number of investigators studying IBD. The latter should be achieved both through increased interest in the laboratories of basic investigators and the scientific development of investigators focused on IBD. We believe all of these goals are achieved through the scientific and material resources provided via the organizational framework of this Center. In addition we believe that in further fostering the numerous collaborative interactions among members of the Center whose expertise spans a continuum from basic laboratory to creative clinical investigation, the CSIBD serves to integrate progress from the laboratory to clinical application.
The Center goals are as follows:
Our investigations into the IBD disease process are occurring at many levels and take many experimental approaches, from molecular biology and biochemistry to computational analysis. To help illustrate how the CSIBD research base is working to fulfill the Center’s mission, we include a brief description of the central components of IBD disease mechanisms.
One of the greatest challenges in the study of IBD is understanding how particular genetic risk factors contribute to the initiation of disease. More than 100 genes and genetic loci have been linked to IBD, but we are only beginning to understand the biological significance of these loci and how these genes contribute to disease susceptibility. Each of these genes has the potential to yield insight into disease mechanisms. Understanding the significance of these risk factors may also help us to develop individualized drug treatments.
IBD is among the few complex diseases for which genome-wide association studies (GWAS) have been clearly successful. These studies have identified many non-overlapping genetic risk loci, including some that are shared between Crohn’s disease and ulcerative colitis (see Khor et al., Nature 2011). Importantly, many of these genomic regions and specific genes have been confirmed in replication studies. However, the relationship between genetic factors and disease is not entirely straightforward. For example, if one twin has ulcerative colitis, the probability that the identical twin will also suffer from ulcerative colitis is only 10-15%. In the case of Crohn’s disease, the probability goes up to 30-35%. From these statistics, it is clear that risk alleles often require other genetic or environmental factors in order to cause disease. In one of the many susceptibility alleles for Crohn’s disease (Atg16L1), researchers have discovered that the mutated gene requires interaction with a viral cue to manifest disease. This model may apply to other risk alleles, in which an environmental (microbial) cue, in combination with additional environmental factors and commensal bacteria, may determine how disease is manifested in individuals carrying common risk alleles.
Although GWAS studies have identified many genes and genetic loci, it remains unknown how these genetic variations contribute to the onset or progression of IBD. In most cases, the functions of the genes have not been discovered. Characterizing these genetic variants involves (1) identifying the normal function of the affected gene, (2) determining how IBD-associated genetic variations affect the normal function of the gene, and (3) discovering how this altered function contributes to the dysregulation of intestinal homeostasis. CSIBD labs are working to achieve this understanding through many different research perspectives, including novel genomic, genetic, and chemical biology approaches.
Healthy individuals maintain a variety of bacteria in their digestive systems. Many of these bacteria are harmless, and some are actually necessary for processing of nutrients such as certain vitamins. Evidence suggests that the interaction between these bacteria and the host digestive system may be altered in IBD. This evidence includes the therapeutic benefits of antibiotic treatment in some subsets of IBD patients and recent findings suggesting that so-called “healthy bacteria” or probiotic combinations can ameliorate IBD.
Harmless (or helpful) bacteria are normally tolerated by the immune system; that is, they do not prompt the immune system to respond to their presence. However, this tolerance may break down in IBD. Experiments suggest that individuals with IBD generate an inappropriate immune response against these normally harmless bacteria. It is also likely that patients with IBD have a different composition of bacteria in their digestive systems compared to healthy individuals. Some particular strains of bacteria have been found in IBD patients that cause a severe response by the immune system.
Researchers in CSIBD laboratories face particular challenges in investigating host-microbe interactions in IBD. Very little is known about the diversity and complexity of the bacteria that live in the digestive system, and few tools exist to answer these questions. The CSIBD is developing metagenomic and computational approaches to begin to understand how the digestive system interacts with these bacteria and how these interactions are altered in IBD.
One of the most basic defense mechanisms of the digestive lining is the physical restriction provided by intestinal epithelial cells. The main function of the epithelial barrier is to keep large molecules and bacteria from penetrating the stomach lining. Intestinal epithelial cells provide the critical components for a functional intestinal barrier. Specialized intestinal epithelial cells provide the mucus layer, trefoil factors and antimicrobial peptides to protect intestinal function. The physical barrier preventing luminal components from entering the body is regulated by the formation of tight junctions between intestinal epithelial cells. Intestinal epithelial cells are also able to directly modulate the immune responses in the intestine. This complex barrier system may break down in IBD. Some patients with Crohn’s disease show abnormal permeability of this barrier, and samples from patients show that the immune system may be decreasing the integrity of this barrier. Some of the genetic risk factors for IBD are also associated with epithelial barrier function.
When alterations occur in the epithelial mucosal barrier, the epithelium can be directly stimulated or penetrated by luminal microbiota (or their products), which can lead to disruption of the normally tolerant state of the intestinal immune system. Researchers in CSIBD laboratories are investigating the details of how this barrier normally functions, with special interest in how these normal functions go awry in IBD. Specifically, researchers are focused on how the barrier is structurally organized and how the integrity of this barrier is regulated by the immune system.
IBD is driven by the immune system. Under normal conditions, the immune system monitors the digestive system for foreign objects that may cause disease, such as viruses and some bacteria. When the immune system encounters these potential threats, it mounts immune responses to destroy these molecules. The immune system also comes in contact with other objects that are considered harmless, including molecules in food, the bacteria that are normal residents of the digestive system, and the body’s own cells. The immune system learns not to respond to these molecules, establishing immunological tolerance. In IBD, this normal tolerance appears to break down. When IBD is triggered, the immune system may mistakenly recognize a harmless object as a threat and mount an attack. When the immune system attacks the digestive system, the lining of the digestive tract becomes inflamed, which causes bleeding and ulcers.
The immune system maintains a precarious balance, since it must distinguish between bacteria that are harmless/helpful and bacteria that may cause disease. Recently, researchers have found that mutations in some immune monitors – specifically, cellular receptors that recognize and respond to bacteria – are genetic risk factors associated with IBD. When these receptors signal inappropriately, a cascade of events is initiated that results in inflammation. The immune system is enormously complex and has many pathways to translate signals (such as bacteria) into responses (such as inflammation). CSIBD researchers are investigating these pathways as targets for therapeutic intervention.
Inflammation is normally a protective event to remove a threat that may cause infection. However, inflammation is also the process that causes tissue damage in IBD. Some of the major players in inflammation are molecules called cytokines. Cytokines help to amplify immune responses and are known to contribute to the development of IBD. Researchers in CSIBD laboratories are working to identify the particular cytokines that are responsible for the inflammation that occurs in IBD. They are also investigating the sequence of events that occurs between cytokine activation and inflammation, hoping to identify areas for intervention.
The Biomedical Core program has been a central feature of the CSIBD since its inception. These core resources have been developed to accomplish two goals: first, to support the research activities of the center investigators that increase the understanding of IBD, and second, to stimulate new collaborations and interactions. The biomedical cores have been greatly successful in meeting both of these goals. The first goal has been met through both service and educational activities of the individual cores. As a mark of achieving the second goal, the use of these biomedical cores has led to projects that would not have been undertaken if the cores had not been available. We are continually working to maintain this high level of research support and investigator interaction. The Center has Five cores:
Core Objectives:
The major roles of the Genetics, Genomics and Molecular Biology (GGMB) Core are 1) to provide services in the utilization of advanced genetics and molecular biological techniques and 2) to facilitate the implementation of advances in genomics and molecular biology to IBD research. Application of genetics and molecular biological approaches is central to the evaluation of processes underlying the development of IBD according to the hypotheses that serve as a foundation for this center. As genetics play a significant role in determining the risk of developing IBD, identifying specific risk-associated genes is a priority for CSIBD researchers who are seeking to determine underlying disease processes. This core principally provides access to high-demand, mission-enabling tools for the investigator cohort participating in the CSIBD. The core also provides access to capital or resource-intensive methodologies, such as laboratory automation cDNA and siRNA libraries, and BAC-centered recombinant DNA techniques. The importance of molecular methods for the understanding of mechanisms of immunity and generating transgenic/knockout mice is undeniable, and their impact and dissemination throughout biological disciplines grow every year. These techniques permit the identification and characterization of genes regulating epithelial and immune cell function, analysis of the expression of these genes, determination of the functions and interactions of the encoded proteins, and expression of reporter genes and proteins to allow cellular localization and physiological analysis. For those laboratories with limited expertise in molecular biology, the core has developed a major educational effort consisting of the annual current techniques course in molecular genetics and training in genetic epidemiology, quantitative biology, and genomic medicine.
The objectives of the GGMB Core are to provide:
Available Services:
Gene Profiling Services
Research techniques currently available for transfer from the core include the following:
Core Objectives:
The Morphology Core is designed to provide center investigators with the technical support, expertise and access to instrumentation that is necessary for their morphological and cell biological studies related to IBD. The use of these often sophisticated techniques to examine the localization of proteins important in the pathogenesis of various forms of bowel disease is essential to the work being performed by investigators involved in this center.
Services and Activities:
Facilities:
The Morphology Core is based in two locations: the Program in Membrane Biology (PMB) in 8000 sq ft of space in the new Simches Research Center, MGH Histology Research Laboratory on the 8th floor of the Thier Research building and in the Immunopathology Unit equipped completely for light microscopy, immunofluorescence and immunoperoxidase. The Advanced Pathology Imaging Laboratory is located on the 2nd floor of the Jackson building. All the facilities are on the main campus of MGH and correspond to the locations of the laboratories of the Co-Directors.
Core Access:
The Morphology Core facilities have been made available to all members of the Center on as as-needed or by sign-up basis.
Overview:
The Clinical/Tissue Core has been an important component of the CSIBD since its inception, serving as the nexus between investigators exploring the etiology and pathophysiology of the inflammatory bowel diseases and patients with these conditions. The Clinical/Tissue Core has supported the needs of researchers both within and external to the CSIBD through a number of highly organized efforts designed to facilitate connections between bench top and clinic, specifically the IBD and control patient base within the MGH Crohn’s & Colitis Center and the gastroenterology practice at Massachusetts General Hospital. To date, these efforts have included 1) a clinical database of patients with inflammatory bowel disease seen at the Massachusetts General Hospital, 2) tissue samples, 3) tissue sections, 4) a serum bank, 5) immortalized lymphocytes from IBD probands, as well as their affected and unaffected 1st degree relatives and 6) clinical research support. These resources have evolved over the duration of the CSIBD as both needs and capabilities have evolved, and will continue to change and adapt from the current goals:
Clinical Database and Patient Identification:
The Clinical/Tissue Core maintains an active database encompassing patients with IBD seen at the MGH. Because the entire GI staff at the MGH participate in a common group practice organization and all are committed to the success of this project, it has been possible to capture nearly all relevant patients for this base. Retrospective review of hospital admissions, suggest that <5% of patients with an identified diagnosis of IBD are cared for without the participation of members of the GI group. Furthermore, as most of the small numbers missed by these criteria are admitted for surgical procedures, this group is identified through the activity of the tissue collection mechanisms of this core. Demographic data is available on all patients seen through the GI group and hospital at large. The database includes salient disease features: symptoms, duration, medications, location of disease (means of documentation), extraintestinal manifestations, endoscopy, surgery, pathology, family history, hospitalizations. Patients are also asked to indicate if they would be willing to participate in CSIBD related research activities through the PRISM cohort. CSIBD investigators with IRB approved projects have access to this database through Dr. Sands to identify patients needed for study. An additional responsibility of this core is the recruitment of patients for specific study needs through notification of all MGH GI Unit practitioners.
Services:
Overview:
The development of IBD is dependent upon the activation of mucosal leukocyte populations and the production of inflammatory mediators. The central hypothesis of this center’s research program presumes that leukocytes are activated following induced disruption of the mucosal barrier in conjunction with intrinsic genetically determined abnormalities of regulatory mechanisms. In order to effectively define the mechanisms contributing to IBD, it is essential that center investigators have the tools necessary to obtain immune cell populations, determine their functional properties and assess production of key mediators.
Although the CSIBD research base encompasses many investigators exploring mechanisms of immune responsiveness in their laboratories, the Immunology Core offers cost-effective service while providing access to these techniques (by service and/or training) to laboratories not focused on these approaches in their primary research orientation. The specific services offered to CSIBD investigators include:
Specifically, as part of the Immunology core, Dr. Mempel and his laboratory and MP-IVM facility will:
Figure 1: Steps involved in the analysis of in vivo cell motility. A pulsed beam of infrared (IR) laser light is raster-scanned via a high numerical objective over sequential optical planes within the specimen by rapid, synchronized movement of a pair of steering mirrors and graduated motion of the objective relative to the specimen (A). Serial stacks (15 seconds cycle time in this example) of optical sections (B) are rendered as three-dimensional volumes (C) and 2-dimensional renditions are exported as movie files for purposes of demonstration (D). Determination of cell centroids as representatives of cell position allows automated tracking of migration paths of three or more cell populations recorded in separate color channels by assigning track identities to serial images of cells (E). Tracks, consisting of serial sets of xyz coordinates of single cells (F) are used to compute various parameters of cell motility (G). Specialized software for automated cell tracking (if possible in 3 dimensions) and automated computing of the resulting tracks is essential for in-depth, large-scale analysis of migratory behavior of cell on a single cell basis.
Figure 2: The popliteal lymph node model for MP-IVM. A small skin incision gives access to the popliteal lymph node, which is immersed in normal saline and sealed with a cover glass. On top of the cover glass, a water-perfused circular metallic tube the objective lens immersion medium serve to regulate the LN ambient temperature through adjustment of flow of the heated perfusate. Temperature is monitored through a small thermocouple placed in close vicinity to the LN. Blood and efferent lymph flow occur at the LN hilus while several afferent lymph vessels enter the node at its distal and lateral poles.
Educational Activities
Immunology Core of the CSIBD runs weekly MGH Immunology Seminar Series. For more information, see our Education page.
Overview:
Crohn’s disease (CD) and ulcerative colitis (UC) are diseases of the gastrointestinal tract, collectively known as the inflammatory bowel diseases (IBD). Recent efforts in genome-wide association studies (GWAS) identified 30 genes associated with CD, e.g., CARD15, IL-23R, ATG16L1, TNFSF15 and IRGM. These studies have highlighted the significance of the relationship between intracellular responses to microbes (autophagy, phagocytosis and innate immunity) and regulation of adaptive immunity (IL-23 ==> Th17 cells) in the pathogenesis of IBD. Spontaneous gene mutations, targeted disruption and transgenic expression of selected mouse genes have unveiled a number of additional adaptive and innate immune genes that govern the pathogenesis of chronic enterocolitis. Thus, both approaches have proven to be of importance toward understanding the molecular underpinnings of these complex diseases.
Rodent models of chronic intestinal inflammation provide useful tools to dissect the pathways that lead to pathogenesis of IBD. Targeted disruption or transgenic expression of genes, manipulation of selected lymphocyte subsets and spontaneous gene mutations demonstrate that immunoregulatory abnormalities lead to chronic intestinal and systemic inflammation.
Services:
Murine Models:
Eric J. Alm, Ph.D
Frederick W. Alt, Ph.D.
David Altshuler, M.D., Ph.D.
M. Amin Arnaout, M.D.
Dennis A. Ausiello, M.D.
Frederick M. Ausubel, Ph.D.
Joseph Avruch, M.D.
Sarah L. Booth, Ph.D.
Stephen B. Calderwood, M.D.
Lewis C. Cantley, Ph.D.
Andrew Chan, M.D., M.P.H.
Bobby J. Cherayil, M.D.
Daniel C. Chung, M.D.
Raymond T. Chung, M.D
Joseph El-Khoury, M.D.
James G. Fox, D.V.M.
Robert E. Gerszten, M.D.
Marcia B. Goldberg, M.D.
Nir Hacohen, Ph.D.
Richard A. Hodin, M.D.
Curtis Huttenhower, Ph.D.
Ralph Isberg, Ph.D.
Lee M. Kaplan, M.D., Ph.D.
Ciaran P. Kelly, M.D.
Alan S. Kopin, M.D.
Stephen M. Krane, M.D.
J. Thomas Lamont, M.D.
Georg M. Lauer, M.D., Ph.D.
Cammie F. Lesser, M.D., Ph.D.
Towia A. Libermann, Ph.D.
Herbert Y. Lin, M.D., Ph.D.
Benjamin D. Medoff, M.D.
Atsushi Mizoguchi, M.D., Ph.D.
Emiko Mizoguchi, M.D., Ph.D.
Kathryn J. Moore, Ph.D.
N. Nanda Nanthakumar, Ph.D.
Jin Mo Park, Ph.D.
Norbert Perrimon, Ph.D.
Shiv S. Pillai, M.D., Ph.D.
Frederic I. Preffer, Ph.D.
Laurence Rahme, Ph.D.
Klaus Rajewsky, M.D.
David B. Rhoads, Ph.D.
Simon C. Robson, M.D., Ph.D.
Edward T. Ryan, M.D.
David Sabatini, M.D., Ph.D.
David H. Sachs, M.D.
Eveline E. Schneeberger, M.D.
Detlef Schuppan, M.D., Ph.D.
Brian Seed, Ph.D.
Arlene H. Sharpe, M.D., Ph.D.
Lynda M. Stuart, Ph.D.
Vikas P. Sukhatme, M.D., Ph.D.
Megan Sykes, M.D.
Andrew M. Tager, M.D.
Steven R. Tannenbaum, Ph.D.
Ronald Gary Tompkins, M.D., SCD
George C. Tsokos, M.D.
Ulrich H. Von Andrian, M.D., Ph.D.
Bruce D. Walker, M.D.
W. Allan Walker, M.D.
Honorine D. Ward, M.D.
H. Shaw Warren, M.D.
Joel V. Weinstock, M.D.
Ralph Weissleder, M.D., Ph.D.
Gerald N. Wogan, Ph.D.
Mei-Xiong Wu, M.D., Ph.D.
Junying Yuan, Ph.D
Abraham L. Brass, M.D., Ph.D.
Michael Y. Choi, M.D.
Nicolas Da Silva, Ph.D.
Cosmas C. Giallourakis, M.D.
Kevin M. Haigis, Ph.D.
Deborah T. Hung, M.D., Ph.D.
Kenneth E. Hung, M.D., Ph.D.
Chin Hur, M.D., M.P.H.
Andrew C. Keates, Ph.D.
Christine Kocks, Ph.D.
Joshua Korzenik, M.D.
Adam Lacy-Hulbert, Ph.D.
Sam W. Lee, Ph.D.
Terry K. Means, Ph.D.
Thorsten R. Mempel, M.D., Ph.D.
J. Rodrigo Mora, M.D., Ph.D.
Alan Moss, M.D.
Deanna D. Nguyen, M.D.
Biju Parekkadan, Ph.D.
Mikael J. Pittet, Ph.D.
Hidde Ploegh, Ph.D.
Stanley Y. Shaw, M.D., Ph.D.
Hai Ning Shi, D.V.M., Ph.D.
Roy J. Soberman, M.D.
Jatin M. Vyas, M.D., Ph.D.
Vijay Yajnik, M.D., Ph.D.
Seok-Hyun Yun, Ph.D.
Lawrence R. Zukerberg, M.D.
CSIBD Contacts
Phone: (617) 726-3766
Center Director | Ramnik J. Xavier, M.D. email: xavier@molbio.mgh.harvard.edu |
Genetics, Genomics and Molecular Biology Core | |
Co-Director | Dr. Mark Daly Phone: (617) 643-3290 email: mjdaly@chgr.mgh.harvard.edu |
Morphology Core | |
Director | Dr. Atul Bhan phone: (617) 726-2588 email: abhan@partners.org |
Co-Director | Dr. Dennis Brown phone: (617) 726-5665 email: brown.dennis@mgh.harvard.edu |
Immunology Core | |
Co-Director | Dr. Andrew Luster phone: (617) 726-5710 email: aluster@partners.org |
Co-Director | Dr. Rodrigo Mora phone: (617) 643-4366 email: j_rodrigo_mora@hms.harvard.edu |
Genetic Animal Models Core | |
Co-Director | Dr. Cornelis Terhorst phone: (617) 667-7147 email: cterhors@bidmc.harvard.edu |
Clinical/Tissue Core | |
Director | Dr. Joshua Korzenik phone: (617) 726-0267 email: jkorzenik@partners.org |
Co-Director | Dr. Gregory Lauwers phone: (617) 726-2931 email: glauwers@partners.org |
Consultant | Dr. Atul Bhan phone: (617) 726-2588 email: abhan@partners.org |
Consultant | Dr. David Nathan phone: (617) 632-2155 email: david_nathan@dfci.harvard.edu.org |