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

[Simon M]

Hi,

I’ve not been able to closely follow the status of ME research for quite a while, but my take is that we’re not getting very far.

Mostly, it seems to be researchers publishing fairly weak evidence in favour of pet hypotheses. This has been the main approach for the last few decades, and I’m not convinced it’s going to prove very productive.

One piece of research that I thought might be productive is that by Bhupesh Prusty on herpesviruses and mitochondrial fragmentation. I think he had a significant paper published on this. And I know he has been working on linking that to ME/CFS, specifically.

I had found the work hard to follow, but I saw his recent (May) presentation about his findings, and couldn’t see much to get excited about, sadly.

Unsurprisingly, I am excited about the prospects of DecodeME. Above all, that’s because it’s a genetic study and so well designed to identify causal clues. I think that's the approach we need most. I don’t have any special information on when the first results will be available from the study, but I’m expecting it within the next year.

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?

I'm focusing on research quality, not how plausible things might sound or how they might chime with the current zeitgeist.

Thanks

 

[Wyva]

It is the NIH Intramural ME/CFS study that many of us are waiting for to get published in the next couple of months (or maybe in a year). It is really just the publication itself that we are waiting for now. Thread: https://www.s4me.info/threads/usa-national-institutes-of-health-nih-intramural-me-cfs-study.2980/

Avindra Nath says they have found something consistent but we really have no idea how this holds up until we actually see the study. It's a small study though, so even if it is something really exciting, it will need to be replicated probably. No preprint available.

 

[Trish]

I agree DecodeME is an excellent study. I don't have great hopes of something clear and distinct being found, more likely some possible clues that will still need a lot of follow up research.
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Of work published so far I think I'm most hopeful about the research team working under Maureen Hanson at Cornell University.
USA: Cornell Center for Enervating NeuroImmune Disease and Maureen Hanson

They did a big study of I think 80 pwME and matched controls doing 2 day CPET, and taking blood and urine samples before and after each as well as symptoms.

Threads I've found on this work:

Plasma metabolomics reveals disrupted response and recovery following maximal exercise in ME/CFS, Arnaud Germain, Maureen R. Hanson et al, 2022

Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2023, Maya et al

Urine Metabolomics Exposes Anomalous Recovery after Maximal Exertion in Female ME/CFS Patients 2023, Glass, Hanson et al

Recovery from Exercise in Persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) 2023, Moore, Hanson et al

Exploring the Genetic Contribution to Oxidative Stress in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2023, Hampilos et al

Proteomics and cytokine analyses distinguish myalgic encephalomyelitis/chronic fatigue syndrome cases from controls, 2023, Giloteaux et al

I think a particular value of this is all these studies are on the same patients, and they are a team with funding from NIH as one of the centers funded to do ME/CFS research. I'm impressed with Hanson, and the fact that they are a team not an isolated individual working alone on just one aspect is valuable as they can try to build a picture from all their findings, and work out what is worth following up.
_____________________

The other one we're all waiting for of course is the NIH intramural study which should be published soon:
USA: National Institutes of Health (NIH) intramural ME/CFS study
That has the advantage of being able to do all sorts of tests on each person, but the big disadvantage of a very small sample size, so anything found will need replicating at a much larger scale.

 

[Hoopoe]

To me it seems like some progress is clearly happening. We're seeing more marked abnormalities being published, and ones that fit with previously published research. It doesn't seem like almost only barely statistically significant findings are being published that don't fit into a bigger picture, as was the case years ago. So the impression is that the researchers are getting closer to the root of the problem but haven't gotten there yet.

One reason for this is better funding and the use of provocation tests. But it's not clear how close we are to significant progress. Maybe the NIH has already achieved that but not published yet.

But it seems too slow to have any realistic hope of having a treatment in the next years. We need a lot more resources and effort to go towards ME/CFS research.

 

[EndME]

I'm not getting my hopes up too much on the intramural study. Usually, when researchers really have found some true breakthrough results they try to make that public quicker than is the case here and it doesn't seem like follow-up projects are planned. I think it'll be one of those "we found something and maybe in 10 years someone we will try to replicate the findings".

I think the biggest hope is that there would be a change in Long-Covid research funding that would eventually dripple over to ME/CFS research since some of the biggest researchers there, for example Iwasaki, have been made very aware of ME/CFS. If someone like Scheibenbogen were to get 100mil in funding for Long-Covid research a good chunk of that would translate to ME/CFS research as well. If they don't solve Long-Covid they won't solve ME/CFS.

If one compares other scientific conferences with the ME/CFS conferences, for example the ones that recently happened, one would be absolutely shocked by the current state of research. That being said the direness of research is of course due to the lack of resources and the researchers are of course not at all to blame for the situation.

 

[wigglethemouse]

First, have I missed anything substantial from the last couple of years?

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.

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.

 

[Jaybee00]

Nath claims there are potential druggable targets in their to-be-published research.

Also looks like potential drug targets in the Avik Roy/Gottschalk/Simmaron work.

https://www.s4me.info/threads/eleva...microglial-cells-2022-gottschalk-et-al.27343/

https://www.s4me.info/threads/mtor-activation-atg13-inactivation-and-suppression-of-autophagy.33161/

 

[Simon M]

It is the NIH Intramural ME/CFS study that many of us are waiting for

That’s a good point (also @Trish). As you both say, it is a very small sample.

Usually, when researchers really have found some true breakthrough results they try to make that public quicker than is the case here and it doesn't seem like follow-up projects are planned

That was my thinking too. But...

Nath claims there are potential druggable targets in their to-be-published research.

That would be very interesting if the findings are strong.

Of work published so far I think I'm most hopeful about the research team working under Maureen Hanson ...They did a big study of I think 80 pwME and matched controls doing 2 day CPET, and taking blood and urine samples before and after each as well as symptoms.

This seemed the most impressive programme of the 3 NIH-funded centres, and I agree about the team approach and a lot of data on the same cohort., plus using an (exercise), stress test.

Though I was disappointed by the findings. At least some of the studies used only a fraction of the full cohort (20 for T-cells, 8 for urine metabolites). Given the likelihood of subtypes, I think we need big cohorts (ideally 100++) and many measures.

...they can try to build a picture from all their findings, and work out what is worth following up.

Let's hope they can do that.

To me it seems like some progress is clearly happening. We're seeing more marked abnormalities being published, and ones that fit with previously published research..... So the impression is that the researchers are getting closer to the root of the problem but haven't gotten there yet.

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

 

[Jaybee00]

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.

Yes, Khosla funding is helpful. Apparently there is an Amar Foundation in the UK that is distinct entity from the USA foundation, which is Khosla’s entity?

Regarding PB, I am not optimistic about AP’s quest to find viruses—I worry that this is funding that could be better deployed elsewhere [exempting MVE’s research from this comment].

 

[Simon M]

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. ... The technique seems to separate severity reasonably well.

I seem to remember being impressed by the first study and much less so by the second. That might be a comment on my memory rather than the research - could you summarise the key replication data?

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.

Interesting, and certainly under my radar.

That point about expertise is key IMO. So often researchers seem to be operating beyond their key area of expertise (e.g. with immunology and energy metabolism studies). Almost any number of biosystems have been implicated in and studied in ME/CFS - we need experts in each area to be bringing their skills to bear. Long Covid has been very lucky with Akiko Iwasaki and immunology.

 

[chillier]

Agree that the things have been worth looking forward to are Prusty's biomarker, NIH intramural study and decode ME. Prusty's paper isn't out yet afaik but agree that what we know has underwhelmed. Agreeing also that Hanson lab is doing solid seeming work and that they had an interesting urine metabolomics finding where controls had an increase in certain amino acid related metabolites after exercise that was absent in patients (@Trish linked the paper). I think they're going to replicate it and I hope they select their sedentary controls extremely carefully.

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.


I think VanElzakker (EDIT: actually PolyBio not sure if VanElzakker is involved) may be working on probes that could be used to visualise pathogens in tissue in vivo with radiology. I don't know much about this but seems like a good approach.

For wetlab work even now I think the 'factor in the blood' experiments as reported in your good blog post are the best lead! So a concerted effort to replicate the work from the various different sources tronstadt/prusty/bertinat and so on with decent power is what's needed.

 

[chillier]

Oh and also Fluge and Mella are beginning pilot studies using the CD38 monoclonal Daratumumab - which additionally targets plasma cells (which rituximab does not). They reported some preliminary data on this at the Charite conference but far too early to make any conclusions. Still knowing the quality of their work this will be interesting to follow.

 

[wigglethemouse]

I seem to remember being impressed by the first study and much less so by the second. That might be a comment on my memory rather than the research - could you summarise the key replication data?

The model achieved high performance on the independent test set with
* a sensitivity of 91% and specificity of 93% for the ME/CFS group;
* a 90% sensitivity and 92% specificity for the MS group.

The overall accuracy on the test set was 91% (87–93% at a 95% confidence interval) (Figure 5B). These results support our approach of a blood cell-based diagnostic test combining single-cell Raman spectroscopy and ensemble learning as a diagnostic tool for ME/CFS.

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

 

[Simon M]

I think the biggest hope is that there would be a change in Long-Covid research funding that would eventually dripple over to ME/CFS research since some of the biggest researchers there, for example Iwasaki, have been made very aware of ME/CFS.

I agree, my biggest source of optimism (along with Decode ME) is the amount of money and scientific expertise going into long Covid research).

 

[wigglethemouse]

Interesting, and certainly under my radar.

Here is a link to a list of PolyBio's current projects.
https://polybio.org/projects/

I'm particularly wow'ed by the full body PET imaging to look for activated T-cells and virus pockets that has been used previously in HIV research.
https://polybio.org/projects/use-of...t-cell-responses-in-patients-with-long-covid/

Tissue biopsy samples from the lymph node and gut will also be collected from Long COVID study participants undergoing imaging. These tissue samples will be analyzed for SARS-CoV-2 RNA, spike, and nucleocapsid proteins, other chronic viruses (e.g., Epstein-Barr virus and cytomegalovirus), and cellular immune responses. Data collected on the tissue samples will be correlated with the imaging data, so that potential viral reservoirs and T cell activity in study participants can be validated by overlapping methods.

If the project team can successfully image SARS-CoV-2 reservoirs in patients with Long COVID, they can begin to radiolabel therapeutics that target other pathogens implicated in human chronic disease. This would greatly increase the general understanding of pathogen persistence throughout the human body, with strong implications for cancer, Alzheimer’s disease, and other conditions increasingly tied to persistent viral or bacterial activity in tissue.

 

[EndME]

That’s a good point (also @Trish). As you both say, it is a very small sample.
That would be very interesting if the findings are strong.

Logically if Nath would have strong findings in ME/CFS he would have tried to see if the same holds in a similar subset of Long-Covid patients or at least the younger research members in his team would have tried to get grants for this. Their published Long-Covid findings and also the one finding of the Intramural study that is already available, make me think that this isn't the game-changer with possible treatment implications many are hoping for.

It was also a good point mentioned above that the Long-Covid field has more researchers with the desired expertise. You need the HIV researchers (like the team at UCSF) and post-Ebola researchers that have been using similar methods for years to look at viral persistence, immunologists like Iwasaki to udnerstand immunoligical problems etc. Many ME/CFS researchers are naturally out of their expertise. Long-Covid can change that. It's very easy for an expert to just repeat a previous Long-Covid study for ME/CFS or just include some patients in the test set.

 

[Jaybee00]

Logically if Nath would have strong findings in ME/CFS he would have tried to see if the same holds in a similar subset of Long-Covid patients or at least the younger research members in his team would have tried to get grants for this.

Nath has stated (I think on the recent NIH call) that they are considering conducting clinical trials based on their findings—to me this is a good indication that they found something.

 

[EndME]

Nath has stated (I think on the recent NIH call) that they are considering conducting clinical trials based on their findings—to me this is a good indication that they found something.

To me that's more of an artefact on what ME/CFS researchers have decided to be the best solution. Simultaneous research and drug trials has become a much hotter topic than it used to be, the same holds for the Long-Covid field. Drug trials to figure out a biomarker, rather than biomarkers to figure out drug trials is the en vogue method.

 

[boolybooly]

I don't like to sound pessimistic but... when I think of Decode ME I remember Prof J Kerr's affymetrix gene expression study which didnt find statistically valid patterns in the data, though it was a small study.

Decode ME should provide a lot more data of a different type which will be useful for decades but getting the data is just the start and any worthwhile conclusions hinge on having a top of the class statisticians, programmers and AI getting to grips with it. I am not holding my breath as I expect it will take a few years after publication of the data but I think that when its out the ME organisations will do well to promote it to researchers over the longer term.

If I have a rose tinted hope it is that a brilliant AI will be developed that can rise above the madding crowd, form its own hypotheses and test them iteratively and crunch it into something useful. After COVID I think getting the attention of big computing with an offering of big data will be a lot easier.

 

[Hutan]

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.

So many of the longitudinal proteomics and immunology studies we have seen so far are tiny, and some are of poor quality with heterogeneous samples. Even so, there do seem to be some indications of perturbed pathways and differences in immune cells. And I'm sure that there will be more studies, hopefully with well defined participant selection. I too like Hanson's Cornell lab for the steady way they seem to be approaching questions. The tools and the knowledge base about both proteins and immune cells are improving. There will be increasing capacity to identify proteins - we have seen studies where a substantial chunk of proteins identified as differentially expressed can't be identified yet.

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.