Blog: 'Summary so far of "Something in the blood"' by Simon McGrath

@Simon M has a new version of this on his blog here, https://mecfsresearchreview.me/2019/04/25/something-in-the-blood/

 

Also of possible relevance is Tomas et al, 2019. Note that this isn't a plasma swap study, but they were able to demonstrate that:

"Results showed there to be no significant differences in individual mitochondrial complex activity or respiratory activity supported by fatty acid oxidation or glutaminolysis between healthy control and CFS cohorts in either skeletal muscle (p ≥ 0.190) or PBMCs (p ≥ 0.065). This is the first study to use extracellular flux analysis to investigate individual mitochondrial complex activity in permeabilised cells in the context of CFS. The lack of difference in complex activity in CFS PBMCs suggests that the previously observed mitochondrial dysfunction in whole PBMCs is due to causes upstream of the mitochondrial respiratory chain."

In their study, Tomas et al, used a specialised technique to examine the workings of the mitochondrial compartment itself in isolation from whole cells. They determined that the machinery of the mitochondria itself is intact. This might be in agreement that there is a factor in the blood, upstream of the mitochondrial respiratory chain, causing havoc.

The full Tomas paper can be accessed here, from 'Conclusions':

"The results showing no difference in mitochondrial activity in permeabilised PBMCs were unexpected given that mitochondrial function in PBMCs has previously been shown to be significantly lower in CFS (Tomas et al., 2017).

However, the lack of difference in complex activity in CFS PBMCs is in agreement with results reported by other groups who showed normal mitochondrial respiratory chain complex activity (Lawson et al., 2016; Vermeulen et al., 2010), and postulated that changes in mitochondrial ATP synthesis should be attributed to other causes such as the transport capacity of oxygen (Vermeulen et al., 2010).

Given the results here, the future of bioenergetic studies in CFS should concentrate on mechanisms upstream of the mitochondrial respiratory chain."

I'm confused by the apparent contradiction here between F&M reporting increased oxidative metabolism and Morten reporting reduced cellular uptake of oxygen.

"Dr Morten revealed how when examining mitochondrial function, they took blood plasma from ME/CFS patients and added it to healthy muscle cells, and this resulted in a startling effect on the cells ability to absorb oxygen. They are continuing with work in this area and hope to determine why the energetics of the cells are affected in this way."

 

Blog preview
Something in the blood​

It is remarkable that four independent groups have now found 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.
....
What they found was, surprisingly, that the muscle cells produced more lactic acid 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.
....

> Also Ron Davis, Karl Morten, Bhupesh Prusty with their different approaches that also found an effect.

....
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.

Read the full blog

 

[my bolding]

Just a mad thought:
The graph in @hinterland 's link shows the concentration (amount) of oxygen in the cells. This is lower in cells treated with ME plasma.
Is it proven that this is caused by a reduced UPTAKE?
Could it instead be caused by increased CONSUMPTION?

Maybe that "something" in the plasma makes the mitochondria burn the intracellular oxygen like mad?

ETA: The Blog says this about Morten's findings:

So no contradicition. I think the "reduced intracellular uptake" bit on MEA might be wrong or misleading.

 

Both groups use the same method, the Seahorse analyser.

as Lisa says, the findings are consistent because the most obvious exclamation for the load oxygen consumption in ME/CFS plasma is increased mitochondrial activity, the same as Fluge found.

 

Slide from the talk at the Emerge Symposium by Dr Paul Fisher, https://mecfsconference.org.au/videos/paulfisher/

which would seem to confirm that he, and his team, agrees with the idea of increased mitochondrial activity.

 

Would this, in simple terms, explain, or go part way to explaining, the seemingly lower anaerobic threshold in PwME? - the mitochondria are simply running out of oxygen coz they are burning more due to being less efficient?

Or have I got the wrong end of something that isn't even a stick?

 

fluge & co said (i think):

increased oxygene consumption
AND
increased lactate production

is it known if in the healthy blood "infection" the lactate production increased, too ?

 

would this fluge/mella "oxygen/lactate issue" be shown in the usual lactate blood test after exercise (taking a drop of blood from the finger tip) ?

(perhaps it may show in the mecfs case some "unusual" result ?)

 

The odds are every single lead will fail. Then one wont. We don't know which lead that will be, so we have to pursue them all.

 

Oops. Then maybe I added to it by putting a link on my Facebook page. Mea culpa. Still not removing the link though.

 

I also got the impression Prusty was saying there were some infected cells. However, I would have assumed Ron Davis's, or Ian Lipkin's [AKA -the great virus hunter - Cort Johnson], teams would have found viral RNA/DNA in the blood - if there were virus's present. Of course, the detection limits, for the viral RNA/DNA in the blood, could be too low -- I don't know much about this but I assumed the assays (PCR?) were really sensitive. I think Prusty has made a significant contribution - well done to him and Solve ME/CFS for funding this.

I also recall (accurately?) that Lipkin demonstrated that you can identify the causal agent for a disease, even if it's not present. He found a bacteria/virus was responsible for a disease even though the pathogen was long gone - interesting.

Thanks

 

it may be because i have no research/medical understanding...
i cant believe, its not known what it is.
actually, i feel arsed

when i understand right...
its been shown already years ago, that pretty much everyone (ill) has "something in the blood".

in MS they found miRNA150 which comes on exosomes.
if this is filtered out, there is improvement.
think, there was some same "mechanism" with PD as well.

the mecfs-thing may be the miRNA part of an exosome as well.

all have been identified, just not ours.
though it seems, there is no technical reason for non-identification.
all can, just not "our" research.

when big pharma companies hold back information, they often have invested a lot of money.

 

Do you have a link to a study that shows that? miRNA is one possibility that is being investigated by at least one group as a possibility.

 

sorry for the mess, all quotes

no link:
Exosomes — packed with RNA, DNA, and proteins
microRNAs — short stretches of RNA —

Removing a specific microRNA molecule — miR-150 – eased disease severity, inflammation, and loss of myelin in a mouse model of multiple sclerosis (MS), researchers report.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052910/
https://multiplesclerosisnewstoday....sease-severity-myelin-loss-in-ms-mouse-model/

https://www.dovepress.com/biomarker...-findings-peer-reviewed-fulltext-article-DNND
Interestingly, CSF and plasma levels of miR-150 are altered by DMTs and the effects are medication specific. Thus, fingolimod treatment decreased plasma miR-150 levels and did not affect CSF levels, whereas natalizumab treatment increased plasma miR-150 levels and decreased CSF levels.83 These results suggest, not surprisingly, that miRNA levels in CSF compared to plasma reflect different aspects of underlying disease pathophysiology.
(( disease-modifying therapy = DMT ))

They also found that deleting miR-150 eased the activation of microglia and astrocytes in the spinal cord — two cell types implicated in MS.
miR-150 has been linked with a number of cancers. It is thought to promote cancer cell proliferation in gastric cancer and has also been found to be more than 50x overexpressed in osteosarcoma
miR-150 levels in blood plasma can be indicative of early sepsis; it could have a future use therapeutically in treating the condition.[8] In addition, miR-150 is one of a number of microRNAs whose expression profile could be used as a biomarker of hepatocellular carcinoma
https://en.wikipedia.org/wiki/MiR-150

no link:
found that MS patients had a different setup of microRNAs than healthy people.

They also noted that patients with PPMS differed from those with RRMS in their microRNA signature
(( PPms = progressive, RRms relapsing-remitting ))

Their study, “Exosomal microRNA signatures in multiple sclerosis reflect disease status,” appeared in the journal Scientific Reports. It focused on analyzing the microRNA content of so-called exosomes — tiny packages that virtually all cells release as a means of rapid communication. Inflammatory diseases like MS involve a significant increase in exosome levels

“Exosomes are released by brain cells circulating in the blood, so they offer an easily accessible way to monitor diseases of the brain,”

“We are only now starting to wake up to their enormous potential as clinical tests.”

 

I think there's enough here [https://mecfsresearchreview.me/2019/04/25/something-in-the-blood/] to justify the funding of a validation study i.e. to develop at least one of these into a diagnostic test. Some of these methods even appear to be based on off the shelf technology e.g. Karl Morten, Oxford university, used a "molecular probe" to measure oxygen inside the cells. I Googled and found these [https://www.agilent.com/…/mitoxpress-intra-intracellular-ox…].

The European Elections are next month; so those in the EU should be getting lobbying material from candidates soon:

• ask them how come the EU has given 33.9 million euros to Lyme research in the past 10 years and ZERO to ME?
• ME affects approximately 2 million people in the EU and Lyme approximately 1 million.
• ME/Lyme are virtually indistinguishable and there are no reliable diagnostic tests for either - many people who are given an ME/Lyme diagnosis probably have the same disease.
• the EU Commission has funded the development of a diagnostic test for Lyme and treatments (vaccine). So, also ask your Government appointed EU Commissioner [Julian King in the UK] the same question - why no funding for ME Research?

Put your question on a public (social media platform) so that the question/answer are visible to as many people as possible. There are resources on the ME Action web pages i.e. how to lobby using social media etc.

Eliana lacerda (EUROMENE) made a presentation at the recent Australian Emerge [https://mecfsconference.org.au/videos/eliana-lacerda/]. EUROMENE is funded by the EU Commission; here are a few sections to consider:
10 to 12 minutes – commitment that the EUROMENE biomarker group will make recommendations on biomarkers (potential diagnostic tests) in February/March 2020.
13 to 14 minutes - commitment that the EUROMENE group will advocate (lobby) European MPs (MEPs) i.e. to deliver the EUROMENE recommendations – so we might be able to assist by lobbying for funding for biomedical ME research (diagnostic tests and treatments).


Consider lobbying as part of the Millions Missing day.

There's an ME Action European Union Face Book page.


The delivery of a diagnostic test for ME seems to be technically feasible; the issue is the lack of funding.


@EspeMor

 

Which is why I think a case study use of the Hemopurifier to see if it cleans the "something in the blood" is worth trying and funding. We need to write letters to Aethelon Medical about the potential of their Hemopurifier product.

 

It is tentatively very encouraging that the three studies that have investigated cell/mitochondria energy handling, all seem to show ME/CFS impacting ability to produce and/or utilise energy effectively. Is it that the food energy is not being converted as it should be? Or maybe it is being converted OK, but its throughput is being restricted (throttled back) in some way? Or maybe energy supply is not the problem, but some of the energy is being siphoned off and wasted (akin to driving with brakes partly on). Whatever it is that is going on, it really does sound like there is some good science, and good scientists, underway here. And wouldn't it be fantastic if it were reversible. It may prove applicable only to a sub group or groups. Or maybe it would prove only directly applicable to sub groups, but still identify some disease mechanism common to all groups.