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.
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.
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.
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.
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).
Morton 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 Morton 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 plasma from 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.