• Major Takeaway a new hypothesis emerges suggesting that an overactivated immune system may be stealing resources from the rest of the body. A readily available assay is available to test that hypothesis and provide a way to easily test possible drugs
  • Mark Davis – a Stanford immunologist – and Ron Davis scored a rare large NIH grant to use some cutting-edge technology to study T-cells and HLA genes in ME/CFS back in 2018. Nothing has been heard from Mark Davis since then until now.
  • It was assumed that the grant didn’t work, and in fact, it mostly didn’t. It was saved, though, by an enterprising graduate student named Vishnu Shankar, who excited by what he’d learned about the energy depletion found ME/CFS, made it his mission to explore that aspect of T and B-cells in ME/CFS.
  • His goal was to find a molecular marker for fatigue – perhaps the most nebulous symptom in the book – but not just any fatigue – the fatigue that results from an energy deficit: the energy depletion-associated fatigue in ME/CFS.
  • He focused on oxidative stress; i.e. unbalanced molecules called free radicals or reactive oxygen species which in an attempt to balance themselves can rip electrons out of cells and damage them. Oxidative stress is a natural outcome of energy production and, indeed, most of it comes from the mitochondrial engines that power our cells.
  • Because high levels of oxidative stress can damage immune cells, Shankar and Davis first looked for evidence that high levels of oxidative stress were present in the T and B cells of ME/CFS patients – and found it – but not in men, only in women.
  • Moving forward to assess the system designed to keep antioxidant levels in check – the antioxidant system – they found evidence of dysregulation in both men and women with ME/CFS. The unusually high levels of antioxidants in both sexes’ immune cells suggested they were both battling to contain the high levels of oxidative stress present.
  • While the cause of oxidative stress was not identified it was likely due to mitochondrial problems. This is because immune cells have to dramatically ramp up their engines to deal with pathogens – thus putting a lot of strain on their mitochondria. In fact, the immune system is one of the most energy intense systems in our bodies. Because of this, if mitochondrial problems are going to show up, the immune system is a good place to look for them.
  • Taking a deeper look they found that higher levels of oxidative stress in the female ME/CFS patient’s T-cells resulted in increased T-cell proliferation – not necessarily a good thing. That’s because producing more T-cells requires more energy. That puts a greater strain on ME/CFS patients’ possibly already damaged mitochondria. The oxidative stress produced by the damaged mitochondria could further damage the mitochondria – and that possibility formed the basis for the authors’ model of what may be happening in ME/CFS.
  • Davis proposed that an infection triggered increased immune cell proliferation.  Over time that proliferation put too much stress on the mitochondria – causing them to break down and release high levels of free radicals/reactive oxygen species. Those high levels then damaged the mitochondria – causing even more oxidative stress – and throwing people with ME/CFS into a vicious cycle.
  • Adding antioxidants like NAC, metformin, and liprostatin-1 provided proof for their idea that oxidative stress may causing high levels of immune cell proliferation in ME/CFS. While studies do suggest that metformin may help with ME/CFS/Long COVID, Davis felt these options were the beginning of the road – not the end. He noted that the cell cultures he was using could also easily be used to assess many other drugs.
  • This is not the first study to find energy problems in our immune cells. At least three other ME/CFS studies have found that our immune cells are having problems producing energy.
  • Davis proposed that by using up all this energy, the immune system is operating as an “energy sink” thats diverting energy from other parts of the body.  This is, in effect, what happens when you have an infection – everything goes into fighting off the infection. That would appear to be a very nice solution, if correct!  If the immune system is the driver of ME/CFS we have only to deal with it – not the myriad other systems in the body.
Joesph Breen from the National Institutes of Allergy and Infectious Diseases (NIAID) – which sponsored the conference – started the if off by referring to the last NIH ME/CFS conference – in 2019 – which was intended to accelerate progress in chronic fatigue syndrome (ME/CFS) research. Breen felt that we’ve made progress in identifying relevant pathways in ME/CFS, and indeed we have.

The field feels like it’s beginning to cohere around pathways involving energy metabolism, lipid metabolism, and gut and immune issues. Parts of the brain (brainstem, motor cortex, limbic system, prefrontal cortex) have shown up multiple times. While progress is inevitably slow in such a complicated and poorly funded disease, ME/CFS researchers slowly but surely seem to be closing in on some key features.

One would like to think that progress in any field would be rewarded by more funding but not at the inexplicable NIH – not yet. While NIH ME/CFS funding rose from 15 million in 2017 to 17 million in 2021, it has since then fallen to $13 million and is projected to stay there. The 3 small NIH-funded ME/CFS research centers were (somehow) supposed to help increase funding, but ME/CFS research at the NIH is in decline.

This conference amply demonstrates why the NIH is such a maddening institution. The scintillating results from some of the NIH-funded studies simply underscore how much faster we could move on this disease if the NIH chose to throw a bone the ME/CFS community’s way. Former NIH Director Francis Collins promised 8 years ago that the NIH was finally going to become “serious” about ME/CFS. It still clearly is not. Whatever has been done is not working.

Onto better things. In this blog, an NIH-funded study first goes bust – and then turns up roses.

Highlights from the December 2023 Conference on “Advancing ME/CFS Research: Identifying Targets for Intervention and Learning from Long COVID”

Mark Davis

How nice to see Mark Davis again! Some may remember that Mark Davis – a Stanford immunologist – and Ron Davis scored a rare large NIH grant to use some cutting-edge technology to study T-cells and HLA genes in ME/CFS back in 2018. Nothing has been heard from Mark Davis since then.

Vishnu Shankar

Vishnu Shankar, an enterprising graduate student, turned a struggling NIH grant into a win.

I assumed that the study didn’t work out, but here Mark Davis is presenting at the NIH conference – not on T-cells or HLA genes – but on oxidative stress! Indeed, Mark Davis did not produce any results from his study – but did talk about the results of a PhD student of his, Vishnu Shankar, who came to ME/CFS after reading “The Puzzle Solver” a book by Tracie White on the Ron Davis and his search to solve ME/CFS.

Struck by the idea of an energy depletion disease, Shankar got to work. Davis described an enthusiastic and curious researcher who, he said, went to every department possible at Stanford to learn about the mitochondria.

The goal was to find a molecular marker for fatigue – perhaps the most nebulous symptom in the book – but not just any fatigue – the fatigue that results from an energy deficit: energy depletion-associated fatigue.

That’s about as close to the holy grail in ME/CFS needs as you can get. A biomarker for energy-depleted fatigue states would: a) tell us more about how the fatigue is produced, but more importantly perhaps; b) would give pharmaceutical solid ground to test out their drugs in ME/CFS.

I recently talked with a pharmaceutical executive about why drug companies are so reluctant to take on ME/CFS – and the lack of a biological marker they can use to test their drug’s effectiveness is right there at the top of their list. (Blog coming up.)

The Oxidative Stress Gambit

oxidative stress

High levels of oxidative stress can tear holes in cells damaging them.

Davis noted that for all the focus on the energy usage of the brain, the immune system uses every bit as much energy as it – and during an infection – it uses more – a key distinction to keep in mind. So, into the immune system, they went.

Then it was onto “reactive oxygen species” (which I grew up learning to call “free radicals”). These unbalanced oxygen-based molecules (hydroperoxide (O2H), superoxide (O2-), hydroxyl radical (OH), peroxynitrite (ONOO-)) have an unpaired electron in their outer shell. Seeking to achieve balance, these oxygen-based molecules rip holes in the proteins, lipids, and DNA in our cells.

Far from being something foreign or even unwelcome, they are an inevitable byproduct of aerobic energy production (note their oxygen base), and we use them to good effect in our immune system to kill pathogens and infected cells. In the same way that a campfire that provides welcome heat can turn into a raging forest fire, too many ROS can, by damaging lipids, proteins, etc., in our cells, produce more ROS, which then feeds the flames.

The goal is to not get rid of ROS – the goal is to keep them in check and manage them properly. Many studies have shown that people with ME/CFS are not doing that. High levels of oxidative stress may be the most consistent finding in all of ME/CFS and Martin Pall formed his ONOO hypothesis for ME/CFS from them.

Given the potential connection between high levels of oxidative stress and its possible effects – reduced mitochondrial activity/energy production, an impaired immune response / cellular membrane damage (lipids) / altered cellular signaling – all of which have been seen in ME/CFS – the idea that high levels of oxidative stress are causing problems in ME/CFS makes perfect sense.

Oxidative stress, though, has always seemed like a rather nebulous solution to this disease. Lots of diseases (cancer, cardiovascular diseases, neurological diseases, kidney diseases, respiratory diseases, and rheumatological diseases) also feature increased levels of oxidative stress. If you have a chronic disease, it’s not unlikely that you will also have increased oxidative stress.

The question is not whether oxidative stress is present in ME/CFS, but what might make it special. What might make it a core part of this disease instead of a kind of secondary byproduct? Problems with the mitochondria could. Davis explained that 90% of the reactive oxygen species are produced in our mitochondria and the mitochondria, of course, and energy production is an active focus of study in ME/CFS.

The Male/Female Dichotomy Shows Up Again

Oxidative stress T-cells

Once again, we see dramatic differences – this time in oxidative stress levels in female immune cells – once ME/CFS patients are separated according to gender. (Females on the top – males on the bottom.)

Back to the T-cells we went. Most immune cells stay in a quiescent state until they encounter a pathogen and then rev up their engines to pump out. Once that happens, they have to rev up their engines and start pumping out cytokines, more immune cells, more ROS, etc.

Looking at T and B cells, Davis and Shankar quickly bumped into the male/female dichotomy that is rapidly becoming a key feature in ME/CFS and long COVID. While male immune cells of people with ME/CFS or long COVID did not show high levels of ROS, females did. (Don’t worry, men – your turn is coming.)

Our cells, of course, evolved to take care of the dangerous compounds (ROS) produced during energy production. Since ROS shouldn’t be a problem in a healthy cell, the researchers looked at the enzyme tasked with keeping them under control – glutathione peroxidase – and found very high levels in both the males and females of the ME/CFS patients and long-COVID patients compared to the healthy controls.

The antioxidant systems of both men and women with ME/CFS, then, were going full bore trying to keep the reactive oxygen species (ROS) in check. In men, that seemed to be working – the levels of ROS levels in their immune cells were normal, but not in women – their immune cells were loaded with reactive oxygen species (ROS). Something, then, was tweaking the antioxidant systems of both the men and women – and that something was probably damaged mitochondria.

Dramatically high rates of antioxidant production in the immune cells of BOTH sexes, though, suggested that both sexes had ramped up their antioxidant defenses – possibly in response to a mitochondrial problem.

When they looked at ROS production and T-cell activation, something interesting became clear. The higher ROS levels in the female ME/CFS patients resulted in increased T-cell proliferation – not necessarily a good thing.

Producing more T-cells requires more energy – putting a greater strain on ME/CFS patients’ possibly already damaged mitochondria – producing even more reactive oxygen species (ROS) – and potentially more damage to the mitochondria.

(Could this increased T-cell proliferation combined with reduced energy production be another version of the “wired but tired” processes we’ve seen where systems that are always engaged and never rest poop out quickly when called to respond?)


The big question, of course, is whether there’s a way to calm these immune cells down. Note that Davis isn’t talking about curing the problem – we haven’t gotten to the root of the problem (the presumed mitochondrial dysfunction) – but what about bringing down the reactive oxygen species levels in the meantime by calming our immune cells?

They found that adding ROS inhibitors like NAC, metformin, and liprostatin-1 did reduce T-cell proliferation. Metformin, of course, was found to help some people with long COVID, and NAC was found to help some people with ME/CFS, but Davis felt these options were the beginning of the road – not the end. He noted that the cell cultures he was using could also easily be used to assess many other drugs.

In a major paper on ME/CFS, Bindu Paul, Martian Lemle, Tony Komaroff, and Solomon Snyder laid out how problems with oxidative stress could be causing ME/CFS and proposed that much more effective antioxidants are possible as well.

Could a Free Radical Explosion Be Causing ME/CFS and Long COVID?

The Energy Sink Hypothesis

If the immune system is using up all this energy, it could produce an “energy sink” that’s diverting energy from other parts of the brain. This is, in effect, what happens when you have an infection – everything goes into fighting off the infection. Given that, Davis speculated that we will not see high ROS levels or mitochondrial problems in brain tissue. We should know the answer to that in the not-too-distant future as RECOVER analyzes lots of brain and other tissues in their long-COVID autopsy.

The Beginnings…

Speculating why some people come down with ME/CFS after an infection, Davis proposed that mutations in perhaps thousands of genes could result in a prolonged level of T and B cell activation. The high energy requirements to meet those needs – and the high levels of reactive oxygen species (ROS) that would inevitably result – could ultimately damage the mitochondria, resulting in an inability to produce normal amounts of energy.

It could also be the inability ME/CFS patients’ immune systems to clear the infection could result in long periods of immune activation, and damage to the mitochondria and energy production systems.

A Marker of Energy Depletion-Induced Fatigue?

Did we get a molecular marker of energy depletion-induced fatigue? It’s possible. Davis said the assay that assessed ROS, glutathione peroxidase, and T-cell proliferation is not a difficult one.

Davis reported that he’d worked on ME/CFS for 6 or 7 years (that big NIH grant) without success until Vishnu, with his single-mindedness and passion, brought this new approach to the fore. How gratifying it is to merge two major facets of ME/CFS –  immune dysfunction and energy production – together.

Thanks to Vishnu then, and thanks to Mark Davis for supporting him, and to the Khosla Foundation and NIH for supporting them. Davis also acknowledged Ron Davis, Mike Snyder, and Hector Bonilla.

One would think these findings deserve a nice, juicy NIH grant.

Could the immune system be sucking energy from other parts of the body?

Immunometabolic Findings in ME/CFS

This isn’t the only study to plug together immune functioning and energy production. Alerted by increased levels of a stress factor on B-cells, Geraldine Cambridge in London has been digging into B-cells and energy production for quite some time. Taking a different approach, she and Chris Armstrong recently found that an ongoing “stress response” (immune activation?) was associated with reduced mitochondrial mass, and dysregulated energy metabolism in ME/CFS.

Likewise, several studies, including one from Jessica Maya at Cornell, suggest that T-cell exhaustion is present. Maya’s study was funded by Vinod Khosla (again!), the Alfred P. Sloan Foundation, and the NIH, and a large NIH-funded T-cell exhaustion study is underway. Given the Davis/Shankar findings, it was intriguing to find that an antioxidant (i.e., a reactive oxygen species inhibitor) helped reduce markers of T-cell exhaustion in a small ME/CFS study that was funded by patients (Ramsey/Solve M.E. Award, Open Medicine Foundation, and the Invest in ME charity)

Slowly but hopefully, surely researchers are finding that the energy depletion found in ME/CFS patients is also found in their immune cells. Could the immune system be an energy sink, sucking the energy from all the other systems in ME/CFS? Time will tell, but that could be a very nice answer. Being able to concentrate on just one system in the body would be oh-so-helpful in this complex disease.


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