Speculations about the genetics of ME/CFS and DecodeME

Yes, not easy, but it's the way forward. We will not reach a tipping point for ME/CFS unless there is significantly more investment and engagement by patients and more importantly their loved ones. Fundraising appeal is dependent on how well one can explain what needs to be done and why, the more educated the target audience is the better the chances for funds will be. My sense is that large parts of the ME community are very well informed about the scientific status quo and engages in seemingly endless debates (led by people with very little energy!) about intricacies of vague theories they have mostly no influence over but know very little abou the greater picture in terms of bottlenecks that hold back more research. That's what needs to change. People affected by this disease and by proxy need to understand that nobody will ride in to save the day and that there are better and worse ways to invest what little energy and resources we have. People writing novels (that 20 or so people will read) about phantasy bio molecular pathways leading to heaven and the cure who at the same time have no energy to write a letter to their political rep and people throwing out money for useless supplement number 100 who at the same time have no funds for funding political work are people who need to be informed that there are better ways. There is no way around it, I believe.

You can't find large layman Parkinson's patient populations discussing highly complex biology, and the ME population doing exactly that is largely a trauma response, albeit an extremely unproductive one.

 

I understand what you are saying, but in most cases, 'criticizing bad research' on a patient forum or a blog will not improve it—not even the next iteration of it. That's not really happening, that’s what should happen, maybe, but it doesn’t in the vast majority of cases.

The reason why PD has 'good research' and ME/CFS has 'bad research' is mainly due to the discrepancy in funding and the stigma surrounding the disease.

Furthermore, there is certainly no need for more ME patients to engage in criticizing research, but there is a definite need for political and fundraising advocacy.

I am obviously not saying there is no value in what you do (very eloquently, I might add!), nor am I telling anyone what they should do with their energy. What I am saying is that if more people, on average, looked at the situation and the current constraints with an open mind, focusing on ‘what it needs to move the needle’ rather than ‘what I want to do because it suits my talents,’ I think we would move faster along and there would be MUCH more and better research to criticize.

 

I am afraid that I totally disagree with this @butter.
The reason progress has been made in Parkinson's disease is simply that for over a century people have known where the structural pathology is. So there is a lead. In ME there is no lead. Money is no use if you do not know what to do with it.

I am not convinced that Parkinson's research is that great. There is a lot of hype but my understanding is that the important research was done in the 1960s and 70s when dopamine depletion was identified and dopamine agonists started to be used.

The 'endless debates' amongst forum members are exactly like the debates we had on rheumatoid at a stage when we could not piece things together. When new techniques finally provided as with new bits of information we needed slotting everything into place was easy because we had thought things through. Progress in ME/CFS research in terms of getting major genetic study going was driven by patient interest. If we are lucky the genetics will provide us with exactly the missing clue that we need. If we have some idea what it is likely to mean we will be in a position to find a solution.

I presume you want a cure and that will depend on knowing a very complex and subtle biochemical pathway that has so far remained hidden - as for RA. What goes on on S4ME is how science really works, not the Twitter science you read about in the papers.

 

Yes, I disagree, telling laymen to invest their little energy in highly complex matters that they will not solve is not optimal to put it mildly. Patients will neither find the structural abnormalities from their beds nor will they crack the complex pathways.

There is a difference between patients pushing for a genetic study (good!) and patients analyzing the data (with what goal?). The 'endless debates' should be held by people who are getting paid for it AND know what they are talking about AND can implement the intermediate results of such debates. The constraint is funding, the idea that there is somehow a lack of 'real science produced on patient forums' but not more funding (producing leads!), with all due respect, is ridiculous!

 

All good, but that is a complete misrepresentation of what I am saying.

I am not saying it has no value, but that relatively speaking, too much energy goes into discussing 'old & bad science' with little to show for it. For an ME patient who is (the right kind of) scientist it could make sense to 'talk and do science' but even then in most (not all) cases it doesn't pay, depending on among other things whether you are well enough to actually implement stuff or have the leverage for others to do it. In other words, even if you are a scientist, in most instances your energy would (that's my sense after 15 years, I am aware most people will disagree on this forum which is why I am posting it here) have a bigger impact in other domains.


PS: I am not typing myself, my caregiver does it for me, so quite challenging. I need to rest a day or two and will be back then, TY!

 

These recent comments in this thread have been interesting. As a mother caregiver who only recently joined this forum I wish I had joined 5 years ago because I would have saved several tens of thousands of dollars that I could have donated to advocacy & research funds. Previously I would read the papers & reports mentioned on various MECFS websites and naively assume it was sound science. I tried to be objective but I now realise I have wasted a great deal of money and my son’s hope.

From a non-expert perspective I think there is considerable collective knowledge & skill in this forum membership and there a many dimensions of value it provides in the wider MECFS landscape. I think I understand what you are saying @butter. however I suspect many members here are probably also active elsewhere in other advocacy or research roles, if they have the capacity.

I do think the forum is under-utilised by researchers who could ask questions, test ideas or seek feedback.

 

The trouble is that it's not old. New iterations keep appearing, new papers are published every week, new harms occur as a result. We talk about it because it needs constant vigilance.

As for bad, we need to be able to say how and why it's bad. We have to be better scientists than the scientists, the same way women have to be better qualified to get CEO jobs than men.

I'm not sure that's what most of us are trying to do.

We're working at being effective parters to researchers, because we know—and the best of the researchers know—that they can't do it without us.

For instance, we try to tease out what we mean when we talk about things, because defining and describing ME/CFS is like bottling fog. We still haven't got sharp enough descriptions of PEM, but we're the only people who can do that work. If we don't do it, we can't expect researchers to grasp it.

There's also a giant hole where meaningful assessment of clinical interventions ought to be. Again, we're the only people well placed to recognise a genuinely effective measure when we see it, and as soon as potential treatments come along we're going to need those tools. So we bat it around and discuss it.

There's a whole raft of work like this: crucial for successful research, yet most researchers can't do it.

 

I agree with basically everthing you say, but, if capacity and resources are a rare good, one should be as conscious as possible/aware of the utility of ones actions and be aware of tradeoffs one is making and be honest about potential shortcomings in terms of setting and reaching concrete goals.

Another way of saying what I want to say is that technocratic types (scientists) often underestimate how important it is to deal with/work with bureaucats and politicians to set the stage for any scientific progress.

 

That's exactly the point: no amount of criticizing bad research will stop it from happening. It happens for ALL diseases but in relatively lower numbers. The (more realistic) goal is to get more funding for better research for that you and people on this forum will be heard, in terms of implementation, wherever deemed sensible.

The core issue often missed is that the vast majority of scientists writing garbage papers have obviously no real interest in finding a cure for you. In other words we don't want to educate fools (not working anyways!) but create the ideal environment for the right kind of people, marked by high intelligence, high integrity and high energy to help us. That type ususally needs a lot of cash. This forum is a great place for such people to ask questions, but we lack the incentives to lure them in.

 

I can't figure out how to eloquently say this, but I'll add that something like fundraising feels much harder than browsing the research landscape. The willpower itself to do something that feels less interesting takes energy, even if it seems to require the same amount of energy typing on here or typing a letter to the government. One feels like a casual treasure hunt where gold might be found anywhere, the other feels like a job with very indirect, ambiguous benefit.

Reading the same amount of words in different contexts doesn't equal the same amount of energy. When I'm extremely tired, all I can do is read pointless Reddit posts to get immediate mental reward, and I have no energy to read the same amount of text from a research abstract. If I forced myself to read a little research, then my brain would be even more fried than "pointless Reddit energy" afterwards, and I'd be brainlessly staring at a TV.

 

That's a VERY important point, I think there are ways to circumvent this issue, granted so far no org has found good structures/means yet.

 

also when you're typing on here it's a communication with people who broadly get where you're coming from, whereas if you're writing a letter to someone in government it takes a paragraph to explain each concept that you could communicate with just a phrase here.

 

This is where I think a more sophisticated iteration of @forestglip’s ME-aware AI-chatbot could come in handy.

 

True. I did fundraising as part of my job, and it's really tough.

At the moment, patients are finding it hard because they haven't got a simple, compelling story, and researchers are finding it hard because they haven't got a simple, compelling question.

Both groups desperately need a hare to chase down—but once we have one, fundraisers will have a much better chance.

 

I'm of a different opinion. If you take individual symptoms, like fatigue or brain fog, it could intersect with many other diseases. In totality, however, it's unlikely that all symptoms are shared with others. And that is especially the case if you take PEM into account; there is no other disease that exhibits such a dramatic worsening after a minor exertion, and the set of just three symptoms {fatigue, brain fog, PEM} already separates ME/CFS from all other known diseases. Can there be multiple *unknown* diseases that produce the same set of symptoms? Possible, but again unlikely. What are the chances that you encounter multiple unknown diseases that produce same set of symptoms? I'm not aware of any in the annals of medicine.

That said, I think it's possible that there are multiple direct causes for ME/CFS. If ME/CFS is a hypersensitivity to exertion, for example, something could be pinching the neuroimmune system to produce that hypersensitivity. For others, the system just became hypersensitive, like allergy. The treatment would be different for each: removing the pinching will do for the former, while you'd have to figure out how to temper down the hypersensitivity in the latter. If you define the disease as {cause, symptoms, treatment} triplet, they could be classified as different diseases. But the underlying mechanism would be the same and identifying that mechanism should be a key in finding the treatment in both cases. And following the symptoms, rather than speculating on unknown possibilities apart from the symptoms, is always the best way to identify the mechanism in any debugging process.

 

I'm excited by the collaborations that DecodeME will facilitate when the data is made available. Subtyping by symptoms or metabolic pathways and looking for relevant genes could tease out more variants and prehaps treatment ideas.

I know of two who are doing this/have done this using the existing UK Biobank genetic data on ME/CFS. Some projects include :

1. Precision Life have published findings already on analysing the UK Biobank data.
https://www.s4me.info/threads/genet...analysis-2023-taylor-et-al.34243/#post-507747

2. OMF - Melbourne group
https://www.omf.ngo/biological-outlier-and-subtyping-software-for-myalgic-encephalomyelitis/

@MelbME - Are you able to comment if you will be extending the tools being developed to DecodeME?

3. OMF Stanford are screening a cohort for common genetic variants in the BH4 pathway using an inhouse screen which they will then compare against actual pathway measurements.
https://www.omf.ngo/genetic-and-metabolic-markers-of-bh4-deficiency-in-long-covid/

4. Liz Worthey and colleagues at UAB are developing tools to analyse Whole Geneome Sequencing data. Jarred Younger stated the first project is out for peer review and hopes for publication by end of year. 7min 25s in

https://www.youtube.com/watch?v=vePEtCKjkfA

Transcript :

I have high hopes that these and other groups will collaborate with DecodeME when the data is made available.

 

For info on applying for access to DecodeME data see https://www.decodeme.org.uk/researcher-access/.