The Massachusetts ME/CFS and FM Association came up with a great idea for a webinar: find out what the three NIH-funded ME/CFS research centers and Avindra Nath’s intramural study have learned over the past four years or so. (Note that that includes a big pandemic fueled gap). These are big, complex, expensive studies, the likes of which the ME/CFS research field sees all too little.

With the Research Center program coming up for renewal, it was a great time to get everyone together and see what’s been learned. (This review was produced from notes taken during the event.)

Watch the Webinar

NIH to Continue Funding ME/CFS Research Centers

It’s been about 20 years since the NIH last funded ME/CFS research centers. With the program renewal of the current research center iteration that was begun around 2016 coming up, the good news is that the NIH has concluded that the 5-year ME/CFS research center experiment was a success. It’s shown that ME/CFS researchers can, in fact, do quality research when given the funding to do so. More research center funding is coming.

There was no word on the funding amount. If we had a strong case for a big research centers program in 2016, it’s magnitudes stronger now. A worldwide pandemic has probably produced millions of people with an ME/CFS-like condition. Plus, the ME/CFS Centers have worked. While we await the results of the interrupted studies the webinar will show that the research centers have engaged in a lot of sophisticated research.

Given the strong indications that ME/CFS and long COVID are kissing cousins, the ME/CFS field needs to be able to quickly take advantage of long COVID research results.  Since the NIH prominently displayed ME/CFS on its RECOVER website as a disease it hopes will benefit from its long-COVID research, one would think it would agree.

The NIH, though – citing the Congressional directive to study long COVID – stepped on that possibility when it decided that no ME/CFS patients will be included in its $1.15 billion worth of long-COVID studies. That means we’re going to rely on ME/CFS’s still pitiful funding to integrate the results from long COVID research. That,funding unfortunately, hasn’t budged since the research centers began.

Even at the NIH, the ME/CFS stigma must be fading as the reality of long COVID hits home. Basically, the times – the emergence of long COVID, the need to merge long-COVID and ME/CFS research, the success of the current research centers, and the intramural program – all call for a dramatic increase in ME/CFS research center funding.

Plus, Nath’s intramural study was designed to boost NIH funding for ME/CFS by uncovering validated areas of research. Because it appears to have done that, that success, alone, calls for the NIH to toss more coins into the ME/CFS field’s coffers.

This field is filled with excellent and creative researchers. There’s Ron Davis with his novel severe ME/CFS study, and his explorations into the nanoneedle, the metabolic trap hypothesis, and red blood cell issues; Nancy Klimas with her supercomputer modeling, her extensive GWI work, her big long-COVID study, and her clinical trials; David Systrom with his groundbreaking invasive exercise studies that now encompass both ME/CFS and long COVID; Jarred Younger’s neuroinflammation, brain imaging, and clinical trials; Ron Tompkins with his background in sepsis, and his brain imaging and muscle work; Bob Naviaux and Chris Armstrong, two metabolomics pioneers; Carmen Scheibenbogen and her autoimmunity work – you can go on and on. This field could readily handle a lot more funding. The announcement should come soon.

Opportunity Missed

What a difference passing H.R. 7057 – the bill that would have given Congress oversight of the NIH funding for ME/CFS – would have made. Passing that bill would have ensured that Congress, not the NIH, would dictate how much the NIH was going to spend on ME/CFS.

This is a Congress, remember, that gave the NIH $1.15 billion to study long COVID. Given that, they might have gladly mustered up $50 million more to study ME/CFS. Solve M.E. and hundreds of ME/CFS advocates made sure Congress got the ME/CFS / long-COVID connection and understood that a tsunami of long-COVID cases was heading our way,

That’s in the past but it’s something to think about when these opportunities – particularly at the federal level – come along. They can make a huge difference.

Now we’re dependent on the NIH to determine how much funding ME/CFS will get. Vivian Pinn of the Office of Research of Women’s Health (ORWH) in the mid-2000s stated – regarding the only funded grant announcement (Neuroimmune RFA) for ME/CFS to that date – that the NIH provided the least amount of money needed to avoid it being “embarrassing”. Even then, it took the late Senator Harry Reid, a major ME/CFS supporter, to twist some arms to get the funding released several years later.

The NIH did something similar with its 2017 research center funding. While it proportionately did provide a big boost in funding for the field – something the NIH rarely does – one researcher told me that the combination of onerous bureaucratic demands and not much funding made it not worth it for them. Despite that, the funding-famished ME/CFS research community jumped at the opportunity.

Let’s hope that the NIH fully embraces the moment. The announcement should come soon.

Avindra Nath – NIH Intramural Study

While we all want the NIH to do more it must be said that the size and complexity of studies the NIH does fund is hard to beat. They’re pretty much in a class of their own.

Avindra Nath’s intramural study which looked at everything from the immune system to energy production to brain imaging surely won the prize for being the broadest effort taken.

Nath’s study got severely curtailed when, in the midst of the COVID-19 pandemic, with everything shut down, Nath and his investigators ended the study and began to analyze the data. Given the already seemingly treacherously small size of the original ME/CFS study (20 patients/20 healthy controls), one wonders how much Nath can dig out of this smaller study. The one grace was that the study did directly lead to the long-COVID study.

One part of the study was, however, completed, and that concerned the intense filtering process the participants went through to determine if they really had ME/CFS or some other disease. In a finding that cries out – in a loud voice – for the need of a biomarker for ME/CFS, Nath reported that he found “all sorts of diseases” that were hidden under the rubric of ME/CFS.

The patients had to have seen a doctor for an infection and been diagnosed with ME/CFS yet Nath reported he found “all sorts of other diseases” including multiple sclerosis, inflammatory conditions, Parkinson’s Disease, and others – in the putative ME/CFS patients.

It should be noted that these patients were – as dictated by the parameters of the study – early-onset patients for whom fatigue problems could easily have obscured diseases that hadn’t gotten severe enough to show their faces. That’s probably not true for people who’ve had this disease much longer.  I assume that forty-plus years in, I, for instance, probably don’t have multiple sclerosis, Parkinson’s disease, etc.

The intramural study, which was apparently Francis Collins’s baby, was designed to open up research avenues the NIH could feel confident diving into. The first week of the study was dedicated to weeding out people with other diseases. No other efforts in this disease have come anywhere close to matching that kind of rigor. If Nath finds something the NIH is bound to follow up on it.

Nath’s energy production work is particularly interesting since he looked at energy production from at least three different angles: exercise testing, cell testing (Seahorse), and the metabolic chamber. Since he was assessing early-onset patients, there would seem to be little chance that deconditioning played a major role.

Nath report that he found reduced work rates and early entry into anaerobic threshold reproduces findings from Workwell and other groups. Nath also reported the cellular tests done in the Seahorse machine indicated that the cells moved into anaerobic respiration “very quickly”.

We don’t know yet about the metabolic chamber results, but finding evidence of an abnormality in different compartments of the body makes it hard to deny they exist. As we will see most of the researchers believe something has gone wrong with the mitochondria. Since these findings potentially get at the core problem in ME/CFS, if there were any findings I’d hoped Nath would be able to validate, these were them. Nath noted that a lot more needs to be done in this area, including determining which cells have these energy problems.

Nath reported that muscle biopsy studies and handgrip strength were normal. Other studies have found that the ability to exert force has not been hit in this disease. The ability to sustain that force, however, has been as numerous studies suggest that people with ME/CFS – whether engaged in physical or mental exertion – become quickly fatigued. This simple, little finding fits in well with other study findings which show a quick diminishment of energy reserves.

With regard to the gut, Nath said it was “very rewarding” to be able to validate Lipkin’s and others’ gut microbiome findings. That finding also suggests that the gut flora gets tweaked early in the disease.

The fact that small fiber neuropathy was not found, on the other hand, suggested that it may come later in the disease. Surprisingly, given how often it’s been validated, natural killer cell functioning was not reduced either – and thus may come later in the disease, as well.

Phil Cherwin’s great question, “What jumped out for you?”, led to what was surely also the most deflating answer of the webinar. I was on the edge of my seat hoping to hear something about the cause of ME/CFS, but Nath replied that it was the big difference in the immune findings between men and women. Still, the answer was illuminating.

Nancy Klimas has been talking about the gender dichotomy in ME/CFS for years. To find that a researcher of Nath’s experience was shocked by it (he wasn’t the only one) said something about some groundbreaking work being done by our researchers.

Ian Lipkin – Columbia University

Ian Lipkin always gives excellent presentations, but he doesn’t mince his words, either. When he said that given the many subsets of ME/CFS may be present, that it’s not at all clear that ME/CFS researchers are studying the same thing all the time, he was speaking a pretty sobering truth.

It would be so much simpler if this was just one disease, and Lipkin did not discount the possibility that many pathways may lead to the same core problem, but ME/CFS clearly presents a complex problem that calls for complex solutions.

That will require large studies that gather massive amounts of data and then use cutting-edge analytic techniques to ferret out the subsets. The good news is that we’ve never been better at dealing with massive amounts of information. Lipkin said he was using artificial intelligence to wade through the enormous datasets that he’s been gathering to identify potential subsets.

Lipkin stated he’s been using “very sensitive” instruments to dig into almost every bodily fluid and tissue (blood, feces, saliva) that he can acxcess. He reported he’s found indirect evidence of the “metabolic disturbances” that he believes are producing many of the symptoms in ME/CFS.

Lipkin is also, if my notes are correct, collecting blood before and after exercise, and then exposing the immune cells to microbial stimuli.

Lipkin’s done more microbiome work than anyone and he noted the increased fecal bacterial load, reductions in butyrate-producing bacteria and reductions in butyrate that he’s found. He noted that butyrate is very important in supporting gut motility and protecting the intestinal barrier. It’s not at all clear that microbiome changes cause this disease, but they certainly have the potential to exacerbate it.

Some more hits were coming: we’re beginning to see some reproducibility in findings indicating expansion of B-cells associated with infection or autoimmunity has occurred. If that keeps up it may be possible to identify what’s triggering those B-cells to act up and eliminate it.

Lipkin’s also finding that the mitochondria are slow to recover after exercise. An accumulation of citric acid which indicated that the aerobic cycle is getting blocked after exercise could help explain what the exercise studies have found. In the Q & A, Lipkin rather emphatically stated that there’s no question that mitochondrial functioning is impacted.

Lipkin also hopes to use antibody tests to tailor treatments for a small subset of patients with herpesviruses. Another goal is to identify genetic markers which make people with ME/CFS susceptible to this disease, and use them to build an animal model.

Derya Unutmaz – Jackson Labs

Unutmaz is all about the immune system and the microbiome, and he used his NIH funding to launch the largest immune profiling study ever done in ME/CFS.

Unutmaz – as Nath did – found major changes in the microbiome occurred very early in the disease. He also found, on the other hand, the gut flora had largely returned to normal after ten years. Given that no ME/CFS studies have found normal gut flora, that finding may not jive with the results of other studies. (None, though, have assessed the effects of disease duration). It’s possible that the disrupted gut flora produced metabolites that wreaked havoc over time.

The immune system certainly doesn’t seem to think everything is kosher, as T-cells which he called “guardians of the bacterial flora” are on high alert.

Unutmaz is also awash in metabolomic data – 500K data points from blood taken twice over a year. Add that to his immune and gut data and you have a very ambitious project that seeks to integrate this mass of data together to paint a system-wide picture of what’s gone wrong in ME/CFS.

Unutmaz, who is also studying long COVID, believes that long-COVID patients may be very early representations of ME/CFS patients but that the disease does change over time and differences will emerge over time. Like Nath, he’s also finding significant differences between men and women.

Maureen Hanson

As no one has uncovered gut problems that are specific to ME/CFS, Hanson doesn’t believe the gut is it. Something’s gone wrong with the gut, for sure – and gut problems may be helping ME/CFS persist – but Hanson reported she’s looking more at the nervous and immune systems and metabolism in hopes of getting at the core cause.

Unfortunately, Dikomo Shungu – who’s managed to get a string of NIH grants to study antioxidant levels, oxidative stress, and blood flows in the brains of ME/CFS, and even got a very rare clinical trial funded – saw his work on the nervous system, including his PET scan study for neuroinflammation, get hit hard by the pandemic

Hanson did not, in the Q & A, seem high on probiotics, which, in contrast to the mostly anaerobic bacteria in the gut, contain mostly aerobic bacteria. Studies have shown these seemingly innocuous substances can produce negative results in some people. Fecal transplants, she thought, might be better but studies, of course, are needed.

Nath jumped in at this point, noting there are many examples of things that seem to make complete sense but which do not work. Tumor necrosis factor antagonists, for instance, made complete sense in multiple sclerosis given the increased levels of that cytokine and the quite successful animal trials – yet they made MS patients worse. Ditto with minocycline. The body, he said, can be very humbling.

Hanson’s been focused on the metabolites for quite some time, and we saw some fascinating results from her group at last year’s IACFS/ME conference.

While she’s found lower levels of metabolites, she doesn’t believe that a single or even a couple of metabolites will provide a diagnostic biomarker; instead, she expects that disrupted pathways will provide the best answers, and indeed, she’s found some pathways that have been altered at all four time points that she’s checked them.

Because she found that the citric acid cycle pathways recover after 24 hours, she doesn’t believe they are causing PEM. Other pathways that do not recover quickly have been found, however.

Immune cells – when activated – ramp up their energy production quickly. They use glycolysis, (anaerobic energy production), not the citric acid cycle to produce energy. Hanson’s 2020 study finding of lower mitochondrial membrane potentials and glycolysis activity in T-cells suggested that these critical immune cells have trouble getting going.

Hanson acknowledged something that’s been pretty clear for a while. Despite their great promise, the gene expression studies have been pretty much a bust. The results haven’t always made sense and they’re rarely reproducible to boot.

She believes that the use of whole blood, which ends up mixing all sorts of cells together, has muddled things. Instead of lumping them all together, Hanson has been comparing the gene expression results from the same types of cells – and is finding that it’s working.

With 270,000 immune cells from ME/CFS patients and healthy controls, Hanson is finally getting gene expression results that make sense. In fact, she’s been getting good enough results that she thinks this new approach could end up being “extremely important”. So far, it’s been able to very, very effectively differentiate patients from healthy controls.

Stating that she’s never believed that “stress” caused ME/CFS, Hanson suggested – citing the asymptomatic long-COVID patients who never got sick during the initial infection – that all of ME/CFS could all be post-infectious. (That includes the numerous enterovirus infections that commonly sweep through our community)

Noting that the mechanisms driving Gulf War Illness appear to be different she, too, was unwilling to say, without more evidence, that long COVID is the same as ME/CFS. Hopefully, she and others will get the chance to assess long-COVID patients right next to ME/CFS ones.

Dr. Bateman

If I have it right, Dr. Bateman reported that she’s seen 60 long-COVID patients (40 which were recruited to NIH-funded research studies). Statistically, she sees no difference in symptoms between ME/CFS and long COVID. Fifty percent have had orthostatic intolerance, and dysautonomia is so common that she’s begun to doubt that they have long COVID if it doesn’t show up. She uses a pulse pressure test to detect a lack of venous blood return to the heart (and circulatory failure).

She’s found that mast cell inhibitors have been quite helpful with long COVID, and stated that it’s clear to her that a large low dose naltrexone (LDN) trial would show that this cheap drug would do as well as opioid drugs in reducing pain. I hope the NIH is listening. After they turned down Jarred Younger’s attempt to get funding, he concluded the NIH is just not going to fund an LDN trial.

Because LDN is a compounded drug, drug manufacturers will not fund a trial -leaving the NIH as one of the few institutions with pockets deep enough to do so. So, we have a cheap, possibly quite effective pain drug that the NIH – engaged in its massive HEAL project to find new pain drugs – is not funding. What a head-scratcher.

Thankfully, eleven mostly small studies are underway in a variety of diseases, including three in fibromyalgia, one of which, from Denmark, is quite large. Plus two, that’s right, two long-COVID studies, including a fascinating one combining metformin and LDN.  Once again, we’re seeing long COVID treatment trials take place in substances that may work in ME/CFS but rarely get tested. Most of the studies are being funded by medical centers and hospitals.

Next Steps

Derya Unutmaz believes it’s time to start doing small interventional trials with some agents while following them very closely to see how they are affecting biology.

Maureen Hanson looks forward to BIG, big data projects that combine the results from all the centers. One of the exciting things about the research center projects is the use of samples from the same people, that provide the opportunity to cross-correlate their findings

Ian Lipkin believes it’s important, given the new analytic techniques that are coming out all the time, that their data is being posted online so researchers worldwide can examine them. The fact that people are getting similar results with the microbiome, proteome and metabolomic studies indicates we are on the right track and are going to be able to find answers.

Avindra Nath, too, felt that immune findings were starting to consistently pop up and the next step is larger studies. He also believes some drugs may be available but that finding biological endpoints (biomarkers) will be crucial.

Vicky Whittemore said the NIH is open to funding clinical trials (!) and that investigators who can support them with that are needed. That would be a big change. Nancy Klimas will be glad to hear that.

Last Days of Health Rising’s BIG (little) Fundraising Drive

Thanks to the many people who have supported us over the past month and a half. This – the last blog of our year-end/year beginning fundraising drive – demonstrates one of Health Rising’s strengths – its breadth. We’re not only focused on energy production or the immune system – we don’t play favorites – we’re trying to understand everything about these diseases.

If you love to learn – as I do – ME/CFS is a good way to learn about so many different parts of the body. That’s exciting but it also takes a lot of digging and a lot of work. If you want as many bases covered as possible, please support us!