Suzanne Vernon’s interest in pathogens and post-infectious diseases goes back to when, as a 20-year-old, she landed a work-study job at the CDC’s Division of Vector-Borne Diseases while an undergraduate at Colorado State University.
Ten years later with her Ph.D. in virology, she was a research microbiologist at CDC Atlanta, leading a team of scientists on the hunt for pathogens and molecular markers in ME/CFS. Her first papers for the CDC’s ME/CFS program in 2002 – searching through cell-free plasma DNA for the sign of a pathogen – and her pioneering use of new gene expression techniques – was emblematic of her focus on using cutting-edge technologies to peer deeply into ME/CFS.
It was during Suzanne Vernon’s time the CDC funded the groundbreaking Dubbo post-infectious studies led by Andrew Lloyd, and Gordon Broderick’s modeling efforts that would later come to define much of Nancy Klimas’s present work and set the stage for her treatment trials in GWI and ME/CFS (and her ample GWI funding.)
One of Vernon’s most creative endeavors came in 2006 when she gathered almost 2 dozen researchers to use cutting-edge statistical analyses to analyze a large data set gathered from over 100 ME/CFS patients and controls during a 2-day hospital stay. The 14 studies that resulted – the largest and most complex of their time – filled up an entire issue of the Future Medicine journal Pharmacogenomics.
The tests were state of the art for that time and arrived at some familiar conclusions. A “supergenes” study plucked out estrogen receptor, TNF-a (which Dr. Klimas is trying to suppress in ME/CFS), three genes involved in calcium and/or sodium ion channel function (channelopathy), two magnesium binding genes, a heat shock gene involved in protein misfolding (amyloidosis), two metabolic genes (acyl-coenzyme binding) and several signaling genes. Another study highlighted genes associated with lipid metabolism – a hot field of study right now – energy production, and the immune system.
The CDC data set was enticing enough to be used by the International Conference on Critical Assessment of Massive Data Analysis in 2006. This time, ten papers were produced, several of which highlighted tryptophan and cortisol, and produced one of the first ME/CFS systems biology papers.
After leaving the CDC, Suzanne was the scientific director of the Solve ME/CFS Initiative from 2008-15. Since 2017 she’s been the research director for the Bateman Horne Center. I was eager to get her take at this crucial juncture in ME/CFS after long COVID had leaped onto the scene.
First, I wanted to know if she thought the ME/CFS field had missed any opportunities. Was there anything the field could have done to better prepare it for when long COVID unexpectedly popped up?
She felt not but noted that she and Kim McCleary – Solve ME’s longtime leader – used to talk about the missed opportunities that the “one and done” studies in ME/CFS presented. Time and again, a study would get done – show some promise – but then, for whatever reason, get dropped. It was all, she thought, the result of poor funding – not enough funding to do large studies or to follow up on small studies; not enough funding ultimately to produce the bang that would really move the field forward.
Combine small studies with the heterogenous illness ME/CFS and you have a recipe for muddled results and slow movement. Citing a few heterogenous factors – people with different triggers, and people with different durations of the illness – she focused on people who use the criteria differently.
She said she was struck by Andrew Lloyd saying years ago that, as a physician, he could recognize a patient with ME/CFS the moment they walked into an exam room. Not all studies have an ME/CFS expert like Andrew Lloyd or Dr. Bateman on board who can ensure that only people with ME/CFS get into a study. Those that do – like Lipkin’s recent peroxisome study (which she co-authored) – are going to be that much more effective, she thought.
The RECOVER Project – “A Thing of Beauty”
The NIH’s $1.15 billion RECOVER (Researching COVID to Enhance Recovery) program has rolled out slowly. Still, Suzanne felt it was a massive, well-thought-out program that will ultimately deliver the goods. In fact, the only program she could think of that compared to it was the fight to conquer HIV. Decades later, we have much more sophisticated technology we can bring to bear on long COVID.
Dr. Vernon said that from a research scientist’s perspective, the program is a thing of beauty.
Instead of being a top-down project, the study is designed to get inputs from many different people – many very smart people she said – and is designed to change over time. Standardized research protocols will ensure all the studies can “talk” to each other. All the data goes into central databases and is managed by the Data Resource Core. Hoarding data – an occupational hazard in the research world – is not allowed.
As big and as slow-moving as the RECOVER project has been, it appears to be a nimble project that will be able to change in response to new findings and is receiving input from a variety of sources.
Three tiers of patients receive a standard testing protocol and produce a baseline data set. Everyone in Tier I gets a clinical examination (including an active standing test), their blood drawn and analyzed (19 lab tests including EBV and coagulation tests), and receives questionnaires every 3 months for 4 years.
Of that group, some will go on to Tier Two which includes things like a 6-minute walk test, home sleep test, cognitive tests, several antibody tests, cortisol, cytokine panel, pulmonary function tests and others.
About 20% of the entire group will move onto Tier 3 where they will get catecholamine, protein, MRI, gastric emptying, nerve conduction, skin and muscle biopsy, lumbar puncture, cardiovagal, tilt table, upper endoscopy, colonoscopy, an in-facility sleep study and several others I had never heard of.
Strong ME/CFS Connection
Plus, a strong chronic fatigue syndrome (ME/CFS) connection is present within the effort. RECOVER includes twelve Task Force Committees that provide in-depth scientific reviews and recommendations to the RECOVER leadership.
The Commonalities with Other Post-viral Syndromes Task Force Committee informs the RECOVER leadership of the similarities between long COVID and post-infectious ME/CFS. Several ME/CFS experts are active on this committee including Lenny Jason, Benjamin Natelson, Hector Bonilla, and Suzanne.
Recently, several of this task force published an Op-Ed in the Chicago Tribune underscoring what ME/CFS could teach us about long COVID. Noting the similarities found thus far between the diseases such as preload failure and EBV reactivation, the authors asserted that having ME/CFS cohorts embedded in the Initiative was critical for understanding both long COVID and ME/CFS.
The Bateman Horne Institute Makes It Into the RECOVER Initiative
I’m always interested in how things happen, so I was very interested in learning how the Bateman Horne Center came to be part of the RECOVER Initiative.
It turned out that they didn’t just get asked in – it took some initiative. Early in the pandemic, Suzanne reached out to Drs. Will Dere and Rachel Hess at the University of Utah to let them know that the Bateman Horne Center was interested in collaborating on post-COVID-19 research. Her ace in the hole in her presentation was the 2006 Dubbo ME/CFS post-infectious study.
There’s no getting away from the gut which produces the lipids that protect the cellular membranes. (For those who don’t know, the Dubbo study followed people with an acute infection of three different pathogens (either Epstein-Barr virus (glandular fever/infectious mononucleosis), Coxsackie burnettii (Q fever), or Ross River virus (epidemic polyarthritis)) over time to see how many people came down with ME/CFS-like illness.
- As head of the CDC’s molecular explorations into ME/CFS, the Solve ME/CFS’s research effort, and now as the Bateman Horne Center’s research director, Suzanne Vernon has been employing a cutting-edge approach to ME/CFS for 2 decades.
- She felt the ME/CFS field has been hampered over the last couple of decades by a couple of things: poor funding and small studies have left the field littered with “one and done” studies that showed promise but which for one reason or another were never followed up on.
- Long COVID and the emergence of the NIH’s RECOVER Initiative is changing almost everything. Calling the Initiative a “thing of beauty” from a research perspective, the only similar project of its scale that she could think of was the work done on HIV.
- She was sanguine about its short-term effects on ME/CFS funding but called the exposure to ME/CFS the long COVID research community is receiving “invaluable”, noted that ME/CFS researchers are embedded in the program, was excited about the potential for RECOVER research to impact ME/CFS, and reported that treatment trials will begin shortly.
- The Bateman Horne Center (BHC) became part of the RECOVER Initiative throughout outreach which highlighted the ground-breaking work the post-infectious Dubbo studies did in ME/CFS 15 years ago. The BHC and NIH Research Centers it collaborates with have now incorporated long COVID patients into their sophisticated immune and metabolic studies.
- Given the key role the peroxisomes play in energy production and cell membrane integrity the peroxisomal problems found recently in ME/CFS could be, if further research reveals them to be so, a core problem in ME/CFS.
- Problems with cell membrane integrity, for instance, could render cells inert and unresponsive – particularly in stressful situations like infections and exercise. Recent studies, interestingly, suggest that, in contrast to healthy controls, that the protein response to exercise is almost nil.
- The gut shows up again! Call it the center of metabolism, Suzanne noted that the lipids that make our cell membranes are manufactured in the gut. The microbiome findings in ME/CFS suggest that the butyrate gut bacteria that produce those lipids are, in fact, deficient in ME/CFS.
- She hearkened back to a Solve ME 2015 study that found exercise disrupted the gut microbiome more, triggered more leaky gut, and left more gut bacteria in the blood for longer periods in ME/CFS patients than healthy controls.
- The NIH refused to fund further studies but the team – puzzled by the unusual immune response seen in ME/CFS – with the addition of Armin Allaedini persevered. A soon-to-be-published paper will explain the immune response and suggest that the gut-exercise reaction could play a major role in the post-exertional malaise seen in ME/CFS.
The presentation worked. Once the RECOVER Initiative funding was announced, the University of Utah investigators invited the Bateman Horne Center to be part of their application. When the application was approved, the BHC became the recruiting center for what is now called the Mountain States PASC Consortium (MSPC).
ME/CFS / Long Covid Cohort Studies Underway
The Bateman Horne Center didn’t wait for that to happen, however, to start their own long-COVID clinical research. By January 2021, several months before RECOVER started, they were enrolling long-COVID patients in their own studies. By the time RECOVER launched, the BHC was able to reach its enrollment target within a couple of months.
Plus, if the NIH hasn’t allowed ME/CFS patients into their studies (yet), the BHC certainly has. They’re conducting their own research comparing the two groups. In addition, they worked with Derya Unutmaz, of The Jackson Laboratory, and Ian Lipkin, of Columbia, to amend their Collaborative Research Center grants to include a long-COVID cohort.
Samples and data collected from these long-COVID patients are being analyzed by both centers and will provide a unique and in-depth look at comparing the immune and metabolomic perturbations in long COVID and ME/CFS.
That’s a potentially very significant effort given the insights metabolomic studies have produced in ME/CFS and the dearth of metabolomic studies thus far in long COVID. It could, one would hope, help convince the RECOVER Initiative to include an ME/CFS cohort in its studies.
The team is already finding important similarities and differences between long COVID and ME/CFS, as reported in this recent paper.
(That study found that a 10-minute NASA lean test produced a narrowing in the pulse pressure (the difference between systolic and diastolic BP) in the long COVD and ME/CFS patients but not in the healthy controls. While more narrowing in the pulse pressure was found in the long-COVID patients, the effects of the NASA lean test on cognition lasted longer in the ME/CFS patients. The authors proposed that reduced blood flows to the brain were causing the cognitive difficulties.)
The Tricky ME/CFS Long-COVID Connection
The ME/CFS long-COVID connection is a tricky one. Suzanne noted that because the researchers studying long COVID are learning about the similarities with ME/CFS, ME/CFS is getting massive exposure in the scientific community. That, she thought, was invaluable.
She is not certain, though, that NIH will increase ME/CFS funding because of the pandemic. Researchers are going where the funding is and right now, the funding is for post-COVID-19 disorders, including long COVID. While some ME/CFS cohorts may be included in some RECOVER studies, the focus now is on the understanding, prevention, and treatment of post-COVID conditions, including long COVID.
Long-COVID Treatment Trials Coming Soon
She also believes, though, that long-COVID studies will open up many avenues for ME/CFS, including new treatments. The NIH isn’t waiting to understand long COVID before they begin treatment trials: they’re moving rapidly with treatment trials – more rapidly than most of us would have thought.
The RECOVER Initiative put out a funding opportunity for clinical studies and named Duke University as the Clinical Trial Management Center. A short list of trials has already been created and trials are slated to begin by the last quarter of this year.
At the recent NIH Telebriefing for ME/CFS, Walter Koroshetz, the director of the National Institute of Neurological Disorders and Stroke, seemed rather excited for a change, and for good reason – he had some good news to report. He reported that the steering committee for the long-COVID trials was bulging with ME/CFS (15) and POTS (11) experts.
Koroshetz stated that the clinical trials are going to focus on eliminating persistent viral reservoirs and impacting immune functioning, as well as helping with specific symptoms like fatigue, sleep, cognition, exercise intolerance, and autonomic nervous system functioning.
The really nice thing about these treatment trials is that they’re not going to end up being slotted into the “one and done category”. They’ll be rigorously produced, and if positive findings result, they will be followed up on.
Suzanne believes new treatment possibilities will show up before we know how long COVID is caused.
- Update on the RECOVER Initiative: Enrollment has been picking up. RECOVER now has enrolled almost half (8,637) of the adults it wants (17,680). They are low, though, in people who are coming down with COVID-19 now.
- Find a study site near you
The New Organelle in Town – the Peroxisomes
We’d never heard of peroxisomes prior to the last year or so, but Suzanne was clearly jazzed at the result of the recent Lipkin study (of which she was a co-author). The peroxisomes’ small size belies the impact they have on cell functioning. Not only do they break down the long-chain fatty acids that are used to power the mitochondria, but they also produce phospholipids and other components that make up the cellular membranes.
That cell membrane connection could be critical. Since cells communicate with their environment via receptors embedded in their cellular membranes, damaged membranes could leave cells inert and unresponsive – a particular problem during stressful times such as infections and exercise. (We recently saw evidence of an enormous slump in protein activity after exercise in ME/CFS. Did exercise whack the cell membranes so hard that they were unable to respond?).
Vernon remembered the strange – at the time – signaling issues that kept cropping up in her early gene expression work. She couldn’t explain them at the time – now with these findings suggesting multiple ways the lipid membranes of the cells in ME/CFS are damaged, maybe they make sense.
The recent Lipkin study also brought back memories of her two hypotheses that loomed large in the patient community back in the early 2000s.
People who’ve been around for a while may remember Rich Van Konynenburg and Martin Pall. Rich Van Konynenburg was a kind of citizen researcher who championed the idea that depletions in the master antioxidant in the body (glutathione) played a significant role in ME/CFS. Martin Pall was a Washington State University biochemistry professor who, after coming down with ME/CFS, originated the NO/OHNOO- hypothesis which proposed that chronic elevations of nitric oxide and the peroxynitrite radical were causing ME/CFS.
Massive forum threads were devoted to their ideas and treatment implications, but both made little headway with the mainstream research community. Rich died an untimely death and Pall seems to have faded away. Now, given the focus on lipid breakdowns, oxidative stress, and peroxisomes, Suzanne wondered if they may have been right all the time.
With peroxisomal dysfunction, you’re potentially getting at some fundamental factors: the ability to produce energy and the ability of cells to communicate and function. Could peroxisomal dysfunction be the smoking gun in ME/CFS? Time will tell.
The Long COVID Research Initiative recently launched a $15 million effort to determine if the coronavirus was alive and well, or in pieces and creating problems in the tissues of long-COVID patients. As an infectious diseases specialist, I asked her if pieces of the virus, or the virus itself, might remain.
She thinks that’s possible. She noted that a couple of publications report persistent viral shedding has been found. Having viruses, bacteria, and protozoans hanging around is nothing new for humans – they’re all basically part of the human package – but she wondered if people with ME/CFS and long COVID now had trouble tolerating them.
“The Root of All Metabolism” – The Gut
The fact that it’s the gut flora or microbiome that produces the lipids that make up our cellular membranes makes the gut all the more interesting. If the microbiome is off – and every study indicates it is in ME/CFS – problems in the gut could be affecting the lipid membranes of our cells. Throw in the fact that it’s the butyrate-producing bacteria – which play an important role in lipid metabolism – that appear to be deficient in ME/CFS – and the potential linkages build up.
Dr. Vernon led one of the most interesting “one and done”, or as we’ll see, “almost one and done” studies in 2015. The study, conceived and funded by Solve M.E., examined the effects of exercise on leaky gut in ME/CFS. It found that exercise altered the gut microbiome more, and induced significantly greater amounts of gut leakage, in people with ME/CFS than healthy controls. People with ME/CFS also had more trouble clearing the gut bacteria from their blood: their bacterial levels were still high 24 hours later.
It was a fascinating study that potentially showed how exercise can affect an area we generally don’t associate with exercise – the gut – and produce a result – inflammation – that is likely associated with post-exertional malaise (PEM). Despite the positive result – and the high p values in this small study – the NIH declined to fund a larger study.
If the NIH wasn’t jazzed by the study findings, the researchers were. Armin Alaedini – a gluten and celiac disease expert – collaborated with Sanjay Shukla and Dane Cook to further analyze the before and after exercise samples. Alaedini didn’t find evidence of celiac or gluten problems but, struck by the strange immune response the team had found in the ME/CFS patients, he kept looking for ways to explain it.
He succeeded, and seven years after the last paper, this paper should be published soon. Suzanne said it demonstrates that the microbiome and immune changes that exercise produces may be key contributors to ME/CFS; i.e. the study could help explain why exercise is so problematic in ME/CFS. Columbia University thought the finding was important enough to list it as a potential therapeutic target or ME/CFS biomarker on their technology ventures website. She also noted that leaky gut is a cell membrane problem – which means that peroxisomes may be involved there as well.
Maybe the NIH will fund the team’s next grant application.
It was good to hear this longtime ME/CFS researcher express excitement about the RECOVER Initiative and its ultimate effect on ME/CFS. While Suzanne could not say the ME/CFS funding will increase in the short term, she believed the exposure ME/CFS was getting was invaluable, expected many insights to come out of the Initiative, noted that ME/CFS experts are embedded in the effort, that the Bateman Horne Center is part of the Initiative, and reported that treatment trials will begin shortly.
Peroxisomes have shown up big time recently in ME/CFS research. Noting the key roles they play in energy production and maintaining the cellular membranes, Suzanne suggested that damaged cellular membranes could leave the cells inert and unresponsive. Since ME/CFS patients’ guts are deficient in the bacteria that produce the metabolites needed for the cellular membranes, the gut may come into play in this equation as well. In fact, an upcoming gut study will show that exercise-triggered gut issues may play a key role in ME/CFS.
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