ME/CFS Collaborative Research Activities at MGH and the Harvard Affiliated Hospitals
(Update October 10, 2018) We are proud to announce that OMF has funded $1.8 million for the establishment of a new ME/CFS Collaborative Research Activities MGH and the Harvard Affiliated Hospitals, which includes Massachusetts General Hospital (MGH), Brigham and Women’s Hospital (BWH), and Beth Israel Deaconess Medical Center (BIDMC).
The new Harvard Activities will be led by OMF Scientific Advisory Board members Ronald G. Tompkins, MD, ScD, and Wenzhong Xiao, PhD, and will work synergistically with the ME/CFS Collaborative Research Center at Stanford led by Ronald W. Davis, PhD, of Stanford University, also funded by OMF. All science funded by OMF continues to be under the overall direction of our Scientific Advisory Board, directed by Ron Davis.
The new initiative begins with a dozen faculty from the three Harvard Institutions together with critical collaborators from the University of Birmingham, England and University of Nottingham, England, who comprise the MRC-Arthritis Research UK Centre for Musculoskeletal Aging Research, as well as long term highly valued collaborators in the fields of proteomics and metabolism from the Pacific Northwest National Laboratory (PNNL).
This new Collaborative Center seeks to conduct basic science mechanistic studies with very high priority. This research focus will discover and understand the multi-omic signature of muscle biopsies of ME/CFS patients during their recovery from mild to moderate muscular stress, by comparison to healthy individuals’ signatures at baseline, during recovery from muscular stress, and during immobilization. Our hypothesis is that the inflammation-related recovery mechanisms in ME/CFS patients are dysregulated, and that this delays recovery from post-muscular stress. In addition to the direct tissue studies, both structural and functional neuroimaging will be conducted at the very advanced MGH/HMS imaging center, the Martinos Center for Biomedical Imaging (www.nmr.mgh.harvard.edu). This will allow testing of hypotheses related to neuro-immune interactions, including exaggerated vagus nerve signaling, microglial activation, and disrupted autonomic and metabolic functioning in the central nervous system.
These clinical research studies are designed to characterize the multi-omic signature (genomic, proteomic, metabolomic, as well as ultrastructural morphology) of ME/CFS patients as compared to those in healthy individuals who are recovering from muscular stress. The proteomic, phosphoproteomic, and metabolomic studies will be conducted at the PNNL. These comparisons will be correlated with the neuroimaging results with the intent to identify biomarkers and suggest drug targets for use in the development of therapeutics for ME/CFS.
This new Collaborative Center also will seek support to develop an infrastructure for rigorous clinical investigations to identify and fast track promising potential treatments through clinical trials. This clinical research center working with the OMF-supported Stanford ME/CFS Collaborative Center also represents a unique opportunity to establish standards and infrastructure for rigorous clinical investigations and trials in ME/CFS. The Center will be designed to evaluate the potential for new ME/CFS therapeutics and to conduct well designed, CRO-supervised, pivotal clinical trials for those novel promising compounds.
Scientific Team
The faculty participating in this collaborative initiative are listed below along with brief introductions to follow.
| Stanford University | University of Birmingham (U Birmingham) | |
| Ron Davis, PhD | Janet Lord, PhD | |
| Massachusetts General Hospital (MGH) | University of Nottingham (U Nottingham) | |
| Ronald Tompkins, MD, ScD | Philip Atherton, PhD | |
| Wenzhong Xiao, PhD | Paul Greenhaff, PhD | |
| Donna Felsenstein, MD | ||
| Jonathan Friedstat, MD | Brigham & Women’s Hospital (BWH) | |
| Daniel Irimia, MD, PhD | David Systrom, MD | |
| Amel Karaa, MD | Anthony Komaroff, MD | |
| Michael VanElzakker, PhD | ||
| H. Shaw Warren, MD | Pacific Northwest National Laboratory (PNNL) | |
| Yongming Yu, MD, PhD | Richard Smith, PhD | |
| Andrew Alexander, MBA | Jon Jacob, PhD | |
| Wei-jun Qian, PhD | ||
| BI Deaconess Medical Center (BIDMC) | Open Medical Foundation (OMF) | |
| Janet Mullington, PhD | Linda Tannenbaum | |
Introduction:
Ronald Tompkins, MD, ScD, Sumner M. Redstone Professor of Surgery at HMS and MGH, is a surgeon and scientist who also trained at the Massachusetts Institute of Technology (MIT) receiving a ScD in Chemical Engineering. Dr. Tompkins has been the Chief of the MGH Burn and Trauma Services as well as the Chief of Staff, Shriners Hospitals for Children – Boston for more than 20 years. Dr. Tompkins has been active in medical research supported by more than $200M from the NIGMS in the fields of inflammation and metabolism with emphasis on genomics, proteomics, and small molecule metabolomics. Dr. Tompkins has collaborated for more than two decades with Dr. Ron Davis of the Stanford Genome Technology Center (Department of Biochemistry). Dr. Tompkins has actively participated on the Scientific Advisory Board of OMF since its establishment.
Wenzhong Xiao, PhD, Associate Professor of Surgery (Bioinformatics) at HMS and MGH, directs the MGH Inflammation & Metabolism Computational Center and leads the Computational Genomics Group at Stanford Genome Technology Center. Dr. Xiao received his PhD from the University of California Berkeley. Dr. Xiao develops bioinformatic and statistical tools for use in understanding human diseases, especially in studies of immuno-metabolic response. He focuses on integrative analysis and interpretation of multi-dimensional molecular, cellular, and clinical data of many types of patients, including those with ME/CFS. Dr. Xiao’s expertise will be essential for the interpretation of the massive data sets that will be collected in this project.
Donna Felsenstein, MD, Physician in Medicine and Assistant Professor of Medicine at HMS and MGH, is a senior attending in the Infectious Disease Unit at MGH. She has been diagnosing and caring for patients with ME/CFS since 1979. She has a large number of ME/CFS in her clinical practice, some of whom she has followed for more than 20 years. Dr. Felsenstein has participated in several clinical research studies on ME/CFS. Her clinical expertise in evaluating, diagnosing and treating patients with ME/CFS will be highly valued in the new OMF Center.
Jonathan Friedstat, MD, Assistant Professor of Surgery at HMS and MGH, is a plastic surgeon who has been well-trained in clinical trial protocols and research. His expertise and competence will be essential for proper conduct of the muscle biopsies.
Daniel Irimia, MD, PhD, Associate Professor of Surgery at HMS and MGH, is a longtime collaborator whose primary interest is in the role of neutrophils in sepsis. Daniel has developed an assay using neutrophil behavior within a microfluidic circuit that predicts sepsis with a high degree of precision (Nature Biomedical Engineering 2:207–214, 2018). Daniel’s expertise in neutrophils and neutrophil extracellular traps (NETs) will be important to clinical research in ME/CFS going forward.
Amel Karaa, MD, Assistant Professor of Pediatrics at HMS and MGH, is a board-certified pediatrician with specialty in medical genetics. This is an expertise that is very much needed in our MECFS research for many reasons but particularly because many mutations are and have been discovered but there is little medical expertise to assist us to better understand the medical implications of these mutations. She treats many ME/CFS patients in the MGH Mitochondrial Disorders Clinic will be critical to coordinate and recruit patients as well as interpret the multiple genomic findings in patients. In addition, she is critical to coordination with the mitochondrial genomic specialists at the MGH Center for Genomic Medicine.
Michael VanElzakker, PhD, Research Fellow at the MGH and HMS Martinos Center for Biomedical Imaging in the Neurotherapeutics Division, and lecturer at Tufts University. As a graduate student, Dr. VanElzakker wrote an influential hypothesis paper on the potential role of the vagus nerve in ME/CFS that has now been downloaded more than 10,000 times. Dr. VanElzakker’s expertise in neuroscience is focused on identifying abnormal patterns in brain metabolism, inflammation, structure, and function in this condition. He has enthusiastically engaged the ME/CFS community as both a scientist and patient advocate. Dr. VanElzakker will be critical to develop and conduct the neuroimaging clinical studies with the Martinos Center, which is one of the most advanced neuroimaging centers in the world.
H. Shaw Warren, MD, Physician and Pediatrician at MGH and Associate Professor of Pediatrics at HMS, is an internal medicine physician with expertise in pediatric infectious disease. His role follows his extensive experience in research in inflammation, endotoxemia, and genomics. He currently directs a DARPA funded project entitled SPIRIT, which probes the differences in the host’s responses to infectious agents in multiple mammalian species. His research competence in these fields together with his clinical experience with ME/CFS patients will make a tremendous contribution to the new initiative.
Yong Ming Yu, MD, PhD, Associate Professor of Surgery at MGH and HMS, is classically trained in nutritional biochemistry at the Massachusetts Institute of Technology (MIT). He is highly experienced in metabolism following the severe stress of injury and inflammation, prolonged fasting or nutritional depletion, and immobilization. His understanding of metabolism will be essential to understand the metabolic findings seen in ME/CFS patients.
David Systrom, MD, Assistant Professor of Medicine at BWH and HMS, is an internal medicine and pulmonary disease physician with certification in critical care medicine. Dr. Systrom’s expertise focuses on cardiopulmonary function resulting in highly specific phenotype characterization of ME/CFS patients particularly those with POTS syndrome. His research involving ME/CFS particularly seeks to discover the link between small fiber polyneuropathy (nerve damage) and exertional intolerance. His participation in this new initiative has tremendous value to more precisely characterize ME/CFS patients with their ME/CFS disease characteristics and to study these well-characterized patients in clinical trials.
Anthony Komaroff, MD, Distinguished Simcox-Clifford-Higby Professor of Medicine at HMS, and Senior Physician at BWH. He served for 15 years as Director of the Division of General Medicine and Primary Care at BWH. Dr. Komaroff’s contributions to ME/CFS include his pioneering work in the definition of, epidemiologic studies of the prevalence of the illness, and assessment of the biological changes present in chronic fatigue syndrome. He will be a consultant to the new OMF Center and he currently leads the human studies core at the Columbia NIH-funded ME/CFS Collaborative Center.
Janet Mullington, PhD, Professor of Neurology at HMS and BIDMC, is Director of the BIDMC Clinical Research Center and directs the HMS Human Sleep and Inflammatory Systems Laboratory. Dr. Mullington is a well-respected expert in the physiological and neurobehavioral effects of insufficient and/or inadequate quality sleep including autonomic, metabolic and inflammatory system consequences of sleep loss. Her perspective and participation will be extremely helpful for our new initiative particularly as issues relate to the very common symptoms of non-restorative sleep and sleep disorders in ME/CFS patients.
Janet Lord, PhD, Professor of Immunology, University of Birmingham, and Chair of Immunology. Dr. Lord directs the Institute of Inflammation and Ageing and the MRC-Arthritis Research UK Centre for Musculoskeletal Ageing Research. Dr. Lord brings together fundamental scientists and clinicians to translate the understanding of inflammation to new treatments for chronic age-related inflammatory diseases. Her research focuses on the dysregulation of immunity in old age, and in particular, the decline in neutrophil function and how this compromises the response to infection and tissue injury. Her knowledge and leadership in the natural findings of inflammation upon tissues will be critical to understand many of the findings that are discovered in ME/CFS patients in this new initiative. She brings two essential colleagues to the new OMF Center, Drs. Paul Greenhaff and Philip Atherton.
Paul Greenhaff, PhD, Professor of Muscle Metabolism, University of Nottingham, is a physiologist and the Deputy Director of the MRC-Arthritis Research UK Centre for Musculoskeletal Ageing Research (Nottingham). Dr. Greenhaff is also an active member of the ARUK Centre for Sport, Exercise and Osteoarthritis and the Musculoskeletal Disease theme of the Nottingham NIHR Biomedical Research Centre. He is classically trained in the field of muscle metabolism with research interests centered on the loss of muscle mass and the dysregulation of metabolism in aging, inactivity, inflammation, trauma and disease, and strategies to offset these pathophysiological events. His expertise will be critical to understand what the nutritional and sedentary effects are contributing to patients with ME/CFS in the new initiative.
Philip Atherton, PhD, Professor of Clinical, Metabolic & Molecular Physiology, University of Nottingham is classically trained in stable isotope nutritional biochemistry, providing tremendous experience in the inflammation and metabolism fields. His laboratory is in the Royal Derby Hospital under the auspices of our UK Medical Research Council/Arthritis Research UK Centre of Excellence for musculoskeletal aging research and the newly awarded NIHR Biomedical Research Centre (BRC) under a clinical musculoskeletal theme. His research seeks identification of central mechanisms regulating metabolism in human musculoskeletal tissues. These interests and expertise will be critical to the new OMF Center.
Richard Smith, PhD, Battelle Fellow and Director of Proteome Research at PNNL, is also the Director of the NIGMS Biomedical Technology Research Resource for Proteomic Integrative Biology and the DOE 'Pan-omics' Program at PNNL. He is a pioneer in mass spectroscopy and proteomics technologies, is a long term collaborator with the faculty at MGH, and is the author or co-author of more than 1,000 peer-reviewed publications and more than 50 US patents. His continued development and application of innovative mass spectrometry technologies will be critical in identifying the proteomic and metabolic signatures of patients with ME/CFS in the new initiative.
Jon Jacobs, PhD, Senior Research Scientist at PNNL, is currently the associate director of the NIGMS Biomedical Technology Research Resource for Proteomic Integrative Biology and the collaborative analytical support for the MGH lead DARPA project SPIRIT. His expertise lies in the development and application of advanced proteomic analysis techniques, specifically in the context of clinical studies focusing on complex disease signatures including inflammatory responses and chronic liver disease. Dr. Jacobs has a history of productive long term collaborations with MGH faculty through the application of proteomic approaches. His role will be to accurately direct the application of the advanced analytical technologies at PNNL towards the ME/CFS patient clinical samples for signature characterization.
Wei-Jun Qian, PhD, is a bioanalytical chemist whose research centers primarily on global and targeted quantification of proteins and post-translational modifications (PTMs), particularly redox modifications and phosphorylation. Dr. Qian is currently a Senior Staff Scientist and the Team Lead for Proteomics at PNNL, and has been the recipient of the NIH Director’s New Innovator Award and the Presidential Early Career Award for Scientists and Engineers (PECASE). Dr. Qian’s team has significantly advanced the sensitivity and robustness of selected reaction monitoring (SRM)-based targeted quantification, thus enabling the direct quantification of extremely low-abundance proteins, protein isoforms, and PTMs for broad biomedical applications. Dr. Qian’s expertise in PTM and SRM efforts will directly benefit analysis of ME/CFS patient samples.
