The current state of ME/CFS research, and its prospects

[Ravn]

First, have I missed anything substantial from the last couple of years?
Second, is there anything big in progress (other than DecodeME) that we might reasonably expect to change things?

When it comes to substantial results I don't think you've missed anything.

It may be wishful thinking on my part but I do get a sense of a positive shift happening, albeit one that's still moving much too slowly and one that could easily stall if nothing much comes out of all the Long Covid studies.

Anyway, I have a sense that there are a few more outside researchers dipping their toes into the field and applying new angles of thinking and technology to it. There seems to be a slight uptick in studies having more carefully diagnosed and more respectably-sized cohorts. The ME biobank is starting to get used and more data sharing is happening. There are more provocation studies looking in more detail at what happens after exertion. And of course DecodeME may help direct research priorities soon(-ish)

So no single big development but lots of bricks falling into place. In a way it feels like we're finally building a proper foundation whereas before every team was out there constructing their own improvised flimsy hut in random places. Too many are still doing that but I have hope enough are coming together to give us a shot at something more solid. Just wish we had reached that stage decades ago

 

[Milo]

The current state of ME research, along with the clinical care has been disappointing. I am not sure there is even one clinical trial in the works that is even worthy of mentioning.

I understand that good science moves slowly and recruitment for 20,000 potential ME subject is hard and takes time. But it is so disappointing.

I am trying to keep myself distracted.

 

[Solstice]

When it comes to substantial results I don't think you've missed anything.

It may be wishful thinking on my part but I do get a sense of a positive shift happening, albeit one that's still moving much too slowly and one that could easily stall if nothing much comes out of all the Long Covid studies.

Anyway, I have a sense that there are a few more outside researchers dipping their toes into the field and applying new angles of thinking and technology to it. There seems to be a slight uptick in studies having more carefully diagnosed and more respectably-sized cohorts. The ME biobank is starting to get used and more data sharing is happening. There are more provocation studies looking in more detail at what happens after exertion. And of course DecodeME may help direct research priorities soon(-ish)

So no single big development but lots of bricks falling into place. In a way it feels like we're finally building a proper foundation whereas before every team was out there constructing their own improvised flimsy hut in random places. Too many are still doing that but I have hope enough are coming together to give us a shot at something more solid. Just wish we had reached that stage decades ago

On the last page I feel I've seen more studies and funding opportunities addressed than I had in the period 2000-2015. I hope it's a snowball-effect where some interesting findings attract more interest, patients connect more for activism and collecting money etc. Quietly hopeful that some will come of this in a time-span that it's of use to most of us.

There have been some huge decisions in favour of better care for ME-patients(IOM, NICE, ZonMw) but we also see that on all of those fronts we have to keep fighting for better care. Also funding from governing bodies needs to be increased and correctly used.

 

[Simon M]

Re replicated Raman Spectroscopy findings

Best Figure for a summary showing split between groups
https://www.medrxiv.org/content/med.../F2.large.jpg?width=800&height=600&carousel=1

That looks very interesting - I can't think of more promising biomarker findings, especially since they could separate ME from disease controls. I'm surprised they haven't been able to get further funding from the MEA or ME Research.

I think the answers must be in longitudinal proteomic and immunology studies (e.g. using exercise challenges or good day, bad day sampling). If the cause is biological, then surely there must be some differences in proteins, although perhaps the differences are in tissues rather than blood and so, are harder to find. I think, with Long Covid, we will see more tissue banks and more studies of tissue....

I think this will yield useful information, especially provocation or good-day-bad-day studies, but there is always the cause-or-effect question. Are these downstream effects of whatever is driving the illness (let's say microglial activity in the brain), or directly related to the cause?

Unfortunately, bio systems are so interconnected, and often poorly understood, that many things might cause any immune or protein disturbances (on top of the tissue issue you mention).

If there is a clear-cut difference between ME and controls (esp sick ones), it's more likely to be a causal clue. But we are short of those. I hope this type of work goes ahead, and a longitudinal approach increases the chance of finding the core problem, but it remains a challenge. , ME is such a Hard Problem.

There have been some studies on microcirculation indicating damage to microcapillaries that have been interesting. I think there have been questions raised about cardiovascular issues, specifically extraction of oxygen, that don't seem to be attributable to fitness differences. Further studies on these might bear some fruit.

I'm fascinated by this whole area, but I wasn't sure if there were any clear cut finding yet.

This paper found an enormous effect size of microclot formation when adding thrombin to serum in vitro, and I think attempts are being made to replicate that finding.

IRC, there was a lot of excitement around that finding until it emerged that the same team had made similar finding for other chronic illnesses, including Type 2 Diabetes, so its relevance isn't clear. (The finding for LC had been more dramatic.)

 

[Solstice]

I think two of the below the radar changes the last few years that have made a difference has been related to substantial funding.
1. The funding of research by Vinod Khosla. Often you might only see a tiny reference to the Amar Foundation on a paper to know such as one of Hanson's papers.
2. The PolyBio research foundation started and is growing. Finally they and their collaborators have a range of studies searching for viruses in tissues and they've attracted significant funding to bring in some world class expertise to collaborate with the latest technology.

Hadn't heard of this, that's very positive.

 

[Hoopoe]

Maybe I’m too pessimistic, but I don’t see that pattern. What would you say is the narrative that connects recent findings?

My impression is that replication attempts and successes have increased. They findings seem much less "all over the place and unreplicated" as was the norm.

The 2-day CPET research led to Systrom's findings which seem closer to the root of the problem.

Metabolomics studies are becoming more refined and are using provocation tests.

LC is highlighting aspects like endothelial dysfunction that are relevant to ME/CFS too and are part of at least one research group's hypothesis.

In Germany there is now an initiative to test treatments for ME/CFS. There is also more interest by private sector to find treatments for ME/CFS.

Maybe I'm too optimistic but to me all this (I haven't mentioned everything) looks like more mature and refined research that is making progress. Even if it's hard to say how much progress is being made. I think the researchers are getting closer to the root of the problem with all this.

 

[Simon M]

Also, thanks to everyone. ME research is not in great shape, but there are more reasons for optimism than I was allowing.

Probably my biggest research disappointment is the failure to follow up the nanoneedle findings. This clearly is never going to happen, but what I really want to see pursued is the salt stress test that revealed search striking differences between people with ME and healthy controls.

It was never clear exactly what the electrical differences picked up by the nano needle actually meant. But there must be some biological changes driving those electrical differences.

I'd like to see cell biologists study how healthy versus ME white blood cells respond to the salt test used in the nanoneedle experiments. The rationale for the salt test is that it is an energy challenge for the cell, which must pump out sodium irons – requiring a lot of energy – to survive. That's perfect for an illness characterised by a lack of energy.

What is causing the differences? The changes in cell shape? In cell membrane permeability? In cell pumping activity, particularly the sodium/potassium pump? I assume they are cell biologist out there who would know what to look for.

It feels like too big a clue to leave abandoned on the lab bench.

 

[Hoopoe]

Some recent findings implicated abnormal autophagy in ME/CFS.

Autophagy seems to fit with delayed PEM, the idea of cells being under major stress they can't handle (or maybe something wrong with stress signalling). This might be due to problems in the vascular system which would fit with Systrom's work or a metabolic deficit (which would fit with other papers) or be more something along the lines of something in the blood that triggers mitochondrial fragmentation and similar.

One could describe more such findings and how they relate to each other.

These findings aren't well connected to each other but don't seem to entirely disconnected either. Perhaps what gives a sense of poor connectedness is that different aspects of the problem are being described, maybe in the context of subgroups (e.g. Systrom believes there are two kinds of vascular problems in ME/CFS).

 

[chillier]

Best Figure for a summary showing split between groups
https://www.medrxiv.org/content/med.../F2.large.jpg?width=800&height=600&carousel=1

Full paper
https://www.medrxiv.org/content/10.1101/2023.03.18.23286575v2.full.pdf

I remember seeing this before and not being convinced so looking again to try and remind myself why. First thing is the wave forms of the different cohorts have been translated up or down in figures A and B to aid visibility. I thought this was a bit misleading as it makes it look like they are strikingly different between the groups when just glancing with the naked eye, when in reality the look pretty much identical. The second thing is the cohorts separate out very nicely in the factor analysis on the right - but this isn't a principle component analysis it's a linear discriminant analysis which is supervised - that is, you give it the information about which cohort each datapoint belongs to in advance. The algorithm goes on to find a way to display the data that separates the groups best.

They do go on to train a classifier to distinguish between the groups and they divide the data into training and testing partitions which is important. So these numbers of 91% and 92% sensitivity and specificity in picking out ME from the others could be fair enough.

You can kind of see a spike in the variation of the cells in the healthy control cell intensity corresponding to a peak around 1000cm-1 in their raman spectroscopy data (I've highlighted it with a red arrow). It looks like this might correspond to the phenylalanine or possibly glycerol wavelength which they quantify in the following figure. They attach the breakdowns of intensity at each wavelength in a supplementary table but I guess we can't access yet if it's in preprint:

 

[Kitty]

What is causing the differences? The changes in cell shape? In cell membrane permeability? In cell pumping activity, particularly the sodium/potassium pump? I assume they are cell biologist out there who would know what to look for.

It feels like too big a clue to leave abandoned on the lab bench.

Unless they're unconvinced by it, perhaps because not enough samples were processed? Or OMF themselves aren't as convinced as they were? Ron Davis has said that it's laborious with the kit they have, but even so, you'd think they'd have found a way to run one more cohort if they really thought they'd got something major.

 

[Simon M]

Re-nanoneedle

Unless they're unconvinced by it, perhaps because not enough samples were processed? Or OMF themselves aren't as convinced as they were? Ron Davis has said that it's laborious with the kit they have, but even so, you'd think they'd have found a way to run one more cohort if they really thought they'd got something major.

They published a paper in a prestigious journal and made a lot of noise about it, and the results were pretty striking. I thought the main problem was that the researcher leading on the nanoneedle have moved on, But even so it does seem strange how they’ve lost all enthusiasm for it. Maybe they had some discouraging unpublished results

In any case, what I’m proposing is not to pursue nanoneedle research, but to study the effects of a salt stress test on ME/CFS white blood cells. Potentially, that could reveal biological changes as a cellular level that are specific to ME/CFS (or potentially not).

 

[Hoopoe]

Re. sodium. There was this study that found increased sodium content in ME/CFS muscle and the authors believe this is due to a dysfunction in the sodium-potassium pump (which transports sodium out of the cell).

Maybe this has something to do with the reaction to sodium observed in the nanoneedle tests. Exporting sodium costs ATP and Ron Davis appeared to believe that this energy stress was the problem. But maybe it was a dysfunction of the transporter.

Muscle sodium content in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03616-z

 

[rvallee]

I saw a tweet from yesterday by Medscape, an article with something like "Long Covid is real" and whether it is unique to COVID. It's been 3 years, some are still barely capable of saying it's real. Most long haulers are still gaslighted, there is obvious awkwardness in most MDs just acknowledging any of it. The article has zero mention or even a hint at the mass of prior chronic illness, including ME. They talk of long flu and other stuff.

So I'd say that's where we are: research is very slowly ramping up, at the absolutely slowest possible speed (the parking brakes are still on), it hasn't yielded anything yet, the cover-up of chronic illness continues unabated and no one is getting any real help.

But it could change. That's the best they can do so far.

 

[Hutan]

The Morten group have replicated their own Raman Spectroscopy studies I believe twice, with different cohorts, but are stumped by funding to take this where they want to. Somehow they have kept this work going. The technique seems to separate severity reasonably well. Alain Moreau's group are now doing their own Raman Spectroscopy work - hopefully it will replicate.

Thread for the Morten paper:
Preprint: Developing a blood cell-based diagnostic test for ME/CFS using peripheral blood mononuclear cells 2023 Xu et al
Looks like I missed this, thanks for posting.

 

[SNT Gatchaman]

I think that the labelling and subsequent view of "long Covid" has been beneficial, even if some unnecessary mistakes and repeat exercise studies are being done. It arose accidentally (well, more as a predictable consequence) via patients themselves, when medicine had nothing for the large number of people developing severe postviral symptoms, many after mild or asymptomatic/proven infection. When this happened with SARS1 it was simply called ME/CFS, however that didn't become a massive global pandemic in 2002-4 (thank you public health).

Now we have this "totally new disease" being investigated from multiple angles with a sufficient proportion of investigators coming in with a purely biological lens. While the definition of LC is vague and broad, it's becoming increasingly clear that ME/CFS is a major outcome. Much LC research is therefore ME research and many teams are newly involved, bringing new ideas and techniques, and are untainted by BPS pseudoscience. Would things have moved faster or slower if it had been called ME not LC?

Second, is there anything big in progress (other than DecodeME) that we might reasonably expect to change things?

From our perspective, there is also a very left field research area that might contribute important knowledge: via Nasa's Moon and Mars projects. It seems to me that there is substantial overlap between ME findings and those seen in long-duration spaceflight*. This research is well funded, taken seriously, with the aim to develop countermeasures. Very speculatively, it is just possible that in order to successfully achieve a crewed mission to Mars, first we need to solve ME**.

---
* vascular/microvascular/endothelial dysfunction, metabolic reprogramming, impaired oxygen transport, DNA methylation changes, microbiome disturbance, cell-mediated immune dysregulation, latent (herpes) viral reactivation, mitochondrial stress/dysfunction, plasma/saliva cytokine changes, brain connectivity changes, circadian rhythm disturbance.

** If there are sufficiently overlapping upstream pathways, eg if it were the case that latent viral reactivation and immunometabolic changes were responsible for the other effects. It might then not matter if the proximate cause for the latent viral reactivation differs between those in space and those on Earth.

 

[Milo]

Good research takes time. It is so painfully slow for us patients to watch. We are just emerging from the pandemic, where a lot of the in-person patient research was halted for several months. Labs closed. It delayed research further.

 

[Hoopoe]

Would things have moved faster or slower if it had been called ME not LC?

The pretense that LC is totally new is a way to get research done without upsetting people that are invested in trivializing and psychsomaticizing ME. To some degree, also without upsetting power structures.

It would have been better if society had admitted that LC is often probably a form of ME. But that would also require admitting that a serious mistake and injustice was made. That seems to be too much, at least for now.

 

[Simon M]

Re. sodium. There was this study that found increased sodium content in ME/CFS muscle and the authors believe this is due to a dysfunction in the sodium-potassium pump (which transports sodium out of the cell).

Maybe this has something to do with the reaction to sodium observed in the nanoneedle tests. Exporting sodium costs ATP and Ron Davis appeared to believe that this energy stress was the problem. But maybe it was a dysfunction of the transporter.

Muscle sodium content in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03616-z

Thanks, this is very interesting research.

But I don’t think it can bear too much weight. It’s very small ( n = 6/6). And the findings could be explained by Fitness: 78% of men and 86% of women in the population meet their definition of 'sedentary' used to select controls. The authors noted a strong (R = 0.4) correlation between handgrip strength and sodium levels - and handgrip strength is a surprisingly good proxy for fitness. I think this is worth pursuing, but we would need larger studies and a design to tease out the effect of fitness

 

[EndME]

The pretense that LC is totally new is a way to get research done without upsetting people that are invested in trivializing and psychsomaticizing ME. To some degree, also without upsetting power structures.

It would have been better if society had admitted that LC is often probably a form of ME. But that would also require admitting that a serious mistake and injustice was made. That seems to be too much, at least for now.

I think the power structures are particularly relevant. For a large part this means that LC is still viewed as psychosomatic. Admitting that LC is physiological and at the same time can cause ME/CFS at a political level, doesn't only mean that one has neglected and forcefully harmed ME/CFS patients for decades, but also that other "programmes" currently running for example for "long-Q-fever" or "long-MERS-SARS" are nothing short of a harmful form of pseudoscientific money waste. Who would take the fall for that?

In countries like the Netherlands this leads to the most absurd situations, where proper biomedical ME/CFS research is going to be conducted on the basis of pseudoscientific criteria. Damming the research from the get go. This is also a massive problem for Long-Covid research where a big European project that has been set up that includes the Lifelines cohort and is conducted by Finnish researchers who openly state and treat both of Long-Covid and ME/CFS as FND's https://longcovidproject.eu/methology/.

 

[Solstice]

The pretense that LC is totally new is a way to get research done without upsetting people that are invested in trivializing and psychsomaticizing ME. To some degree, also without upsetting power structures.

It would have been better if society had admitted that LC is often probably a form of ME. But that would also require admitting that a serious mistake and injustice was made. That seems to be too much, at least for now.

Which is understandable yet evil. Admitting that they treated us poorly will open up a lot of people for liability I'd imagine.