Cort Johnson from the Health Rising blog looks back at some of his highlights from the last year in the world of ME/CFS research.
What phrase better encapsulates ME/CFS than “a failure to respond”? You try to walk down the block and become exhausted. You fail to comprehend reading material you used to gobble up. You fail to just sit or stand up without having symptoms. In every case you ask your body to do something and frustratingly and inexplicably it fails to respond as it used to.
Last year more than any other, ME/CFS researchers have illuminated on a physiological level how this failure to respond appears to be happening.
Exercise
Maureen Hanson’s exercise study at Cornell University found that when tasked with perhaps the greatest stressor of all, exercise, ME/CFS patients exhibited a failure to respond on a molecular level. With many fewer proteins activated than normal, their bodies appeared to be in a kind of strange stasis when it comes to exercise – on multiple levels they simply did not respond.
Immune cells
Immune cells provide another kind of failure to respond. Once aroused by a pathogen, they have to rev up their engines in order to pump out cytokines, antibodies and clones, so they’re the perfect kind of cell to study in an energy-depleted disease.
In early 2024, UK researchers found that, when stressed, ME/CFS patients’ B-cells failed to respond in a rather fundamental way – they failed to generate as many mitochondria as healthy control cells and relied more on glycolysis, a much less efficient energy-producing process.
Across the pond, Nath at the NIH, found evidence that ME/CFS patients’ B-cells failed to respond in another way. Increased percentages of naïve B-cells and decreased levels of switched-on memory B-cells in the blood also suggested that patients’ B-cells were failing to mature. Nath also found signs of both immune activation and exhaustion.
Nath was so struck by this finding that he proposed that the immature B-cells found actually constitute “the primary defect” in ME/CFS! He suggested that the B-cells’ failure to respond to an infection shifted the burden onto the innate, more inflammatory part of the immune system – asking it to do something it wasn’t designed to do.
Metabolism
Next, a metabolomic study suggested that the mitochondria in females are built in such a way that their failure to respond to metabolic stressors left them more susceptible to coming down with ME/CFS.
The brain
The failure-to-respond theme also extended to the brain. Speaking at the 2024 NIH ME/CFS Conference, Xiang Xu found increased blood oxygen levels in the arteries but decreased blood oxygen levels in the venous blood leaving the brain, suggesting that ME/CFS patients’ brains have a voracious appetite for energy.
That made sense to an Australian/Swiss and US team [including ME Research UK-funded researcher, Zack Shan] which found that ME/CFS patients’ brains used more energy than healthy controls to accomplish the same task. They proposed that a failure to send more blood to the parts of the brain that needed it was leaving it metabolically crippled.
Finding increased levels of lactate throughout the brain in a subset of ME/CFS patients, Jarred Younger [who currently receives funding by ME Research UK on his project tracking peripheral immune cell infiltration of the brain] proposed that ME/CFS patients’ brains had failed to respond aerobically to their energy needs, had run out of oxygen, and were burning other fuels to keep it going.
Energetics
A study of ME-like patients who’d come down with the Crimean-Congo haemorrhagic fever may help to explain how this failure to respond at an energetic level started.
People whose immune cells couldn’t generate enough energy during the early hypermetabolic stage turned to alternative anaerobic energy pathways to do so. Despite apparently vanquishing the virus, they were left symptomatic in an ME/CFS-like condition and a state of “metabolic insufficiency” or hypometabolism.
A presentation at an October Neuromuscular Disorders conference proposed that ME/CFS patients’ serum produces a failure to respond at the energetic level. Exposing muscle tissue to serum from ME/CFS and long-COVID patients put the muscle cells under high energy stress, and caused the mitochondria to break up, fuse, and become dysfunctional.
Mirroring the immune-cell findings, the authors hypothesised that a “stress-induced hypermetabolic state” had resulted in “severe deterioration” in muscle-cell functioning.
When asked, Bob Naviaux, the author of the cell danger response (CDR) hypothesis, stated that he believes this hypermetabolic-to-hypometabolic switch plays a key role in ME/CFS. He wrote:
“While everyone experiences a transient hypermetabolic state… during an acute infection… ninety percent of the time this resolves without any consequences after a few days to weeks.”
In people who “develop ME/CFS, long COVID, and many other hypometabolic, multi-system, chronic fatigue syndromes, mitochondria and cells enter a chronic but reversible physiologic state… at the expense of a dramatic decrease in functional capacity.” In this state “very small stresses trigger setbacks”.
Epigenetics
Possibly the most intriguing example of a failure to respond this year concerned epigenetics. Epigenetics refers to how our bodies regulate our gene expression over time. By turning genes on and off, cells adapt to the changes in our bodies and the environment over time.
Because infections are drivers of epigenetic change, the idea that some sort of epigenetic shift triggered by an infection might be contributing to ME/CFS, long COVID, post-treatment Lyme Disease, etc. has always been enticing.
The Hanson group found that “ME leaves epigenetic scars” on some T-cells leaving them “epigenetically predisposed toward terminal exhaustion”; i.e. the patients’ T-cells had possibly responded to an infection in a way that doomed them to become exhausted.
With signs of cellular exhaustion showing up in NK, T-cells, B-cells, monocytes/macrophages and dendritic cells, one has to wonder if other immune cells are also epigenetically predisposed to exhaustion in ME/CFS.
Conclusion
The end of 2024 leaves us in a most interesting place. A failure to respond, particularly on an energetic level, showed up in multiple tissues (immune, brain and muscle) in people with ME/CFS. Plus, the hypermetabolic-hypometabolic model – with its focus on mitochondrial dysfunction – provides a nice basis for further study.
At this point, the small ME/CFS field seems far ahead of the long COVID field in understanding the physiological basis of the strange failure to respond that permeates post-infectious diseases. While those failures unfortunately persist in people in ME/CFS, the field has clearly responded, and at the end of 2024 it seems to be uncovering core issues in this disease – and that provides much hope for the future.