In his response to the NIH's request for Information on ME/CFS Ron Davis called for a massive effort to understand the molecular roots of ME/CFS. This effort would require the NIH to fund studies focused on developing hypotheses instead of answering them. It would result in new ways to analyse proteins, cells and data. Researchers would develop new ways to collaborate. In effect, Davis is trying to usher in a new approach to researching diseases and producing treatments. He argues that such an approach would benefit many. (The full text is below)
An Overview
The Stanford Chronic Fatigue Syndrome Research Center (this is the Davis Stanford Center not Montoya Stanford center) is focused on producing not just a diagnostic biomarker but a molecular diagnostic biomarker; that is, it is focused one finding the shakers and movers in ME/CFS at the cellular level.
A Parkinson's Connection?
[fright]
[/fright]It was fascinating that Davis has found transcriptomic (gene), and metabolic (breakdown products of the cell) overlaps with Parkinson's Disease. Parkinson's, in fact, was the only other disease directly mentioned in connection with ME/CFS. It's hard to know how much to read into that mention, but the possible connections between the two diseases - which until recently have hardly ever been mentioned together - are intriguing. Both could be classified as movement disorders, both involve the basal ganglia, both appear to feature reductions in dopamine and inflammation probably plays a major role in both.
From a funding and research perspective, getting ME/CFS allied with Parkinson's - a major neurodegenerative disease - would, of course, be quite helpful.
A Parkinson's - ME/CFS connection could be the kind of surprise we get as researchers dig deeper into the molecular underpinnings of ME/CFS.
More Host Response Than Infection
Davis doesn't appear to put as much faith in the idea that an active infection is causing ME/CFS, as he does that an infection or other stressor probably triggers a more or less system-wide "hypometabolic" or low energy state. (One wonders if Nath's metabolic chamber is going to pick up that hypometabolism.) A system-wide hypometabolic state could explain one of the conundrums in ME/CFS - how so many different systems could be affected.
Davis suggests that ME/CFS has a strong genetic/environmental component. It may be that the genetic factors that underpin this disease get expressed only under certain circumstances such as during an infection or some other trauma. Absent those circumstances, ME/CFS never appears.
Davis noted that even mitochondria diseases - which are largely genetically determined - may remain unmasked until an infectious event occurs. This underscores Davis's belief that the host response to infection is the key, not necessarily the infection itself.
A New Approach To Disease
Davis acknowledges that ME/CFS is likely a very heterogeneous disease but asserts that the way to understanding that heterogeneity is for research efforts to get even more precise. Given our ability now to effectively assess astounding amounts of data, he believes that researchers should engage in massive molecular profiling studies that use new advanced computational techniques to pluck out the heterogeneity present.
How to get those exploratory studies, funded, though, given the NIH's penchant for hypothesis driven studies? Have the NIH produce more "open" RFA's that explicitly call for studies to generate hypotheses. (If the NIH wants a hypothesis driven study the hypothesis could be "We hypothesize that this study will allow us to generate valid hypotheses regarding ME/CFS
)
Davis also wants the NIH to create a collaborative mechanism that allows researchers across the world to share data. To that end innovative new computational techniques that allow researchers to share and analyse data across multiple databases should be developed. (With his Harvard/Stanford connection Davis has already enrolled researchers in developing new ways to analyse the enormous amounts of data the OMF's project is creating.)
In fact, Davis believes that chronic fatigue syndrome with all its complexity offers the opportunity for the medical field to develop new ways to study complex diseases.
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[/fleft](Despite its small size the ME/CFS research field has been an incubator of new techniques. Suzanne Vernon produced one of the first attempts ever to merge clinical, genomic and lab data while at the CDC. Gordon Broderick is doing cutting edge modeling and computational analyses at the Institute for Neuro-Immune Medicine. In order to test treatments more quickly Jarred Younger wants to produce a way to fast-track trials at the Neuroinflammation, Pain and Fatigue Laboratory.)
Davis wants to develop better and more sensitive ways to characterize molecular and cellular data and new computational methods to analyze them. He believes the techniques developed to do that could provide breakthroughs in other diseases.
There's something to being in on the expansion of a field that lends itself to creativity. Because ME/CFS hasn't been well studied it hasn't been captured by one hypothesis or one field of thought. Researchers know that they don't know and they know they need to develop ways to learn as quickly and comprehensively as possible. Developing ways to more or less quickly produce well-founded hypotheses may be the main gift the ME/CFS field can, at this point, provide for other diseases.
Interestingly, Davis emphasized the need for long term studies - something that has rarely if ever happened - but which the Center for Infection and Immunity is now featuring. He closed by making a plea for an open and collaborative effort that brings together researchers of all kinds to solve the many questions facing ME/CFS.
The Full Text is Below
An Overview
The methods we need to understand this complex disease may very well not exist yet. Ron Davis
The Stanford Chronic Fatigue Syndrome Research Center (this is the Davis Stanford Center not Montoya Stanford center) is focused on producing not just a diagnostic biomarker but a molecular diagnostic biomarker; that is, it is focused one finding the shakers and movers in ME/CFS at the cellular level.
A Parkinson's Connection?
[fright]
From a funding and research perspective, getting ME/CFS allied with Parkinson's - a major neurodegenerative disease - would, of course, be quite helpful.
A Parkinson's - ME/CFS connection could be the kind of surprise we get as researchers dig deeper into the molecular underpinnings of ME/CFS.
More Host Response Than Infection
Davis doesn't appear to put as much faith in the idea that an active infection is causing ME/CFS, as he does that an infection or other stressor probably triggers a more or less system-wide "hypometabolic" or low energy state. (One wonders if Nath's metabolic chamber is going to pick up that hypometabolism.) A system-wide hypometabolic state could explain one of the conundrums in ME/CFS - how so many different systems could be affected.
Davis suggests that ME/CFS has a strong genetic/environmental component. It may be that the genetic factors that underpin this disease get expressed only under certain circumstances such as during an infection or some other trauma. Absent those circumstances, ME/CFS never appears.
Davis noted that even mitochondria diseases - which are largely genetically determined - may remain unmasked until an infectious event occurs. This underscores Davis's belief that the host response to infection is the key, not necessarily the infection itself.
A New Approach To Disease
Davis acknowledges that ME/CFS is likely a very heterogeneous disease but asserts that the way to understanding that heterogeneity is for research efforts to get even more precise. Given our ability now to effectively assess astounding amounts of data, he believes that researchers should engage in massive molecular profiling studies that use new advanced computational techniques to pluck out the heterogeneity present.
How to get those exploratory studies, funded, though, given the NIH's penchant for hypothesis driven studies? Have the NIH produce more "open" RFA's that explicitly call for studies to generate hypotheses. (If the NIH wants a hypothesis driven study the hypothesis could be "We hypothesize that this study will allow us to generate valid hypotheses regarding ME/CFS
Davis also wants the NIH to create a collaborative mechanism that allows researchers across the world to share data. To that end innovative new computational techniques that allow researchers to share and analyse data across multiple databases should be developed. (With his Harvard/Stanford connection Davis has already enrolled researchers in developing new ways to analyse the enormous amounts of data the OMF's project is creating.)
In fact, Davis believes that chronic fatigue syndrome with all its complexity offers the opportunity for the medical field to develop new ways to study complex diseases.
[fleft]
Davis wants to develop better and more sensitive ways to characterize molecular and cellular data and new computational methods to analyze them. He believes the techniques developed to do that could provide breakthroughs in other diseases.
There's something to being in on the expansion of a field that lends itself to creativity. Because ME/CFS hasn't been well studied it hasn't been captured by one hypothesis or one field of thought. Researchers know that they don't know and they know they need to develop ways to learn as quickly and comprehensively as possible. Developing ways to more or less quickly produce well-founded hypotheses may be the main gift the ME/CFS field can, at this point, provide for other diseases.
Interestingly, Davis emphasized the need for long term studies - something that has rarely if ever happened - but which the Center for Infection and Immunity is now featuring. He closed by making a plea for an open and collaborative effort that brings together researchers of all kinds to solve the many questions facing ME/CFS.
..future funding programs should not only encourage, but establish frameworks for highly collaborative data sharing and strategizing that bring together researchers and clinicians. All data should be made publicly available as early as possible (even before publication), in both raw and accessible formats. This will not only facilitate collaboration (for example by encouraging biocomputing experts to engage with the data) and integrative analyses, but also empower patients to understand more about their disease and what progress is being made. As we have all seen, the ME/CFS patient community is extremely active, engaged, and eager for actionable results.
The Full Text is Below
To whom it may concern:
We are grateful for the opportunity to provide input to the Trans-National Institutes of Health (NIH) ME/CFS Working Group as they develop strategies to guide NIH's research efforts and priority setting for research on ME/CFS. Our mission at the Stanford Chronic Fatigue Syndrome Research Center is to discover causes, a molecular diagnosis, and treatment options for ME/CFS. Through our research efforts, collaborations with the ME/CFS research and clinical community, and extensive engagement with patients, we have defined several elements of importance for future ME/CFS research programs.
A key consideration in ME/CFS research efforts is the complex and multisystemic nature of this disease, and we are happy to see the involvement of several NIH institutes in developing this plan. Because the causative factors driving the disease remain unknown, and because work from our team and others has indicated effects on neurology, metabolism, immunity, and more, it will be crucial that calls for proposals allow for open, unbiased, multifaceted, and systematic research.
Broadening the scope of ME/CFS research will create opportunities for engaging researchers in other disciplines. Similarly, investigating numerous organ systems and biological pathways perturbed in ME/CFS may well reveal informative parallels to other diseases – for example, we and others have observed symptomatic, transcriptomic, and metabolic overlap between ME/CFS and neurodegenerative disorders like Parkinson's Disease.
It is important not to limit research to single organs like the brain, and to integrate results from many different organs and molecular processes so that they can be understood at the systems level. Big data approaches and high-throughput, large-scale molecular profiling should therefore be prioritized. Such efforts hold promise to identify key genes or pathways underlying ME/CFS. Similarly, large-scale in vitro drug screening efforts would help point to a variety of molecules and molecular processes as therapeutic targets.
Understanding the molecular etiology of ME/CFS is another important opportunity. A long-standing belief in the field is that an infectious agent causes the disease, and that the pathogenicity of the as-yet-undiscovered organism is responsible for the severity of the illness. An equally plausible explanation is that a stressor such as trauma, infection, or genotoxic stress may trigger a series of events that lead to a hypometabolic state. This model is observed in children with congenital mitochondrial disorders, where the phenotype does not present itself until after a serious viral infection.
This shift in thinking opens up the possibility that ME/CFS has strong genetic and environmental associations, which may also explain the extensive heterogeneity in its presentation, progression, and recovery across patients. The search for novel infectious agents should continue, but research efforts should also focus on understanding individual host susceptibility and response to infection. For example, it may not be a particular infectious agent that results in the disease, but rather a particular host state as a function of numerous biological and external factors that governs an individual’s susceptibility.
This perspective mirrors the NIGMS-funded Glue Grant on Inflammation and Host Response to Injury, which used an integrated omics approach to define variable responses to infection and trauma. Characterizing host responses to infection and understanding the mechanisms of the long-term sequelae may reveal insights into ME/CFS that are relevant to numerous other diseases of infectious origin, such as Chronic Lyme Disease and Post-Ebola Syndrome (Mattia et al., 2016). Moreover, such precision medicine approaches would build a more comprehensive understanding of ME/CFS and offer richer opportunities for therapeutic intervention.
Another major challenge is our lack of understanding of the prevalence and landscape of ME/CFS, which is largely due to the difficulty in diagnosing the disease. The search for precise molecular biomarkers is a great opportunity afforded by this research program, which would be accelerated through multi-omics approaches in large patient cohorts.
Current estimates of the prevalence of ME/CFS vary widely (800,000 to 2.5 million cases in the US) due to varying diagnostic and data collection methods. There is an opportunity here to improve these estimates based on modernized methods and community-defined standards, including criteria specified in the 2015 Institute of Medicine Report, and by considering questionnaire-based responses like the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort in the United Kingdom (Collin et al., 2016).
An Opportunity for A Breakthrough in Medicine
Because of these complex scientific challenges, ME/CFS research presents an excellent opportunity for developing and piloting novel methods and technologies in discovering biomarkers, elucidating disease mechanisms, and revealing therapeutic possibilities. The methods we need to understand this complex disease may very well not exist yet. Engineering and technology development efforts towards highly sensitive, quantitative molecular profiling and/or measuring novel cellular properties, as well as novel computational analyses that integrate multiple datatypes to define disease mechanisms, should be encouraged. Again, it is highly likely that such efforts will prove useful in the study of other diseases, be they infectious, genetic, or complex in origin.
Beyond scientific considerations, we would like to note several programmatic considerations that we believe are key for rapid progress. Long-term studies of patients are absolutely essential. Such a mechanism has proven effective in the NIGMS Glue Grants described above.
Moreover, maintaining an open structure in RFAs will allow scientists to develop and refine their hypotheses as research progresses, as appropriate for the unknown/uncertain nature of the field. As highlighted in several places above, the opportunities for collaborative efforts within and beyond the ME/CFS research community to understand and treat this disease are numerous. There are numerous experts spread across the world, each taking their own approaches based on their own expertise.
We believe future funding programs should not only encourage, but establish frameworks for highly collaborative data sharing and strategizing that bring together researchers and clinicians. All data should be made publicly available as early as possible (even before publication), in both raw and accessible formats. This will not only facilitate collaboration (for example by encouraging biocomputing experts to engage with the data) and integrative analyses, but also empower patients to understand more about their disease and what progress is being made. As we have all seen, the ME/CFS patient community is extremely active, engaged, and eager for actionable results.
We thank you once again for the opportunity to provide input on this matter, and look forward to the new strategies for ME/CFS research efforts put forth by this working group.
Yours sincerely,
Ronald W. Davis, Ph.D.
Professor of Biochemistry and Genetics, Stanford University
Director, Stanford Chronic Fatigue Syndrome Research Center and Stanford Genome Technology Center
Director, Scientific Advisory Board, Open Medicine Foundation
References:
Collin SM, Norris T, Nuevo R, Tilling K, Joinson C, Sterne JA, Crawley E. Chronic Fatigue Syndrome at Age 16 Years. Pediatrics. 2016 Feb;137(2):e20153434. doi: 10.1542/peds.2015-3434. Epub 2016 Jan 25. PMID: 26810786.
Mattia, J. G., Vandy, M. J., Chang, J. C., Platt, D. E., Dierberg, K., Bausch, D. G., ... & Kamara, A. P. (2016). Early clinical sequelae of Ebola virus disease in Sierra Leone: a cross-sectional study. The Lancet Infectious Diseases, 16(3), 331-338. PMID: 26725449
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