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.

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:

• Facilitation of the application of advanced experimental platforms for genetics, genomics and high throughput data analysis to discovery efforts relevant to inflammatory bowel diseases. The GGMB Core will provide access to and training in the use of bioinformatics analysis and software, including the large variety of databases and software tools available via the internet, as well as molecular biology and statistical applications. 
• A centralized facility and personnel for performing state-of-the-art recombinant and PCR-based DNA procedures and RNA interference.
• Cost-effective and high-quality supplies of molecular biology reagents and services including nucleic acid probes, expression plasmids, reporter gene constructs, viral vectors, real-time PCR, mutagenesis, expertise for differential mRNA display analysis, RNA purification for DNA microarray analysis and facilitated access to bioinformatics support.
• A resource for disseminating a wide range of molecular biology, genetic and bioinformatics technologies. Services are initially provided by the core as part of hands-on training for center personnel, allowing transfer of the technology to the laboratories of individual CSIBD investigators. Training opportunities include the formal molecular biology laboratory course, (directed by Dr. Reinecker) as well as ad hoc focused training experiences within the GGMB Core laboratories. Techniques covered have included methods to examine gene expression and transcription regulation, library preparation, several types of expression screening and differential display protocols, competitive and real-time PCR, microarray analysis, protein expression in prokaryotes, yeast, insect cells and mammalian cells, site-directed mutagenesis, two-hybrid screening, recombination engineering of gene targeting constructs, and methods to examine signal transduction, cell-cell, protein-protein and DNA-protein interactions.

Available Services:

Gene Profiling Services

• Real-time qPCR validation of profiling data 
• DNA Sequencing
• High Throughput Oligonucleotide Synthesis 
• Research Laboratory Automation for siRNA and cDNA library screening 
• Plasmid Repository 
• Technology Transfer Services 

Research techniques currently available for transfer from the core include the following:

• Preparation and analysis of genomic DNA, including DNA isolation from tissues, cell lines, and paraffin-embedded specimens, PCR amplification of genomic DNA, and Southern and dot blot analyses 
• mRNA preparation and analysis, including extraction from cells and tissues, RNA purification, Northern blot and in situ hybridization analysis, S1 nuclease and RNase protection mapping, and primer extension analysis 
• General PCR applications, including anchored PCR, quantitative, real-time PCR, in situ PCR, inverse PCR and single-stranded conformation polymorphism analysis for mutation detection
•  
• Subcloning and sequencing of DNA fragments, including single- and double-stranded sequencing protocols, and direct sequencing of PCR products 
• Transfection of DNA into eukaryotic cells by chemical and electrical protocols, and generation of stably transfected eukaryotic cells 
• Generation of targeting constructs by recombination engineering in bacterial artificial chromosomes, as well as by standard cloning techniques 
• Use and assay of reporter gene constructs to examine gene transcription and protein synthesis 
• Nuclear run-on assays, intron-specific hybridization and mRNA half-life analysis to examine the molecular basis of gene regulation 
• Assay of DNA-protein interactions, including avidin-biotin DNA complexes, gel mobility shift, DNA footprinting and methylation interference, UV crosslinking and southwestern blotting 
• Analysis of protein-protein interactions by precipitation-based techniques and yeast two-hybrid and related technologies 
• Chromosomal gene localization by fluorescent in situ hybridization (FISH)
  Protein expression in bacteria, yeast, insect cells, mammalian cells, and eukaryotic virus systems, including His6 and glutathione-S-transferase fusion proteins
  Site-directed DNA mutagenesis, including use of PCR, oligonucleotide hybridization, exonuclease III digestion and insertion of oligonucleotide cassettes
  Immunoassays, including immunoprecipitation, Western blots, enzyme-linked and radioimmunoassays 
• Measurement of signal transduction, including protein phosphorylation and phosphatase activities, cAMP and IP3 generation, and protein association/dissociation
  Gene expression profiling by DNA microarray technology, including statistical analysis of results 
• Use of bioinformatics tools for molecular biology and genetic analysis

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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:

• Core Methodology
• Tissue and Cell Fixation 
• Immunofluorescence Staining 

• Tyramide Activation 
• Immunoperoxidase Staining

• Electron Microscopy 
• Immunogold Staining 
• Low Temperature Embedding in Lowicryl K4M and HM20 
• Freeze-substitution 
• Ultrathin Frozen Sections

• Confocal Microscopy, Spinning Disk Confocal and TIRF Microscopy 
• Laser Scanning Confocal Microscopy 
• Spinning Disk Confocal Microscopy 
• Total Internal Reflection Fluorescence (TIRF) Microscopy 
• Calcium/pH ration Imaging 

• 3D and 4D in vitro and in vivo Analysis of Cell Interaction and Migration in the Mucosal Immune System 
• Digital Image Processing and Archiving 
• Central Antibody and Reagent Bank

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.

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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:

• To help to elucidate the phenotypic implications of disease loci with regard to clinical manifestations 
• To assist in understanding the functional implications of disease-variant associated genetic loci with regard to mucosal immunology and epithelial biology 
• To facilitate leveraging knowledge of the functional implications of disease-associated genetic loci to explicate environmental factors in the onset and expression of disease 
• To promote the ability of investigators to capitalize upon observations in the functional biology of IBD to improve clinical diagnosis, prognostication, and treatment. 

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:

• Tissue Samples 
• Tissue Reference Bank 
• Issue Sections 
• Serum Bank 
• This bank also includes serum from IBD patients not undergoing surgery according to the following categories:
• Ulcerative Colitis: Active/Non-active 
• Universal/Left-sided/Rectum only 
• Crohn’s Disease: Active/Non-active 
• Small Intestine/Colon/Both/Other 
• Treated/Non-treated 
• Extraintestinal Manifestations 
• Immortalized IBD Lymphocytes and DNA 
• Clinical Research Support 
• The Clinical/Tissue Core provides the means to undertake a complete spectrum of research in patients. Through the clinical resources of the MGH/GI Unit and the newly opened IBD clinical and clinical research facility and General Clinical Research Center of the MGH the following services can be provided: 
• Patient Identification and Recruitment 
• Phlebotomy 
• Endoscopic evaluation and procurement of tissue specimens 
• Inpatient monitoring 
• Radionuclide scanning and comprehensive radiologic services 
• Bacteriologic Services 
• Biostatistical Analysis

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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:

• Flow cytometry
• Immunophenotyping 
• DNA/Cell Cycle Analysis 
• Analysis of Intracellular Cytokine Expression in Permeabilized Cells 

• Leukocyte isolation and cell sorting 
• Magnetic Bead Isolation 
• High Speed Cell Sorting 

• Multiplex cytokine assays 
• Flow Cytometer Based Cytokine Bead Array 
• Luminex Multiplex Cytokine Array 

• T and B lymphocyte functional assays 
• Intravital imaging of immune cells in vivo 
• T and B lymphocyte function assays 

• T and B lymphocyte function services/assays currently available in the core lab include: 
• Measurement of mitogen and antigen-induced proliferation by 3H Tdr incorporation. 
• ELISA and ELISPOT assays for cell associated cytokine production. 
• Morphological and biochemical assays for antigen-induced cell death. 

• Intravital imaging of immune cells 

Specifically, as part of the Immunology core, Dr. Mempel and his laboratory and MP-IVM facility will:

• Provide instruction, equipment and assistance in the execution and analysis of intravital based cell migration studies in mouse peripheral lymph nodes (Fig. 2). 
• Provide expertise in the planning, execution and analysis of cell migration protocols using novel intravital imaging models to be developed by individual CSIBD investigators.

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.

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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:

• Breeding and maintenance of mutant mouse stocks 
• Characterization of murine models 
• Sample collection from murine models of IBD 
• New murine model development 
• Bone marrow transfers and adoptive T cell transfers 
• Maintenance of GFP- and RFP- reporter mice 
• In vivo tracking of fluorescently labeled bacteria and cells 
• Mouse bright field and fluorescent endoscopy 
• Whole body imaging of bioluminescent and fluorescent signals 

Murine Models:

• Spontaneous chronic colitis in mutant mice, e.g., IL-10-/- and TCR-α-/- 
• Colitis induced by adoptive transfers of wt or mutant T cell subsets into: 
• CD4+ CD45Rbhi transfer into immuno-deficient mice (RAG-/-). 
• Double or triple mutant mice derived by genetic crosses between Rag-/- and mutant mice 
• Anti-CD40 induced colitis in Rag-/- mice or into double or triple knockout mice derived by genetic crosses between RAG-/- and mutant mice that are impaired in innate immune responses 
• Colitis induced by bone marrow transplantation into tge26 immuno-deficient mice; followed by adoptive transfers of mesenteric lymph node derived CD4+ T cells into tgε26 or Rag-/- mice 
• Chemically induced colitis in mutant mice, e.g., DSS or TNBS 
• Isolation and functional characterization of lamina propria and intestinal epithelial lymphocyte subsets, dendritic cell subsets and macrophages isolated from wild type and mutant mice with or without disease 
• Gnotobiotic Mouse facilities 
• Mouse models for functional imaging of the mucosal immune system

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Ramnik J. Xavier, M.D., Ph.D.
Atul K. Bhan, M.D.
Cornelis P. Terhorst, Ph.D.
Dennis Brown, Ph.D.
Mark J. Daly, Ph.D.
Joshua Korzenik, M.D.
Andrew D. Luster, M.D., Ph.D.
Shannon Bromley, Ph.D.

Dr. Hans Clevers
Dr. Charles O. Elson, III (Chair)
Dr. Gail Hecht
Dr. Lloyd Mayer

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.