Simmaron Celebrates Ten years of Innovative ME/CFS Research
"We envision a world where ME/CFS is treatable and well-understood. To get there, we are scientifically redefining ME/CFS." The Simmaron Research Foundation
Dr. Peterson
It's been ten years since the Simmaron Research Foundation for ME/CFS opened its doors. Dr. Daniel Peterson, one of its founders, was restless. Ever since people with a strange, debilitating illness began knocking on his door in the Incline Village outbreak in the mid-1980's, he'd been focused on ME/CFS. Since then he'd been patiently collecting data and samples - including precious spinal fluid samples - and biding his time until the researchers were ready - and now he thought they were.With the formation of the Simmaron Research Foundation, Peterson was given the opportunity to put his experience and samples to the test. It turned out that the ME/CFS research community was very interested in what he had to offer.
Research
A Special Partnership
Since its founding, the Simmaron Research Foundation has enjoyed a special relationship with Dr. Mady Hornig and internationally renowned virologist Dr. Ian Lipkin at the Colombia Center for Infection and Immunity. Dr. Lipkin’s interest in chronic fatigue syndrome (ME/CFS) – which began with Dr. Peterson – dates back to 1984. Dr. Lipkin talked about that and his search for more resources in a 2014 video. https://www.youtube.com/watch?time_continue=33&v=z_v3bfbBupA&feature=emb_logo
Simmaron's Signature Research Effort:
The Cerebral Spinal Fluid Studies
A gateway to the brain - the cerebral spinal fluid
Simmaron’s signature research effort over the past ten years has involved the most intense and potentially difference-making exploration of the spinal fluid yet done in ME/CFS. Bathing the brain, the cerebral spinal fluid provides a unique access to an organ many believe plays a central role in ME/CFS.Dr. Peterson’s dogged accumulation of cerebral spinal fluid samples over the years paid off in two unique studies. With recent studies providing more evidence of neuroinflammation in ME/CFS, Simmaron’s early decision to commit a substantial amount of resources to spinal fluid investigations is looking prescient indeed.The first study published in 2017 assessed more cytokines, used more sophisticated statistical analyses (logistic regression/network analysis) and was larger (n=91) than past ME/CFS spinal fluid studies.The studies started with a collection of samples from many of Dr. Peterson's sickest patients, which Dr. Hornig called "unparalleled" in their breadth and rigor.Simmaron sent off two sets of spinal fluid samples - one to Mady Hornig and Ian Lipkin at the Center for Infection and Immunity (CII) for a pathogen and cytokine study and another smaller set to Griffith University researchers in Australia to assess for immune abnormalities.The CII added a set of multiple sclerosis patients to the mix to produce one of the most interesting studies in years. Few studies had compared MS and ME/CFS patients, and none had assessed the crucial immune factors present in the spinal fluid.The cytokine levels in both the ME/CFS and the MS patients differed widely from those of the healthy controls. Interestingly, both ME/CFS and MS patients demonstrated reduced cytokine levels – a fascinating finding given the similar finding in the blood for longer duration ME/CFS patients. That finding prompted Dr. Hornig to speculate that, “I think what we’re seeing is an immune system exhaustion over time.”Despite both diseases demonstrating the same general trend towards immune exhaustion, they differed markedly in the cytokines affected. The cytokines highlighted in ME/CFS suggested an allergic type of reaction - similar to that found in central nervous system infections – was present. Cognitive decline and aging - two themes in ME/CFS research - as well as reduced neuron production were also highlighted.The fact that the alterations in the immune factors in ME/CFS were almost as extreme as those found in multiple sclerosis – a disorder characterized by severe central nervous system dysfunction – suggested that a significant pathological process was indeed occurring in the central nervous systems of ME/CFS patients.
A Hunch Pays Off - The Peterson Subset
“Dr. Peterson’s clinical acumen, his long-term follow up of this patient population and his attentiveness to the full range of complex, serious medical disorders that might develop. The classical group had been followed for similar lengths of time but had not developed these more severe, serious comorbidities.” Mady Hornig
Peterson subset
Next, Simmaron and the CII turned to an unusual subset of patients. Dr. Peterson has long asserted that a classical (infectious onset) subset of patients is present in ME/CFS, and is different from what he called a “complex atypical” subset of patients.Dr. Peterson’s believed his typical “classical” ME/CFS patients came down with a flu-like illness from which they never recovered. His atypical patients, on the other hand, tended to be sicker, have more cognitive problems, have more severe comorbid diseases (autoimmune diseases, cancer), tended to have unusually severe neurological symptoms (such as seizures), and had experienced things like blood transfusions, exposure to infectious agents during international travel, etc.Many of these illnesses appeared long after the ME/CFS diagnosis. In fact, at the time of diagnosis Peterson reported that the atypical patients looked like a typical ME/CFS patient but felt that some other underlying central nervous system process was underway.Dr. Peterson was so sure, in fact, that an atypical subset of ME/CFS was present - and probably bollixing up study results - that he requested that the group be assessed apart from the other patients in the first Simmaron/CII spinal fluid study. Peterson's intuition turned out to be correct: the atypical group affected the results so thoroughly that it had to be removed from the first study.The next study compared the atypical and typical patients. Using Peterson’s spinal fluid samples, The Center for Infection and Immunity (CII) at Columbia found that the “Peterson Subset” displayed a markedly different pattern of immune results: something quite different was going on in their central nervous systems.Given how sick the atypical patients were, one might have expected their immune factors to be even more reduced, but instead they were increased. In stark contrast to the classical patients, the atypical patients had higher levels of virtually all the immune factors assessed.Their immune presentation over time differed as well. Almost half their immune factors were lower early in the illness but as the illness proceeded, in contrast to the typical patients, the atypical groups’ immune systems actually revved up again.Since the higher levels of cytokines in the atypical group would have negated the lower levels of cytokines in the "classical" patients, Peterson's request that the atypical patients be set aside saved the biggest CSF study in ME/CFS history from a null result. Given the size and expense of the study, that negative result would have dampened interest in the immune aspects of the CSF in ME/CFS for years.The study demonstrated how critical it is for savvy ME/CFS experts to work hand in hand with research teams to explore ME/CFS - and put the research field on the alert for the apparently very biologically different atypical patients.
The Gut
Since its inception, Simmaron has collaborated with the Columbia Center for Infection and Immunity on several gut studies, including, in 2017, the first study to characterize ME/CFS patients gut flora all the way down to the species level. Prior to this study, ME/CFS gut studies had identified genera, each of which contain many different species, some with very different characteristics. This time, Ian Lipkin used a new approach called metagenomic sequencing to get at the actual players in the gut - the bacterial species.For the first time, the gut flora of ME/CFS patients with and without irritable bowel syndrome (IBS) was assessed, as well.Such dramatic differences in bacterial species showed up between the two groups that the researchers were able to distinguish the two simply by comparing their gut flora.
See - Columbia & Simmaron Gut Study Uncovers Another Chronic Fatigue Syndrome (ME/CFS) Subset - for more.
In 2018, Dr. Peterson participated in another innovative CII gut study. Melding together gut flora and metabolomic findings for the first time, Nagy-Syzkal and Lipkin found that ME/CFS and ME/CFS-IBS patients again displayed significantly different gut flora as well as metabolomic signatures.While problems with fatty acid metabolism were present in both groups, the study found that ME/CFS patients with IBS had additional problems with ATP production and the urea cycle. Plus, the findings suggested high loads of bacterial toxins could be triggering IBS, and pathogens in the gut could be triggering ME/CFS in both groups. On the treatment end, the study findings suggested SMAse blockers might be helpful if the findings are validated.For all the focus on metabolomics in ME/CFS, a gut microbiome analysis was better able to distinguish ME/CFS patients from healthy controls than a metabolomic analysis. That surprising finding suggested the gut may play a bigger role than we've thought in this disease.
See The Subset Maker”: Lipkin Chronic Fatigue Syndrome Study Highlights Energy Issues In Gut Subset for more.
Natural Killer (NK) Cells
Dr. Peterson was the co-author of the first NK study, over thirty years ago, to find deficient NK cell functioning in chronic fatigue syndrome (ME/CFS). Following a year-long collaboration between Dr. Peterson and Griffith University in Australia, Griffith found reduced natural killer cell functioning at all time points - indicating that NK problems in ME/CFS are consistent and pervasive.Peterson's next Griffith University collaboration found that small bits of mutated RNAs called miRNAs may be contributing to the problems with cytotoxic NK and T-cells in ME/CFS.
Immunology Workshop
In 2014, Simmaron hosted the first ever Immunology Workshop at the IACFS/ME International Conference:
Validating Treatment Successes
Making more effective treatments available for ME/CFS patients has been a goal of Dr. Peterson's for years. Dr. Peterson's focus on and his creative approach to infectious onset patients, in particular, has resulted in using and documenting treatments that other doctors might not try.Dr. Peterson has reported that almost 30% of his patients test positive for active HHV-6 or human cytomegalovirus (HCMV) (via PCR, rapid culture, antigenemia), and a whopping 50% test positive for active Epstein-Barr virus (EBNA) infection.Simmaron's core work includes efforts to analyze the effects of little used immune treatments such as Cidofovir (Vistide), Ampligen and IVIG on ME/CFS with a goal of publishing treatment data.
Vistide
In 2013, Dr. Peterson reported on the results of the first retrospective analysis of Vistide's effectiveness in ME/CFS. Few ME/CFS experts use Vistide but Peterson found that 70% of 65 patients treated from 2005-2012 for HHV6 and/or HCMV infection were either full (able to return to work) or partial (significant increase in functionality) responders; a very high rate of success in an illness characterized by a poor response to treatments.Only 30% of Vistide recipients did not have a significantly positive response to the drug, and no serious side effects were seen; ironically the minor side effects seen were attributed to a drug, Probocenid, that's used to ensure that Vistide is absorbed into patients' systems effectively.See Report From Paris: Peterson Reports Antiviral (Vistide) Effective in Treating Herpesvirus Infected Chronic Fatigue Syndrome (ME/CFS) Patientsfor more.
Ampligen
In 2018, Simmaron and Dr. Peterson reached out to Maureen Hanson and the CDC to help with a project to assess the effectiveness of Ampligen. To this day, Ampligen still remains the only drug the FDA has assessed for ME/CFS. With no Ampligen trials forthcoming Peterson searched for ways to provide a boost for a drug he knows from long experience that can work very well.The novel project took advantage of a year-long lapse in Ampligen availability to assess changes in immune and other factors and symptoms at three time points: (1) while Dr. Peterson's patients were on Ampligen; (2) when they were off Ampligen; and (3) when they went back on Ampligen.The extensive testing included NK cell function, cytokine expression, multiple symptom surveys, an exercise tolerance test and Cornell-designed research protocols. Besides demonstrating how Ampligen works, the study could begin to uncover which subsets of patients it works in.Gunnar Gottschalk presented preliminary results from "The Workshop for Young Investigators" at the NIH's ME/CFS Conference in 2019. He reported finding "significant and sustained clinical reduction(s) in both the physical and neurological symptoms following Rintatolimod (Ampligen®)”, including improvements in physical functioning, pain and energy after 6 months of treatment.An analysis of the biological data is underway.
Next Up For Simmaron
Simmaron's highest priority is publishing data on ME/CFS subsets and effective treatments - two factors which experience has shown are inextricably linked to one another. Simmaron believes the hidden subsets in ME/CFS have the potential to cloud or nullify the results of biomarker and research efforts as well as treatment trials. On the flip side, elucidating those subsets could produce breakthrough results. To this end, Simmaron's work is strategically focused on helping the field break out of that conundrum.
Expanded Treatment / Subset Effort
Simmaron
Simmaron recently began fundraising for an expanded effort to analyze data from Dr. Peterson's patients who've responded to treatments like Ampligen®, IVIG and cidofovir, as well as amino acid infusions, saline, etc. The goal of these studies is to biologically identify which patients respond to which treatments, and build a scientific roadmap for getting a first medication approved by the FDA for ME/CFS.Maureen Hanson, PhD of Cornell, is leading the scientific arm of the study, the U.S. Centers for Disease Control is doing statistical analysis; and Dr. Peterson will provide the patients and the treatments.Simmaron believes the rigorous data analysis being used in these efforts can provide a building block for designing rigorous placebo-controlled trials that have a stronger chance of approval, and ultimately attract pharmaceutical companies to the disease.
Spinal Fluid Study - Round Three
The second phase of the Simmaron/Columbia spinal fluid study now in progress expands the prior studies, and breaks new ground by including a metabolomics analysis. Metabolomics - the study of metabolic by-products - has suggested that a hypometabolic state akin to hibernation may be present in ME/CFS. This study should shed light on both the metabolic and immune underpinnings of the neuroinflammation believed present in ME/CFS.