Speculations about the genetics of ME/CFS and DecodeME

[butter.]

That’s really interesting idea and that’s not just for a WGS. Crowd funding is a lot harder than people imagine, but the sums involved would be more doable. Though I don’t know how much fundraising appeal hiring lobbyist and people to write grant apps would have.

That’s really interesting idea and that’s not just for a WGS. Crowd funding is a lot harder than people imagine, but the sums involved would be more doable. Though I don’t know how much fundraising appeal hiring lobbyist and people to write grant apps would have.

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.

 

[Hutan]

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.

We are heading off-topic for this thread, we will probably need to split this conversation off if it continues, but:

I don't think the situations are at all comparable. My sense is that Parkinsons researchers are, on the whole, doing a good job (edit - and there are also good support services). I think there will still be some Parkinsons patients engaged in research, but there is much less need for any but the most qualified and committed to do so.

With ME/CFS, so many of us have looked at the research being done on our disease and gone 'what?!'. The work being done (both the psychosomatic stuff and the biological stuff) has mostly been so egregiously bad, and the resulting conclusions so harmful, that we have rightly felt the need to get involved. Doing that has in fact been part of breaking those bottlenecks holding back more and better research. It is the key to getting loved ones more engaged in fundraising - if our loved ones think we just need to exercise more to get over our faulty effort preferences, or would be fixed by acupuncture or vitamins, they aren't going to recognise the gaping lack of useful treatments and help campaign for real research.

For sure, people waste so much money on supplements and various ineffective treatments - but that's another argument for people with ME/CFS being involved in considering the science behind those treatments, to try to reduce the waste. I guess many conversations among people with inadequate scientific training on the causes of ME/CFS are largely unproductive, but, frankly, if it helps people get through their days, maybe that alone is good enough. With the involvement of people who do have deep knowledge of relevant subjects, some of them with ME/CFS and some of them without, maybe the conversations can reduce the harm uninformed speculation causes and, just maybe, a bit of information will spark the study that finds a crucial answer.

I don't think we should underestimate people's capacity to learn. There are people here without doctorates and professorships who have, over time, become at least as knowledgeable as some of the young doctoral students and post-docs responsible for carrying out research.

For sure we need the letters to the political representatives and the fundraising. We need to be providing support to advocates around the world. I agree with much of what you say, we do need to think carefully about priorities. There is so much to be done.

 

[butter.]

We are heading off-topic for this thread, we will probably need to split this conversation off if it continues, but:

I don't think the situations are at all comparable. My sense is that Parkinsons researchers are, on the whole, doing a good job (edit - and there are also good support services). I think there will still be some Parkinsons patients engaged in research, but there is much less need for any but the most qualified and committed to do so.

With ME/CFS, so many of us have looked at the research being done on our disease and gone 'what?!'. The work being done (both the psychosomatic stuff and the biological stuff) has mostly been so egregiously bad, and the resulting conclusions so harmful, that we have rightly felt the need to get involved. Doing that has in fact been part of breaking those bottlenecks holding back more and better research. It is the key to getting loved ones more engaged in fundraising - if our loved ones think we just need to exercise more to get over our faulty effort preferences, or would be fixed by acupuncture or vitamins, they aren't going to recognise the gaping lack of useful treatments and help campaign for real research.

For sure, people waste so much money on supplements and various ineffective treatments - but that's another argument for people with ME/CFS being involved in considering the science behind those treatments, to try to reduce the waste. I guess many conversations among people with inadequate scientific training on the causes of ME/CFS are largely unproductive, but, frankly, if it helps people get through their days, maybe that alone is good enough. With the involvement of people who do have deep knowledge of relevant subjects, some of them with ME/CFS and some of them without, maybe the conversations can reduce the harm uninformed speculation causes and, just maybe, a bit of information will spark the study that finds a crucial answer.

I don't think we should underestimate people's capacity to learn. There are people here without doctorates and professorships who have, over time, become at least as knowledgeable as some of the young doctoral students and post-docs responsible for carrying out research.

For sure we need the letters to the political representatives and the fundraising. We need to be providing support to advocates around the world. I agree with much of what you say, we do need to think carefully about priorities. There is so much to be done.

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.

 

[Jonathan Edwards]

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.

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.

 

[butter.]

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!

 

[Trish]

I strongly disagree with the suggestion that patients should not be discussing the details of scientific research and should devote our energies instead to fundraising to pay the real scientists to do the research.

Of course we need more funds for research, but that doesn't preclude patient involvement in discussing and participating in research too. Lots of patients are scientists too, and a forum like this is a space where those able to can learn from each other and we hope get more active scientists involved in the discussion too. The aim is mutual learning that can lead to better science.

In my case I'm too old and sick to return to employment and contribute directly, but I am still learning and see when some research and the treatments based on that research are flawed. Without that sort of patient involvement by others long before I got involved, the work to get PACE data reanalysis, and critiques of the Cochrane exercise review would not have happened.

Given the poor quality of much research, especially in the psychobehavioural and alternative medicine fields, if we don't take action more pwME will be harmed.

Also we need pwME to take an active part in helping to run research. It’s important to have pwME with a good understanding of how good research works and a lot about ME beyond their own personal experience so their contribution as part of the research team has real value.

Look at the contrast between the excellent scientist/patients collaboration in the DecodeME project, and the mess that the NIH made of the intramural study and their defensive reaction when pwME tell them their effort preference nonsense is wrong. If they had had expert patients involved as equals in the design of the study, how much better it could have been.

 

[butter.]

I strongly disagree with the suggestion that patients should not be discussing the details of scientific research and should devote our energies instead to fundraising to pay the real scientists to do the research.

Of course we need more funds for research, but that doesn't preclude patient involvement in discussing and participating in research too. Lots of patients are scientists too, and a forum like this is a space where those able to can learn from each other and we hope get more active scientists involved in the discussion too. The aim is mutual learning that can lead to better science.

In my case I'm too old and sick to return to employment and contribute directly, but I am still learning and see when some research and the treatments based on that research are flawed. Without that nome of the work to get PACE data reanalysis, and critiques of the Cochrane exercise review would not have happened.

Given the poor quality of much research, especially in the psychobehavioural and alternative medicine fields, if we don't take action more pwME will be harmed.

Also we need pwME to take an active part in helping to run research. It’s important to have pwME with a good understanding of how good research works and a lot about ME beyond their own personal experience so their contribution as part of the research team has real value.

Look at the contrast between the excellent scientist/patients collaboration in the DecodeME project, and the mess that the NIH made of the intramural study and their defensive reaction when pwME tell them their effort preference nonsense is wrong. If they had had expert patients involved as equals in the design of the study, how much better it could have been.

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!

 

[Deanne NZ]

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.

 

[Kitty]

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.

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.

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.

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.

 

[butter.]

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.

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.

 

[butter.]

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.

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.

 

[forestglip]

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.

 

[butter.]

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.

 

[Eleanor]

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.

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.

 

[Yann04]

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.

 

[Kitty]

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.

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.

 

[poetinsf]

I felt like writing about this.

In my opinion ME/CFS is probably a label for several different poorly understood illnesses that happen to share some characteristics and which do not yet have their own name. We might call them subtypes of ME/CFS. Then, in a ME/CFS cohort there is probably also a significant percentage of patients whose primary illness was erroneously diagnosed as ME/CFS. These could be unusual presentations of common illnesses with some similarity to ME/CFS like multiple sclerosis, or adult-onset forms of rare diseases like primary mitochondrial disorders or muscle diseases that are often difficult to diagnose.

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.

 

[Trish]

This forum is a great place for such people to ask questions, but we lack the incentives to lure them in.

Do you mean financial incentives? I'm not sure what you are saying here. If we all worked on fundraising for research instead of using our energy to discuss research here, who would be here to discuss the research with the scientists when they get the funds and come to find us?

I see part of the role of the forum as educational, so those pwME and carers who have the capacity to work directly with researchers are better informed and able to be useful. I hope more researchers will join the forum. Any ideas for enticing them?

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.

I agree. I think it's a matter of each person doing whatever they feel most able to do. The ME organisations have members who are keen on fundraising and run all sorts of imaginative tea parties and sponsored walks and other fundraisers. That's not something I have any capacity, expertise or interest in doing personally, but I'm grateful for their efforts.

 

[wigglethemouse]

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/

The analytical tool will be developed using pre-existing UK Biobank gene and metabolism data from over 1000 self- reported ME/CFS patients. Findings from this data will then be validated on gene and metabolism data we produce ourselves from blood received from 300 ME/CFS patients recruited by the Australian ME/CFS Biobank.

@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/

Tetrahydrobiopterin (BH4) is a vitamin-like cofactor that is made in the body by a series of enzymatic steps. However, there are common mutations in the biosynthesis pathway that are associated with cofactor deficiency. BH4 is needed for metabolism of a small number of amino acids that are precursors to neurotransmitters, and deficiency leads to cognitive impairment and a wide variety of other symptoms associated with neurotransmitter imbalance. BH4 is also needed for the enzyme nitric oxide synthase, which is a major regulator of blood flow dynamics and immune cell function.

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
Transcript :

last study is our whole genome sequencing for mecfs this is being run by Liz worthy and camil Burch and it's funded by solve me and uh this one is using this really cool genome sequencing approach that for mecfs it basically will tell you what genetic variants you have that are most likely to be driving your chronic fatigue or whatever your primary symptom is and we finished the first project that is about to be sent out for peer review uh so I'm not going to talk about any of the results right now but I'm assuming by the end of this year it'll be published and I can tell you all about that as well ultimately I hope this is something where everyone who has mysterious pain or fatigue or cognitive issues can have this sequencing done and identify what's probably causing it.

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

 

[Andy]

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