Article Dr. Suzanne Vernon: 25 Years of Trying to Crack the Case of ME/CFS

Dr. Suzanne Vernon: 25 Years of Trying to Crack the Case of ME/CFS

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For over 25 years, Dr. Suzanne Vernon has been trying to crack the case of myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS). Image courtesy of Dr. Suzanne Vernon.


by Bronc

I first fell ill with terrible fatigue-like symptoms in the summer of 2010. Besides the bone-crushing fatigue, I felt fearful, confused, perplexed and demoralised by this mysterious illness that had reduced me from feeling like Iron Man to feeling like a breeze could blow me over.

Now it's 12 years on and at times I still feel confused, perplexed and demoralised by the neurological illness that has turned my life upside down. As the weeks, months and years flash by with no prospect of treatments for my illness, the only thing I can do at times is to say to myself, "I just have to keep putting one foot in front of the other and keep on going."

Having ME/CFS is like being a marathon runner. It requires resilience.

It can be said that this equally applies to scientists such as Dr. Suzanne Vernon, who has spent more than 25 years researching ME/CFS. Dr. Vernon is currently Research Director at the Bateman Horne Center (BHC) and has co-authored over 150 articles on ME/CFS. As Research Director, she is developing research into evidence-based treatments and objective diagnostic measures for ME/CFS.

Dr. Vernon took time out from her busy schedule to speak with us.


Phoenix Rising:

How did you get involved in the field of ME/CFS research?

Dr. Suzanne Vernon:

I was a National Science Foundation post-doctoral research fellow in the CDC's Division of High-Consequence Pathogens and Pathology in the early 1990s. The CDC's ME/CFS program was in this same division so I was able to be a part of all the meetings and discussions.​
I was fascinated by ME/CFS and the opportunity to investigate a disease that was new and unexplained. The recommendations from a 1996 peer review of the ME/CFS program included adding a novel pathogens and biomarker discovery effort.​
I jumped at the opportunity. What was cool about this is that we were able to leverage the technology we were using in our HIV and HPV (human papillomavirus) research for ME/CFS research. By 1998, the novel pathogen and biomarker discovery effort of the ME/CFS program was in full swing.​

Phoenix Rising:

In the ME/CFS research community you have a unique perspective, having worked as a U.S. government scientist studying the disease in the 1990s, as well as a non-governmental scientist studying the disease in the many years since then.
From your own perspective, could you briefly describe how you saw the U.S. government's approach to ME/CFS in the 1990s?

Dr. Suzanne Vernon:

I was invited to lead the ME/CFS research program in 1996. I jumped at this because ME/CFS research was a blank slate with lots of opportunity for discovery that could help people.​
During my time at the CDC, the ME/CFS program was well-funded. The [congressional funding bill] included a line item for ME/CFS research at the CDC. This was because of the tireless advocacy by the CFIDS Association [now known as Solve ME]. This funding helped us do cutting-edge "-omics" and "big data" research.​
Another unique aspect of the CDC's ME/CFS program was its partnership with patients and patient advocacy organizations like [Solve ME]. Back then, there was very little engagement or input from patients and patient advocacy groups into research. In many ways, the CDC's ME/CFS program was ahead of the curve when it came to patient-centered research.​

Our well-funded, unique, and innovative ME/CFS program also created acrimony and skepticism among our CDC colleagues. "Toe the party line" and not "rocking the boat" is what is expected at places like CDC.​
Dr. Reeves' style was antithetical to this, which made it challenging at times. But overall, I would say that our approach at the CDC to ME/CFS was disruptive (in a good and innovative way), and comprehensive.​

Phoenix Rising:

Many people with ME/CFS develop the illness after an acute infection, and they then develop a variety of symptoms which fluctuate over time. Several studies suggest that this may be an inflammatory response to persistent infection.
A growing body of evidence also suggests that many inflammatory disease states, including neurological illnesses such as ME/CFS, may be tied to an imbalance of the human microbiome.
How does study of the human microbiome help us understand the disease processes in ME/CFS, and how might it help in the treatment of the disease?

Dr. Suzanne Vernon:

Many acute infections cause gut symptoms — nausea, diarrhea, constipation, bloating, etc. These symptoms are indicators that something is going on in the gut, such as infection and destruction of intestinal cells and inflammation.​
The acute infection causes damage to the gut, dysbiosis or imbalance of the gut microbiome, and at the same time activates the immune response to fight the infection and help repair the damage. In fact, intestinal cells are good at growing back or renewing after infection. Once the infection is cleared, the gut microbiome is restored.​
However, as you point out, dysbiosis and irritable bowel is associated with ME/CFS. It is not yet known why — especially in cases of post-infectious ME/CFS — dysbiosis and microbiome imbalance persists.​
There is evidence that the microbiome in some ME/CFS patients is deficient in butyrate-producing bacteria. Butyrate helps control gut inflammation and helps prevent leaky gut. Less butyrate means more dysbiosis, gut inflammation and leaky gut.​

One of the most important research studies was done by Sanjay Shukla, Dane Cook, and others. This research showed increased bacterial translocation from the gut into the blood in ME/CFS following an exercise challenge, and slower clearance of this bacteria from the blood in ME/CFS. This significantly different response to exercise in ME/CFS patients could explain PEM.​
But we still don't know what is causing the dysbiosis and leaky gut. Is it viral persistence? Is it immune dysfunction? Or a combination of these things?​
A study by Birgitta Evengard found that probiotics improved ME/CFS symptoms in some patients. I am not aware of any peer-reviewed research papers, but there are anecdotal reports of the benefit of fecal microbial transplants (FMT) in ME/CFS. Finally, there is a substantial evidence base of the benefit of dietary and nutritional treatments in ME/CFS patients.​

Phoenix Rising:

Last year you were part of the team which published a preprint that combined study of the gut microbiome with blood metabolomics in recent-onset ME/CFS patients, long-term ME/CFS patients, and healthy controls.
What differences did you find?
Dr. Suzanne Vernon:

This manuscript has been submitted to Cell Host & Microbe and is still under review. Fingers crossed that it will be accepted for publication, because this is a high-impact journal and it will receive a lot of visibility.​
This manuscript comes from data generated from the NIH-funded Collaborative Research Center (CRC) at The Jackson Laboratory (aka JAX), with Derya Unutmaz, MD as Principal Investigator. Dr. Unutmaz put together an amazing team, including Julia Oh, PhD, who leads the microbiome research for the ME/CFS JAX CRC.​
Our role as the Clinical Core for this four-year study was to recruit ME/CFS and Long COVID patients, conduct physical examinations, cognitive and orthostatic testing, and collect blood and fecal samples.​
Our goal was to recruit ME/CFS patients that had a relatively short duration of illness and compare them to ME/CFS patients who had been sick for a long time.​

We defined "short duration" as sick for less than four years and "long duration" as sick for more than 10 years — and we tried to keep everything else about participants the same, so that when we compared the two groups, explanations other than duration of illness would be minimized.​
The reason we wanted to study short versus long duration is because of other published evidence that found immune and cytokine differences in ME/CFS patients who had been sick for less than three years.​
This "multi-omics" study sequenced the microbiome from fecal samples and assessed metabolites in the blood samples collected during the first year.​
There were significant differences between short- and long-duration ME/CFS. Specifically, ME/CFS patients sick for less than four years had less microbial diversity and ME/CFS patients sick for more than 10 years had more severe ME/CFS symptoms, comorbidities, and blood metabolomic abnormalities.​

The "multi-omics" part comes in by combining the various "-omic" data types and, using classification algorithms, seeing whether the combined "-omic" measures identify ME/CFS patients [separately from healthy controls].​
The combined measures were good at identifying ME/CFS patients and importantly, at identifying the host and microbial factors that help explain ME/CFS pathophysiology.​

Phoenix Rising:

You were part of the team that conducted a pilot study of a drug called CT38 for ME/CFS patients.
In the 2021 article reporting the results, the team explained their hypothesis that the widespread disruption of systems in patients may be caused by the up-regulation in the brain of a protein called CRFR2.
Could you explain how this might be responsible for ME/CFS symptoms?

Dr. Suzanne Vernon:

The initial observation that transient CRFR2 up-regulation induced symptoms (including fatigue, slowed movement, etc.) came from animal experiments. It turns out that levels of serotonin — a key neurotransmitter that controls most bodily functions — are regulated by CRFR2.​
Chronic CRFR2 up-regulation leads to excess serotonin, resulting in numerous symptoms (e.g., fatigue, proprioception [dysfunction], dyspnea, sensory sensitivity, dysautonomia, hypothyroidism, [impaired] glucose control, [impaired] immune function).​

Phoenix Rising:

In this study you proposed utilizing "agonist-mediated receptor endocytosis" to down-regulate CRFR2.
What would this treatment involve? Did the results of the trial suggest that this is a viable treatment approach warranting further study?

Dr. Suzanne Vernon:

CT38 is a highly selective agonist that binds to [the receptor called] CRFR2, causing it to down-regulate. If up-regulated CRFR2 causes symptoms, down-regulating CRFR2 should reduce or eliminate symptoms.​
An agonist binds to a receptor to initiate a response. In this case, CT38 binds to the receptor CRFR2 and causes the CRFR2 to [be down-regulated by removing it from the surface of the cell in a process called endocytosis].​
The CT38 trial in ME/CFS patients supported the hypothesis that CRFR2 was up-regulated and that down-regulating CRFR2 with CT38 was a viable treatment option that deserved further study in a larger trial.​

Phoenix Rising:

You were part of a large collaboration of researchers who recently published a metabolomics paper entitled Metabolomic Evidence for Peroxisomal Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
What were the chief findings of this study?

Dr. Suzanne Vernon:

This paper comes from an ongoing collaboration of the listed investigators, and has been funded by the NIH and the Hutchins Family Foundation.​
Patients and their samples from this study came from four ME/CFS clinics (Bateman, Klimas, Peterson, Levine). This is important, and means that patient participants are clinically characterized.​
The novel finding from this metabolomic study was peroxisomal dysfunction. Peroxisomes are organelles found in the cytoplasm of our cells (plant cells have them too). The peroxisome contains hydrogen peroxide and enzymes that break down fats (lipids), which provides the phospholipids needed for cell membranes.​
The peroxisome also has an important role in reactive oxygen species metabolism. Therefore, peroxisome function is essential for health. Evidence is rapidly emerging about the contribution of peroxisome dysfunction in the pathogenesis of diabetes, neurodegenerative disorders, cancer and ME/CFS.​

Identification of peroxisomal dysfunction in ME/CFS means that treatment can be targeted to peroxisomal dysfunction.​

Phoenix Rising:

Can you tell us about your current research into ME/CFS?

Dr. Suzanne Vernon:

I joined the Bateman Horne Center (BHC) in 2015 and shortly thereafter the Institute of Medicine (IOM) published their diagnostic criteria for ME/CFS. The IOM report provided the roadmap for my research at BHC.​
Specifically, I set out to develop ways to measure the [symptoms in the] diagnostic criteria, in the hopes that objective measurement would make it easier, and more appealing, for clinicians to use the IOM diagnostic criteria.​
I really like the idea of passive measurement with wearable [devices], so that data can be collected over long periods of time and so that patients don't have to deal with answering long questionnaires.​

We've come up with "UpTime," which uses a small wearable [device] to measure the amount of time a person is in an upright position with their feet on the floor. Harry Leeming, co-founder of Visible, is working to incorporate UpTime into the activity tracking platform designed for chronic illness that he and his team are building.​
We have also operationalized a passive standing lean test, which we call the 10-minute NASA Lean Test, to objectively assess orthostatic intolerance. We use a cognitive testing app called DANA Brain Vital that assesses reaction time in about five minutes on patients' smart phones.​
When the OURA ring first launched in 2017, we did a couple of small studies to see how it worked in ME/CFS. The OURA ring is designed for wellness and athletes, so it didn't have the kind of utility we wanted to better understand the unrefreshing sleep of ME/CFS. However, there are many patients who like the OURA ring and have found ways to use it and get benefit from it.​

The really exciting aspect of this research is that it is now going beyond BHC and is being incorporated into large health care systems and into platforms like Visible. Our goal at BHC is to mainstream ME/CFS, fibromyalgia, Long COVID and related diseases into medicine and our progress over the past few years has been encouraging!​


Bronc is a former historian who is active in his local ME support group. He enjoys interviewing scientists involved in ME research to help himself and others better understand their illness.
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CRFR2 is the receptor for cortiocotrophin.

Corticotrophin-releasing hormone is the main element that drives the body's response to stress. It is also present in diseases that cause inflammation.

In contrast, CRFR2 is involved in the recovery phase of the stress response, and exhibit a more anxiolytic anti-depression function.

Interesting that both CRFR2 agonists AND CRFR1 antagonists seem to relieve symptoms.

Quercetin is a CRFR1 antagonist.

Reversal by quercetin of corticotrophin releasing factor induced anxiety- and depression-like effect in mice
Urocortin 3 seems helpful to the situation.

"The evidence that urocortin 3 has the potential to influence hormonal components of the stress response and the changes in its expression levels after stressors is consistent with a potential function for the endogenous peptide in modulating stress responses."

I especially appreciate that:
" Intracerebroventricular urocortin 3 increased vasopressin mRNA expression in the parvocellular division of the hypothalamic paraventricular nucleus,"

Urocortin 3 Modulates the Neuroendocrine Stress Response and Is Regulated in Rat Amygdala and Hypothalamus by Stress and Glucocorticoids
Pauline M. Jamieson, Chien Li, Christina Kukura, Joan Vaughan, Wylie Vale
This information can be related to rheumatoid arthritis.

To determine whether a corticotropin releasing hormone (CRH) type 1-specific receptor antagonist, antalarmin, would alter the progression of inflammation in adjuvant induced arthritis

Results indicate that chronic treatment with a CRH-1 antagonist attenuates progressive inflammation induced degeneration of synovia, cartilage, and bone in arthritic joints, suggesting that antalarmin may have therapeutic potential in treatment of human autoimmune and inflammatory disorders.

Corticotropin releasing hormone (CRH) antagonist attenuates adjuvant induced arthritis: Role of CRH in peripheral inflammation
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One type of stress that causes release of corticotropin releasing hormone is hypoxia.

Conclusion: 1) Hypoxia stress activates the secretion of corticotrophin (ACTH) via cAMP; 2) Adrenocotical function of rats decays during chronic hypoxia; 3) Arg and NE regulate the secretion of plasma corticosterone and synthesis of pituitary cAMP at the hypothalamus level; 4) Hypoxia tolerance of the pika was high.

Hypoxia effects on hypothalamic corticotropin-releasing hormone and anterior pituitary cAMP
Cort has an article that expands on the CRFR1/CRFR2 portion of this interview.

One thing that I found exciting is that the drug that has been shown to help regulate the problem had been found to help with: "CT38 had been shown to prevent muscle wasting, but by an unknown mechanism. The search for the mechanism, led to fundamental biology involving control of calcium, and a vast body of literature on the CRF system, and its control of serotonin (misunderstood to be the ‘happy hormone’) in the limbic system (historically relegated to an emotional role)."
I am wondering if corticotropin releasing hormone was involved in mast cell degranultion.

CRH definitely involved in rheumatoid arthritis.

Mast cell degranulation involved in rheumatoid arthritis.
Corticotropin-releasing hormone (CRH) is secreted under stress from the hypothalamus, but also in the skin, where it induces mast cell activation and vascular permeability.

Corticotropin-releasing hormone (CRH; previously known as corticotropin-releasing factor) is the central regulator of the hypothalamic-pituitary-adrenal (HPA) axis, which is the main organizer of the body's response to stress.

The effects were blocked by the CRH-R1 antagonist antalarmin, but not the CRH-R2 antagonist astressin 2B.
While I'm at this article/study...
Corticotropin-releasing hormone (CRH), which activates the hypothalamic-pituitary-adrenal axis under stress
With respect to the process explained by Dr Vernon, does it/can it involve lack of cortisol from the adrenals, which causes a lack of the feedback that shuts off CRH in the hypothalamus?

Corticotropin-releasing hormone (CRH) is released by the hypothalamus, signaling the pituitary gland to release ACTH, which then stimulates the adrenal glands to produce cortisol. Cortisol, in turn, signals back to the hypothalamus and pituitary gland that they can now decrease their output of stimulant hormones.
Probably 45 years ago I was diagnosed with a pituitary tumor. The beginning of a very long road.

In my case, I never needed surgery, a drug called bromocriptine kept the symptoms under control until they finally went away. Little did I know at the time, that it was the least of my worries.

I was exhausted...well, the usual, but in the end three different neurological illnesses were the cause of the problems. That's one of the reasons why I don't think there will ever be just one cure for what causes our illness(es). Yes, we have certain things in common, but most of us have additional problems. I wonder what percentage of the population is affected with either ME or FM? Yours, Lenora
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