SMCI Holds ME/CFS Research Discovery Forum

On October 14, leaders from ME/CFS research, federal health agencies, ME/CFS clinicians, industry medical technology leaders and the biopharmaceutical industry convened in Washington DC to participate in the Solve ME/CFS Initiative’s (SMCI) Discovery Forum 2017: A New Era in ME/CFS Research. Participants included the lead investigators of all the new NIH grants: the three NIH Collaborative Research Centers (CRC) and the Data Management and Coordination Center (DMCC).
The forum sought to spark additional and deeper collaborations, disrupt the too-slow ME/CFS research status quo, incorporate novel perspectives and technologies into the field, and fuel cross-pollination.

SMCI’s Chief Scientific Officer and Vice President for Research, Dr. Zaher Nahle, who convened the Discovery Forum, opened his session with an analysis of the knowledge gap in ME/CFS and its direct correlation with a severe lack of financial investment. Dr. Nahle also provided an outline of recent developments at SMCI and its portfolio of investment in ME/CFS research. Dr. Nahle explained SMCI is driven to improve the ME/CFS research ecosystem through a multi-pronged approach to: 1) support high-quality research, 2) facilitate patient participation, 3) advocate for good policy, 4) facilitate positive federal action, and 5) promote cross-pollination of ideas through gatherings, much like the Discovery Forum. The Ramsay Award grant program, now in its second year, is an important component of this strategic approach to research. Dr. Nahle announced the results of the 2017 cycle, which awarded five project pilot teams with researchers in six countries. SMCI is now funding ten total Ramsay awardees with diverse research concentrations in basic, preclinical, clinical and epidemiological research. He also outlined SMCI-initiated research projects in metabolomics (Cornell, Metabolon, and Levine Clinic), immune-senescence and cell-cycle energetics (Washington University at St. Louis), drug-screening platforms for therapeutic discovery (Memorial Sloane Kettering Cancer Center), metabolic imaging (University of Washington), and cardiopulmonary features (Brigham and Women’s). Dr. Nahle also detailed SMCI’s plans to incorporate electronic health records into a new ME/CFS patient registry.

Newly-funded NIH CRCs and DMCC

Dr. Ian Lipkin of Columbia University, and Primary Investigator (PI) of the NIH Columbia CRC, is a long-standing distinguished researcher in the ME/CFS field. Dr. Lipkin reflected on his own personal and professional experiences to highlight the history, current realities, and future challenges in ME/CFS. He discussed the need for rigor and reproducibility in science. This is a need that is particularly acute in the ME/CFS field. The work that he and a dedicated team undertook to debunk Borna virus (BDV) as a cause of CFS reinforces the importance of discrediting poor science. He acknowledged that conducting this type of systematic inquiry can lead to important revelations. The team observed that although 75% of patients had antibodies to BDV proteins, they also had antibodies to a wide range of other proteins. This discovery led them to suspect an overactive immune system.
Dr. Lipkin also drew from his time with the Chronic Fatigue Syndrome Advisory Committee (CFSAC) to HHS and how it influenced his views on funding—which remains an immense challenge. Broader funding constraints in government are unfavorable to an already neglected disease space, so Dr. Lipkin emphasized the need for private/public partnerships. He noted that private support from the Hutchins Family Foundation enabled his study into immune and infectious mechanisms which ultimately produced robust evidence that ME/CFS is not a psychogenic illness. He also commented on the CRCs and, while congratulatory to all recipients, felt that a lot of good science was left on the table.

Dr. Maureen Hanson of Cornell University and PI of the NIH Cornell CRC provided an overview of the CRC structure and its research goals. The CRC will consist of three research projects. It will be supported by a clinical core and an integrative analysis core, the last of which will work directly with the DMCC. The first project will explore the pathophysiology of ME/CFS by looking at the connection between oxidative stress and neuroinflammation. The second project, led by Dr. Hanson, will examine the contents of extracellular vesicles before and after an exercise challenge, to discern whether signaling proteins—such as cytokines, and microRNAs that can alter gene expression—are driving ME/CFS symptoms. Finally, the third project will seek to characterize “…if there is a type of immune cell that has abnormal levels of expression of particular genes in ME/CFS patients.” Dr. Hanson also spoke about an ongoing project at Cornell’s Center for Enervating Neuroimmune Disease to examine cellular metabolism of immune cells in ME/CFS. Data from T cells (immune regulatory cells) isolated from 20 ME/CFS patients and 20 controls indicate that T cells in the former group are using significantly less of their respiratory capacity. The group is looking for additional quantities of T cells to further explore whether T cell subtypes can be differentiated. Additionally, in coordination with Metabolon and SMCI, Dr. Hanson is conducting a study to profile plasma metabolites in eight different metabolic pathways in ME/CFS patients as compared to controls. Data points to disturbances in fat and lipid metabolism which bolsters results from previous studies.

Dr. Derya Unutmaz of the Jackson Laboratory (JAX) is one of the research organizations recently funded by the NIH. He was originally brought into the ME/CFS field several years ago with a research grant from SMCI. Dr. Unutmaz discussed the organizational plans and scientific goals of the JAX NIH CRC. An administrative core and clinical core will support the work of two projects. A clinical project will look at the biological correlates for clinical subtypes of patients, measuring and analyzing aspects of the microbiome, immune system and metabolomics (study of the metabolites of cells) from patient samples. A second research-focused project will culture bacterial strains from patient samples and analyze them for effects on immune response assays. It will also assess other immunological features for a mechanistic cause of ME/CFS. Both projects are tied into the idea of balance in immune response and how an immunological disequilibrium can get in the way of resolving inflammation, repairing damage, tissue regeneration, and the maintenance of beneficial microflora. The group’s ultimate goal is to propel future clinical trials based on disease mechanisms and treatment targets.  Dr. Unutmaz voiced support for patient perspectives in stating that his “motto in science is that the patient is always right”.

Dr. Rick Williams of RTI International, a leading non-profit that seeks to improve the human condition, is new to the ME/CFS field. He was introduced to ME/CFS by SMCI. Dr. Williams discussed how RTI’s directed data infrastructure, management, and analytics team will help foster collaboration among the ME/CFS network through the development of the NIH-funded Data Management Coordinating Center (DMCC). RTI is experienced at providing data coordinating centers to health research networks and Dr. Williams outlined a “collaborative research lifecycle” that will drive the effective use of data, enhance data interpretation, and spark new study inspiration. The strategic goal is to incorporate extant ME/CFS data elements with new infrastructure and novel components. The RTI group will include the Common Data Elements (CDEs) currently under development in a joint project between NIH and CDC. A key target of the project is incorporating advanced technological components, such as machine learning, secure web access to an analytics portal, and wearable devices. Dr. Williams noted that their partnership with Dr. Peter Rowe (Johns Hopkins Medicine) and Dr. Zaher Nahle (SMCI) was indicated as one of the proposal’s strong points by the DMCC review committee. Meaningfully, an individual with ME/CFS is part of RTI International’s DMCC team and will lend patient perspective to the communications and outreach effort, in addition to other core roles.

New to ME/CFS – High tech research tools and  Biotechnology

Dr. Ralph Garippa of Memorial Sloan Kettering Cancer Center (MSKCC) was also introduced to the field of ME/CFS by Dr. Nahle. He is working on an SMCI-initiated project to apply MSKCC’s technical expertise to ME/CFS for the first time. Dr. Garippa spoke about how RNA Interference (RNAi), in which RNA molecules inhibit gene expression or translation, and CRISPR-Cas9 (gene editing) techniques could have meaningful application to the ME/CFS field. These technologies can provide mechanistic insights into basic and disease physiology. Their use in his work at MSKCC have advanced cancer cell modeling, cell differentiation, and produced novel routes for therapy development. Dr. Garippa highlighted an example from his exploration of cancer development influenced by HRAS, an oncogenic gene mutation which enhances the rate of macropinocytosis (MP), or the mass uptake of nutrient solutes from the space outside a cell. Using high-content screening methods against a library of compounds and gene perturbation methods allowed him to characterize the novel genes and protein families that regulate MP and present the innovative therapeutic approach to inhibit this process in tumors, effectively “starving” the RAS-driven cancer cell. Dr. Garippa also presented on his group’s success in finding a long sought-after protein receptor for the oncolytic Seneca Valley virus. He noted that these particular examples come from cancer biology, but the molecular tools and techniques used could possibly elucidate biological mechanisms that underlie other disease processes, such as ME/CFS.

Dr. Ken Blount of Rebiotix, new to the ME/CFS field, provided an overview of the importance of the human microbiome and its role in human health and influence of various disease states. He also discussed developments in the field of microbiome restoring drugs. He underscored that the Rebiotix “model is [to work] for clinical benefit. Start at what helps patients and work backwards.” Dr. Blount then expanded on this clinical benefit paradigm by focusing on Rebiotix’s development of RBX2660, a microbiota restoration therapy currently in Phase 3 that has shown a reduction in clostridium difficile infection (gastrointestinal) occurrence in participants, as well as a shift in microbiome health to a more normal range. The Rebiotix drug development “pipeline” is designed to rapidly expand out from one microbiota drug platform, such as RBX2660, to other disease-specific formulations. He pointed to some key factors to consider in applying microbiome therapeutics to new indications, such as ME/CFS, including the strength of evidence for a microbiome disease hypothesis, whether there are well understood trial designs, and how to set up endpoints for determining a benefit.


Dr. Nancy Klimas of Nova Southeastern University is a longstanding, leading researcher in ME/CFS. Dr. Klimas provided a comprehensive look at her work to model both Gulf War Illness (GWI) and ME/CFS at the Institute for Neuro-Immune Medicine. She proposed a pathogenesis model for these complex conditions flows from a genetic predisposition activated by a triggering event or infection, which is then mediated by a variety of body systems and contextual factors. She posited that the body establishes a new “homeostasis” and that we should focus our efforts on targeted therapies to reset the disrupted homeostatic networks. Dr. Klimas noted that there are immune abnormalities common to both GWI and ME/CFS, but compelling data which maps immune activation patterns shows that “inflammatory responses in ME/CFS patients go down when they should go up. It’s like opposite land.” Her group is building on their work by capitalizing on novel computational models to characterize the dynamic, interconnected networks apparent in the illness, and derive targets of treatment from biomarker discovery. Dr. Klimas summarized practical implications of the work thus far, including the utility of medications directed at reducing inflammation and oxidative stress, judicious use of supplements to enhance cellular energy, avoidance of toxins, and buffering stress.

Dr. Peter Rowe of Johns Hopkins Medical Center and SMCI Research Advisory Council (RAC) member is a longstanding, leading clinician, and researcher working on ME/CFS. He is part of the RTI/SMCI data management project currently funded by the NIH. Dr. Rowe offered a focused presentation on the strength of evidence underlying orthostatic intolerance (OI) and a presentation of autonomic dysfunction in ME/CFS. Dr. Rowe first provided context for the sides of the debate, comparing the Institute of Medicine (IOM) 2015 report committee’s assertion that OI is prevalent as a clinically important finding in ME/CFS to reports that question whether it is a key feature. He noted, however, that the “pediatric data are very clear. There is a much higher prevalence of OI in children with ME/CFS than in adults. Overall, 96% of pediatric ME/CFS have OI”. The strength of the association is increased by the fact that patients with OI have overlapping symptoms with ME/CFS, but that the severity of symptoms is worse in those with both conditions. Dr. Rowe also emphasized that inactivity can aggravate OI in ME/CFS, but “the notion that deconditioning is responsible for all of these ME/CFS symptoms needs to be dismissed. It is not supported by the facts.” The best available data indicates that the effective management of OI often allows for the tolerance of graded increases in exercise.

ME/CFS Expert Clinicians

Dr. Dan Peterson of Sierra Internal Medicine at Incline Village in Nevada has seen thousands of ME/CFS patients. He was the original clinician from the Incline Village outbreak in the 1980s. Dr. Peterson highlighted some broad research developments on his mind, including the stratification of patients, big data and precision medicine, and increasing evidence of the influence of the microbiome on immune function. He noted that obstacles to progress persist, but given enough funding there are promising avenues. Dr. Peterson outlined several research projects underway, including his long-term study of patients from the outbreak at Incline Village, of whom he is still follows approximately 80%. He also touched on an autoimmunity study at the State University in Albany, NY, which will analyze patterns of secondary illness prevalence among ME/CFS and their families as compared to controls. Dr. Peterson pointed out the notable lack of interest from big pharma in the U.S. and compared this to Norway’s government-funded double blind long-term study of Rituximab. He also focused on educational expansion programs at Simmaron Research that are designed to enhance capacity and knowledge through the training of mid-level practitioners, workshops, and pilot funding for young investigators. He acknowledged some challenges in this effort, in that “[he] had an ME/CFS research fellowship available and it took three years to fill the position.”

Dr. Cindy Bateman, the founder and medical director of the Bateman Horne Clinic (BHC) in Utah, is a deeply experienced clinician and collaborator on the JAX CRC. Dr. Bateman described her experience as a clinician caring for patients with ME/CFS and how her clinic is working to affect positive change in ME/CFS health care and research. Dr. Bateman commented, “…the glaring gaps in this illness can be related to two things: research and access to medical care. And these two things are related.” She drew attention to the broader issues of infrastructure design and lack of an organized hierarchy in healthcare, and how this creates barriers to the acceptance and integration of ME/CFS in health care delivery and research. She discussed the significant capacity issues clinicians have taking on new patients and how the BHC is implementing strategies for “building the ranks” to help address this problem. The BHC Patient Education Program and Indirect Provider Education consists of a class taught by an APRN on how to communicate with your medical provider to equip individuals with information they can bring to their PCP. Dr. Bateman also presents on various aspects of the disease and its symptomology at a weekly lecture series. She also highlighted a need to promote effective and efficient use of the ME/CFS Clinical Diagnostic Criteria from the 2015 IOM report and the FM diagnostic criteria (1990 and 2010) in every educational setting, as well as objective findings that are available now for clinicians to employ (e.g. orthostatic vital signs).

Dr. Sue Levine of the Levine Clinic in Manhattan and former chair of the U.S. Department of Health and Human Services Chronic Fatigue Syndrome Advisory Committee (known as CFSAC) unpacked her perspective on the strengths and weaknesses of the most commonly used diagnostic criteria in ME/CFS and looked at the implications of a research versus clinical criteria paradigm. She broadly noted that case definitions have not been adequately tested and often are unable to distinguish ME/CFS patients from those with other diseases. Dr. Levine outlined critiques of the different diagnostic criteria that hinged specifically on: (1) Fukuda does not require subjects to have PEM, cognitive dysfunction, or unrefreshing sleep; (2) the Canadian Consensus Criteria requires too many symptoms and might capture patients with psychosomatic conditions; (3) SEID, put forth by the 2015 IOM report, is useful as a clinical case definition, but might pick up individuals with comparable symptoms (lupus, MS, etc.). In considering the diagnostic criteria and how to achieve an improvement in methods, she commented that “we have not yet addressed the idea of subgroups in ME/CFS.” Dr. Levine offered additional remarks that praised the creation of the NIH CRC’s, but criticized that the awards are concentrated in metropolitan areas on the eastern seaboard. Speaking from her experience as a clinician, Dr. Levine pondered “where’s the access for the people with ME/CFS who live in the rural Midwest? I’ve been practicing in the same place for thirty years and I still don’t have a good primary care physician or neurologist to refer patients to.”

Dr. Charles Lapp, founder of the Hunter-Hopkins Center in North Carolina, is a pioneer clinician in the treatment of ME/CFS. Dr. Lapp tackled the big question of who will look after those with ME/CFS. This is a particularly salient question for clinicians who have dedicated decades to their patients. He outlined the idea “…that [primary care physicians] are loathe to take care of patients with ME/CFS because it’s so complex. The doctors are absolutely overwhelmed by it. Rather than learn, they dismiss the patient of become hostile.” Dr. Lapp turned to how we might incorporate more robust ME/CFS resources in continuing medical education and create ME/CFS certifications for clinicians. Dr. Lapp specifically highlighted resources available through the Academy of Integrative Health & Medicine and the Academy of Integrative Pain ManagementHe also mentioned the need for ME/CFS-directed fellowships. There is a need to engage the next generation, but the ever-present questions are: who will take up this charge and how will it be funded? Discussion of Dr. Lapp’s points pivoted to some counter examples from recent individual experiences, hinting that the tide might be changing as far as broader engagement of clinicians looking to get involved and educated about ME/CFS.

Government Agencies

Dr. Vicky Whittemore of the National Institute of Health (NIH), and NIH’s leader for the ME/CFS research program, provided an outline of recent NIH efforts to build support for ME/CFS. Dr. Whittemore noted that NIH research grant for FY17 is projected to total $15 million, an increase from approximately $7.6 million spent in FY16. The recently announced Collaborative Research Centers (CRCs) and Data Management and Coordinating Center (DMCC) are an important part of the Trans-NIH ME/CFS Working Group’s long-term goals. She underscored that the group “worked hard to fund these grants before the end of fiscal year 2017. Our long-term goals have not changed. We work to support these centers, as funding allows, and work towards clinical trials.” Dr. Whittemore also provided an update on the NIH ME/CFS Intramural Study led by Dr. Avi Nath at the NIH campus in Bethesda. Ten individuals with ME/CFS and ten control participants have completed Phase 1 of the study, which consisted of detailed phenotyping, neurological, and immunological studies. Phase 2, which so far two controls have returned for, will entail exercise testing and post-exertional malaise evaluation (PEM). Finally, the ME/CFS Common Data Elements project, an integral element for collaboration that will be integrated into all NIH-related ME/CFS research, is slated to accept public comment in December.

Dr. Beth Unger of the Centers for Disease Control (CDC) is the lead CDC individual for all ME/CFS programs. Dr. Unger began with an update on the efforts of the Technical Development Working Group, which is comprised of more than fifty ME/CFS experts. CDC’s website for the general public has been updated to reflect the Institute of Medicine’s 2015 recommendations and the page for healthcare providers is currently under construction. She mentioned that “access is a key challenge in ME/CFS… [and] we will focus on [primary care physicians] because there is still a lack of understanding.” Specifically, they plan to strengthen continuing education through events and partnerships, such as a contract for development of continuing education activity awarded to Medscape, and a push to develop a strategy for the development of formal treatment guidelines. The CDC has also taken steps to stand in solidarity with the ME/CFS community, through activities on May 12th in observance of ME/CFS Awareness Day. The Multi-Site Clinical Assessment of ME/CFS (MCAM) methods paper was selected as Editor’s Choice in the American Journal of Epidemiology, and programmatic developments and follow-up are ongoing. Based on CDC’s experience with the disease, Dr. Unger put forth that the heterogeneity of individuals with ME/CFS may be the greatest obstacle to identifying the underlying pathobiology.


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