Something in the blood

Something in the blood

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A small 2022 study also found evidence of a blood factor. Previous research has suggested there is a problem with blood flow, which could explain why people with ME/CFS struggle to generate enough energy (blood delivers the oxygen we need to produce energy. The new study looked at endothelial cells, which play a big role in expanding blood vessels to improve blood flow. Researchers grew endothelial cells in the lab from umbilical cords.

These cells were then exposed to blood plasma from either ME/CFS patients or healthy controls. Comparing these two groups, they found that ‘something in the blood’ of people with ME/CFS appeared to reduce the ability of endothelial cells to produce nitric oxide (NO) which expands blood vessels.

Original 2019 blog

Remarkably, four independent groups have now found evidence that a factor in the blood can affect cell metabolism/mitochondria in ME/CFS and transfer the effect to healthy cells. Here is a summary of the provisional findings.

Fluge & Mella

The first to find the effect were Dr Oystein Fluge and Professor Olav Mella in 2016.

They were studying energy production in the cell, a logical thing to do when trying to understand an illness where energy is in such short supply.

Cells have two ways to convert food molecules into usable energy. Glycolysis is a process in the cell cytoplasm that extracts a small amount of energy from carbohydrate molecules, producing lactate. But the real houses of energy production are mitochondria, which burn up food molecules with oxygen, producing large amounts of usable fuel.

Mitochondria are the powerplants of the cell, using a process called oxidative phosphorylation to convert food molecules and oxygen into energy, water and carbon dioxide.

Fluge and Mella used an expensive bit of kit called the Seahorse analyser, which measures glycolysis through the lactate production and mitochondrial activity through changes in oxygen levels.

They tested normal healthy muscle cells that had been grown in the lab. But they added to those cells serum taken from either ME/CFS patients or healthy controls. Serum is the fluid left over after blood has clotted and it contains small molecules and other soluble substances.

They have data for 12 people with ME/CFS and 12 healthy controls, a relatively small sample.

What they found was, surprisingly, that the muscle cells produced more lactate and burned more oxygen when they were incubated with ME/CFS serum than when incubated in serum from healthy controls. And the effect was particularly strong when the cells were made to work hard.

So something in the serum (which comes from blood) of ME/CFS patients is affecting healthy cells, and somehow making them work harder.

This is the only published study to date, but three other groups have revealed related findings at conferences.

Ron Davis

Dr Ron Davis provided the most dramatic demonstration of the effect in a plasma swap experiment using his nanoneedle test. Plasma is the liquid left over when solid matter has been removed from blood: the the red and white blood cells, and platelets.

The nanoneedle chip measures electrical impedance of cells. In the presence of salt (which stresses the cells because they have to use energy to pump the salt out) the impedance of cells in ME/CFS blood increases much more than cells in blood taken from healthy controls.

plasma swap slide

Davis’s group then ran an elegant experiment using this set up. They put blood cells from healthy donors in plasma from ME/CFS patients and found that the healthy cells behaved like ME/CFS ones did, with a big increase in electrical impedance. And when they put ME/CFS cells in plasma from healthy controls, they found that these ME/CFS cells behave like healthy cells.

So plasma from ME/CFS patients makes healthy cells behave like ME/CFS ones. And plasma from healthy controls makes ME/CFS cells behave like healthy ones. These are stunning findings.

We don’t know the sample size for this study but hopefully more details will be available soon as a paper has been accepted for publication in the Journal PNAS.

Karl Morten, Oxford university

Like Fluge and Mella, Dr Karl Morten looked at mitochondria/energy metabolism in lab grown muscle cells and also saw an effect.

His group used a molecular probe to measure oxygen concentration within cells to track the activity of mitochondria.

They found that adding plasma from healthy controls made no difference to oxygen levels of the muscle cells. But adding plasma from ME/CFS patients caused oxygen levels to fall, indicating that the mitochondria were working harder (a similar result to Fluge and Mella).

Graph of O2 levels
Plasma from ME/CFS patients leads to lower oxygen levels in cells

Morten said he didn’t know why the mitochondria were working harder: he said it might be that they were working less efficiently, but the goal was to find out.

n said he didn’t know why the mitochondria were working harder: he said it might be that they were working less efficiently, but the goal was to find out.

The study used over 30 patients and Morten noted that on average the levels were lower for patients than for controls. He suggested this might be due to a subgroup effect, where only some patients had the effect, with around a third of patients scoring below the lowest oxygen level for healthy controls.

Bhupesh Prusty, Wuerzburg university

Dr Bhupesh Prusty has also looked at the effect of a blood factor on mitochondria, but his work focuses on a less well-known role of mitochondria, in immunity against viruses.

Although mitochondria are normally shown as single bacteria- or bean-like units, the reality is more complex. In living cells, mitochondria constantly fuse together and separate, and the fact that they are often fused together, like a string of beans, is important for their ability to fight viruses.

Some viruses, including HHV-6, fight back by causing mitochondria to fragment back into their single forms, reducing their ability to fight viruses.

Serum from ME/CFS patients causes mitochondria that were fused together to fragment, whereas serumfrom healthy controls does not.

So far, the group have only looked at five patients and three controls, so these are very provisional results.

In a separate experiment, his group showed that the effect was reversible (they washed away patient serum after three days and mitochondria gradually resumed normal fusing behaviour).


Fluge’s and Morten’s studies are directly linked to energy metabolism. Davis’s is indirectly: the salt added to the nanoneedle test forces the cell to use energy pumping sodium out of the cell. The Prusty research looks at mitochondria, but the changes in morphology are apparently linked to cell defence rather than to energy production.

At the recent NIH conference, Ron Davis said that their work indicates that the factor in the blood responsible for all this are exosomes, tiny membrane-bound packets of biomolecules released by cells. Exosomes are a type of extracellular vesicle, and these are taken up by cells and are believed to be involved in cell to cell communication, though their role is as yet unclear. Extracellular vesicles are being studied by Dr Maureen Hanson as part of her collaborative’s work.

So we have four groups finding that a factor in ME/CFS blood that has an effect on cells. These are still early days: only one study has been published so far, the sample sizes are relatively small and the findings need to be confirmed. But if things pan out, this development could prove to be an important step in understanding the biology of at least some types of ME/CFS.

Image credits: Drop of blood, Wikimedia ; mitochondrion, NIH; Plasma swap slide, Dr Ron Davis; Oxygen concentration graph, Dr Karl Morten presentation; Mitochondial strands, NIH conference 19 presentation, Dr Prusty.

21 thoughts on “Something in the blood

  1. That’s hopeful news. So, what are the chances of getting some substantial funding to look into this further?

    Thanks for a clear and helpful summary.

    1. Thanks. Maybe better prospects in the US, but I think KM is applying for funding in the UK.

  2. Thanks Simon for this summary. I haven’t understood how/ whether these link with Dr Les Simpson’s work in the 1990s on the differences in deformability in the shape of red blood cells of pwme. This latest research focuses on plasma or serum as I understand it, whereas Dr Simpson was looking at the properties of red blood cells in pwme which prevented them deforming so as to go through narrow capillaries. Can you help me understand?

    1. Hi Jill. The studies don’t tell us anything about red Blood cells de form ability. But there is probably an interesting experiment to do, testing healthy blood cells For deformability in plasma or serum from people with ME.

  3. Anyone read “Ramsay’s Disease – Myalgic Encephalomyelitis (ME) and the Unfortunate Creation of ‘CFS’?” Fascinating and makes sense; would explain a lot.

    “The contribution of haemorrheology to the understanding of and potentially effective treatment for the symptoms of ME (in its many aliases!) continues to be ignored by the medical profession, therefore unavailable to people who have ME. In ME, the high proportion of irregularly-shaped red blood cells which cannot traverse the microcirculation results in oxygen deficiency in muscles, the cognitive areas of the brain and the endocrine system. Fish oil, genuine EPO, Vitamin B12 as hydroxocobalamin, and pentoxyfilline have each been found to address this issue in a significant proportion of people with ME, very much improving their well-being.“

  4. Thanks for this helpful article! Hopefully more researchers willen share their findings.

  5. Hi, Before I was diagnosed with M.E, I was convinced my symptoms were due to my autoimmune under active thyroid condition as the symptoms were very similar. After doing some research I begged my endocrinologist to trial me on t3 and after taking it for two days the results were amazing. I went from virtually bed bound to up and about and able to function. I still have symptoms, but no where near as severe. Just wondering if there could be a connection?

  6. Dr. Yoshitsugi Hokama demonstrated that red blood cells are destroyed by the toxin he labeled ciguatera epitote that he found in 95% of patients tested. Could this be the reason for all the sick cells?

    1. This sounds highly interesting. Do you know what kind of toxin this is? Many of us, definitely myself, are constantly feeling intoxicated or poisoned.

      1. The current thinking is that it’s not a toxin but probably some kind of regulatory factor in the blood, a signal from the body

      2. There’s quite a bit about this on the National CFIDS Foundation website. I have followed this info for several years. I don’t know why the work wasn’t continued when Dr, Hokama retired. I had this test done in 2008. I don’t think Hawaii is still offering it.

        When the report came that there is something in the blood I certainly think about this. Perhaps someone else has a perspective on this.

  7. “In the presence of salt (which stresses the cells because they have to use energy to pump the salt out) the impedance of cells in ME/CFS blood increases much more than cells in blood taken from healthy controls.”

    So, does this mean that salt is “bad” for PwME? I have a tendency to be dehydrated so a clinical nutritionist told me to add sea salt and lemon to my water so that it gets into the cells. When I did this, my BUN normalized and I noticed that I urinated much less frequently. So it seems she was correct.

    But the above statement raised my curiosity about salt consumption in PwME.

    1. I’m not a doctor so I can’t advise. But I would comment that I’ve now read the protocol in the paper that has just come out, and as far as I can tell the salt levels they are using are much higher than you would have from any diet, and so the results tell you nothing about what you should do regarding your personal salt consumption. But like I say, I’m no expert.

  8. Thank you, Simon, for this easily understandable review. I would so like to be alive when the cause of ME/CFS is discovered. Or even better, when a cure is uncovered. I am hopeful when I see studies all pointing in the same direction.

  9. Does this new research indicate a need to protect the blood supply from possible contamination by ME/CFS donors?

    1. Unclear. As I understand it, in the US, people with ME/CFS can’t give blood in any case. The current evidence seems to be that the problem isn’t a virus or other pathogen but some particular factor in the blood. Even so, if you were sick, you wouldn’t want such a factor introduced. But really, this research needs replicating and validating before basing health recommendations

      1. Since misdiagnosis and clinician ignorance is a continuing problem, many people don’t know they have ME/CFS. For years, I had many remission periods when I though I was cured, only to relapse. BTW, the Red Cross donor criteria does not mention ME/CFS, it does say, “Most chronic illnesses are acceptable as long as you feel well, the condition is under control, and you meet all other eligibility requirements.”

  10. Thanks for your heartening summary. It’s amazing how far cell biology has come since I studied it, pre-CFS, 25 years ago. I am so thankful that these researchers have taken up our cause!

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