Speculations about the genetics of ME/CFS and DecodeME

butter. said:
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.
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PD patients tend to be older adults who lived full lives prior to being struck down by a well-accepted neurodegenerative disease. Lack of stigma and impending death means there’s little incentive to waste precious remaining life years on futile discussions about biology. ME strikes people in the prime of life with peak onsets being teenage years and another around 30. With 50-60 years left of life, it’s hard to not show any intellectual curiosity about the thing that’s keeping you bed/house/wheelchair bound for that long.
 
butter. said:
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.
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I just think you have got this wrong @butter.

As I have mentioned before, not so very long ago, I, together with two other 'international experts' was approached by the biggest research funder in the UK. We were effectively asked 'if you had as much money as you like what would you suggest we fund'. The three experts had trouble agreeing on anything worth funding but I recommended two things, both of which have been implemented, with the funder contributing millions to one of them.

Why was I asked, as an 'International expert'? Because through the grapevine I am known as someone who is involved in discussing ME/CFS research strategy on a website called S4ME. No other reason. I think you greatly underestimate the power of this organisation. It has made major contributions to steering research behind the scenes for years now. We are still struggling to find the lead that opens the box but that is not because we are not going about it the right way. Many of the people on the forum who make huge contributions are so modest you wouldn't even notice who they are and they wouldn't want to be named. But they have moved mountains.

People of high intelligence, high integrity and high energy are by and large not very bothered about money. It is boring. It is essential to the solving of technological problems in science but has pretty little to do with our current problem - one of identifying what would be worth studying.
 
Jonathan Edwards said:
I just think you have got this wrong @butter.

As I have mentioned before, not so very long ago, I, together with two other 'international experts' was approached by the biggest research funder in the UK. We were effectively asked 'if you had as much money as you like what would you suggest we fund'. The three experts had trouble agreeing on anything worth funding but I recommended two things, both of which have been implemented, with the funder contributing millions to one of them.

Why was I asked, as an 'International expert'? Because through the grapevine I am known as someone who is involved in discussing ME/CFS research strategy on a website called S4ME. No other reason. I think you greatly underestimate the power of this organisation. It has made major contributions to steering research behind the scenes for years now. We are still struggling to find the lead that opens the box but that is not because we are not going about it the right way. Many of the people on the forum who make huge contributions are so modest you wouldn't even notice who they are and they wouldn't want to be named. But they have moved mountains.

People of high intelligence, high integrity and high energy are by and large not very bothered about money. It is boring. It is essential to the solving of technological problems in science but has pretty little to do with our current problem - one of identifying what would be worth studying.
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Yes, let us disagree on this. I do not agree with anything you say, other than that I am sure there are great and good people on this board. I lack the energy to unpack it point for point and I doubt it would change much.

In one sentence, though: ME/CFS patients' future is entirely up to one thing: cash. I am not sure how anyone could think otherwise, it's absurd!

Cash is equivalent to more people with more energy trying to find leads, Dr. Edwards. People needing cash, is not somehow a bad thing, the right kind of people, with the rind kind of attributes, need it like anyone else, to work on the issue, whether the issue is 'technological' or not. I think you also missed that I said such people 'need' and not necessarily 'want money for themselves' (which is true for some, by the way!).

The idea that you and the 'experts on this board' crack this disease, is a nice mission statement, but statistically unlikely, especially given the constraints in cash and energy being so prevalent. The main reason for why you have been approached, next to your considerable knowledge, intelligence and experience is that there is almost no one else to ask! Why is that? Let me guess, because there are no leads?

The reason you can work on this forum is that you are in a situation financially and in your life where you can do it as a hobby! Someone always has to pay the tap! If you are 36 and have two children and have no other reason to do it, how likely would you be doing this and why are not hundreds of other people 'like you' are doing it right now? There is no ceiling on how much Dr. Edwards (plural) you want to have thinking about solutions and leads for ME/CFS as an ME/CFS patient. This is not an issue of 'why is S4ME so bad' but rather 'why is it not ten times bigger and more useful'.

In broad terms, there a different modes of knowledge acquisition, and we could have a long discussion about this; on a fundamental level though there is always a skill vs luck sliding scale involved and no matter where you are on this, more cash will almost always increase your chances to get answers.

It got quite long now, need to log off, but one more thing: Patients should NOT be required to move mountains, Dr. Edwards, and if they try they should do so in domains where they have the best chances to make a difference, while also not hurting themselves!
 
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Sid said:
PD patients tend to be older adults who lived full lives prior to being struck down by a well-accepted neurodegenerative disease. Lack of stigma and impending death means there’s little incentive to waste precious remaining life years on futile discussions about biology. ME strikes people in the prime of life with peak onsets being teenage years and another around 30. With 50-60 years left of life, it’s hard to not show any intellectual curiosity about the thing that’s keeping you bed/house/wheelchair bound for that long.
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You missed the point, it's not that you can't be interested or somehow should not, it's just very likely, largely unproductive in terms of outcome measures.
 
This discussion makes me think of the billion dollars the NIH was given by the US government to research Long Covid, which as I understand it is largely used up with precious little to show for it. Of course we can all agree that money is necessary, but larger amounts of money don't necessarily produce better results.

butter. said:
The idea that you and the 'experts on this board' crack this disease, is a nice mission statement, but statistically unlikely, especially given the constraints in cash and energy being so prevalent.
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I don't think anyone has claimed that this forum will be the place where ME/CFS is cracked. But there are people participating on the forum who have undoubtedly influenced research and I hope will continue to do so. Some are actively involved in running research, others like Jonathan Edwards play other essential roles in influencing good research happening. We can all help to improve some research when the researchers choose to join the forum, tell us about their research, and learn more from us about ME/CFS from patients' perspective. Of course it's not enough, but we're a small corner of the internet run by sick people.
 
butter. said:
In one sentence, though: ME/CFS patients' future is entirely up to one thing: cash. I am not sure how anyone could think otherwise, it's absurd!
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The history of science is against you though. Einstein produced the theory of relativity and the basis for quantum theory as well, while an impecunious clerk with no practical science job when grand physics institutions were getting nowhere.

And I said. The money is there - on offer. It is just that at the moment nobody can think of how to use it. You decide to give $8M dollars to NIH and they produce a complete dud.

If you had $100M to spend on ME/CFS research what would you actually do with it - what would anybody do with it? For the last two years I have sat on a UK government working party that has tried to drive forward research in ME/CFS. Nobody has any suggestions - and that nobody includes a dozen or so major scientists. Nothing was put forward beyond maybe doing a trial of low dose naltrexone. A big genetics study was a good idea driven by people associated with this forum. Hopefully it will give us clues. But pouring money into 'attracting the right people' seems to me unreal. The wrong people are always ready and waiting to jump the queue.
 
forestglip said:
Isn't there an issue of scientists avoiding even entering the field because of lack of research funds? Where they don't want to devote their life to something where every grant will be rejected?
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Not that I am aware of. Good scientists nearly always get their grants rejected anyway - in any field. You learn to get money in for irrelevant projects that sound good and then work on what is important. Pretty much all my applications were rejected. We made progress in RA on the side.

For a problem like ME/CFS you have to start with medical academics having some understanding of what the illness is actually like. The real problem I see is that ME/CFS has no clinical service base that would allow medics to learn what it is they want to study. Scientists only get involved when asked by a medic to solve a clinical problem with lab work. If nobody knows where to start then the scientists are not going to see the point.

If I was rational I wouldn't devote my career to ME/CFS if I was starting out as an academic aged 35 simply because it looks too difficult to expect to get anywhere. People aren't that rational and I decided to devote my career to RA simply because it fascinated me. I do not claim to have had any great altruistic intentions. Moreover, I had no idea of the difficulties I would face in getting anything done. But the powers that be thought it was worth giving me a starting salary to have a go - maybe because they could see I was fascinated and that seemed a good place to start.

There have been good clinicians who have got fascinated by ME/CFS - Melvin Ramsay, James Baraniuk, Derek Pheby ... but they have found it hard to get beyond a certain point because there is nothing to put under a microscope. The scientists don't even have anything to get interested in until you have that. Except that someone had the bright idea of trawling for genes - but nobody can think of any others at present.
 
Jonathan Edwards said:
The history of science is against you though. Einstein produced the theory of relativity and the basis for quantum theory as well, while an impecunious clerk with no practical science job when grand physics institutions were getting nowhere.

And I said. The money is there - on offer. It is just that at the moment nobody can think of how to use it. You decide to give $8M dollars to NIH and they produce a complete dud.

If you had $100M to spend on ME/CFS research what would you actually do with it - what would anybody do with it? For the last two years I have sat on a UK government working party that has tried to drive forward research in ME/CFS. Nobody has any suggestions - and that nobody includes a dozen or so major scientists. Nothing was put forward beyond maybe doing a trial of low dose naltrexone. A big genetics study was a good idea driven by people associated with this forum. Hopefully it will give us clues. But pouring money into 'attracting the right people' seems to me unreal. The wrong people are always ready and waiting to jump the queue.
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That's a bias re Einstein.

Re the 100 Million, it's entirely possible to get that kind of money working in less than 24 - 36 months, and that is exactly the point I am making, you have to flood the zone with calls to get ideas and leads flowing. Whether you or anyone else thinks they are 'worthy' leads is besides the point, partly because you don't/can't know. Disagreements are expected. I agree, that there will be a point where more funding will have diminishing returns, but we are not even close to that point.
 
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Jonathan Edwards said:
So why haven't you done it already?
I don't get this I am afraid.
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Well, that's a very unqualified statement, but, it's not very surprising, I have to say.

Where would I get 100 MIL (you came up with that figure) from as a very severe ME patient? The fact that I can't do it doesn't mean it can't be done.

The discussion is not very outcome oriented and you seem to be 'in the feels' quite easily, Dr. Edwards, so I will abstain from further comments on the matter.

PS:
I would be VERY interested in the modalities of the call(s) you were referring to by the way!

Thank you.
 
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butter. said:
Where would I get 100 MIL from as a very severe ME patient? The fact that I can't do it doesn't mean it can't be done.

The discussion is not very outcome oriented
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I think I understand where you're coming from, @butter. We all want lots of excellent research that will make real progress with understanding ME/CFS and lead to treatments as soon as possible. I feel the desperation and despair. I just wonder if you are aiming your criticism at the wrong target. Most of us here are like you, sick people unable to raise millions or do research. I think if you want to urge people to do more about fundraising for research, perhaps your comments are better addressed to organisations like ME Research UK, OMF and SolveME.
 
Since you ask, here are some examples of projects I would try and fund if I had the capital:

Replication studies on small but promsing ME and long covid papers. E.g. Wust muscle biopsies, complement system, Wirth muscle sodium, IgG mouse model. More than I'm too brainfogged to think of right now

Proper placebo controlled trials of LDN
Mestinon (I know omf are doing these so maybe a moot point)
Campath (since you have speculated on here that it might be helpful)
BC007 (if long covid phase 2 is positive)
Anything that is not a covid specific Antiviral that has a positive phase 2 long covid trial for fatigue.
Anti inflammatory drugs
Jak stat inhibitors
Darturamab if pilot study is positive
Rapamycin, ditto.
Antivirals e.g. valtrex etc.

Funding for Wirths mitocure project.

Funding people like karl morten properly so they are not forced to crowdfund.

I know that drug trials are a shot in the dark now but as was pointed out above, we are people whose lives have been utterly destroyed. I cannot put into words how deeply we are suffering. I hope that decode ME points the way but urgent action is needed to alleviate this suffering. Which might mean taking some big swings. We are a desperate, suffering population and we need a treatment yesterday. Currently our only options are suffer endlessly or try off label drugs prescribed by private doctors based on anecdata.


It is not merely an intellectual problem. Finding a treatment determines whether my parents spend the rest of their lives caring for me because I listened to my doctors over my gut. It is whether my friends with severe and very severe ME are ever able to prepare a meal for themselves or see their friends or go outside ever again. To say nothing of employment, independence, relationships, children, freedom from constant suffering. And never forget that for me and many others this intense suffering was needlessly imposed on us by your medical colleagues' BPS views.

I do find it a little concerning that with so much interesting research emerging that is badly in need of replication, you report that this committee is sitting around with absolutely no idea of what to do. None of this is perfect and of course decode is our biggest hope right now but that doesn't change the fact that there are plenty of projects that could be funded.
 
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V.R.T. said:
Since you ask, here are some examples of projects I would try and fund if I had the capital:

Replication studies on small but promsing ME and long covid papers. E.g. Wust muscle biopsies, complement system, Wirth muscle sodium, IgG mouse model. More than I'm too brainfogged to think of right now

Proper placebo controlled trials of LDN
Mestinon (I know omf are doing these so maybe a moot point)
Campath (since you have speculated on here that it might be helpful)
BC007 (if long covid phase 2 is positive)
Anything that is not a covid specific Antiviral that has a positive phase 2 long covid trial for fatigue.
Anti inflammatory drugs
Jak stat inhibitors
Darturamab if pilot study is positive
Rapamycin, ditto.
Antivirals e.g. valtrex etc.

Funding for Wirths mitocure project.

Funding people like karl morten properly so they are not forced to crowdfund.

I know that drug trials are a shot in the dark now but as was pointed out above, we are people whose lives have been utterly destroyed. I cannot put into words how deeply we are suffering. I hope that decode ME points the way but urgent action is needed to alleviate this suffering. Which might mean taking some big swings. We are a desperate, suffering population and we need a treatment yesterday. Currently our only options are suffer endlessly or try off label drugs prescribed by private doctors based on anecdata.


It is not merely an intellectual problem. Finding a treatment determines whether my parents spend the rest of their lives caring for me because I listened to my doctors over my gut. It is whether my friends with severe and very severe ME are ever able to prepare a meal for themselves or see their friends or go outside ever again. To say nothing of employment, independence, relationships, children, freedom from constant suffering. And never forget that for me and many others this intense suffering was needlessly imposed on us by your medical colleague's BPS views.

I do find it a little concerning that with so much interesting research emerging that is badly in need of replication, you report that this committee is sitting around with absolutely no idea of what to do. None of this is perfect and of course decode is our biggest hope right now but that doesn't change the fact that there are plenty of projects that could be funded.
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I would add the search for a viral reservoir. Labs like PolyBio have lots of ideas for studies, and more money would surely speed trials along, for example with the expensive equipment necessary for specialized scans.
 
V.R.T. said:
Finding a treatment determines whether...
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I realise that. But I say what I do having spent a career in developing treatments from basic animal lab work to actually making up the infusions for my patients. I was sufficiently committed to getting a result that meant something for patients to spend $15,000 of my own cash on buying a drug to give patients because not even the drug company wanted to pay for it. It worked, but during the process of testing it a few people died. On balance I think it was definitely worthwhile (as did the licensing bodies) but there was a very strong lead for thinking it would work (at least I thought so) and I don't see that of any drugs for ME/CFS at present. In that situation I would put the cost/benefit analysis as something like 9 points against to 1 point for. Drugs are toxic. Tens of thousands of people have died from using anti-inflammatory drugs we used to think were safe to hand out for trivial pains.

On the other hand making a drug to order now is so easy that I would be optimistic that once we have an idea what it is we want to put right a drug could be made available very quickly. I strongly suspect that there is some sort of signalling problem and signals are particularly easy targets. But we don't know what they are.

I have overgeneralised a bit. I have recently reviewed two grants for other European countries, one of which looked quite good and may well be funded. There are some things worth following, I agree. Complement might be, antibodies to flagellae might be, pathway analysis proteomics might be, amino acid metabolism might be. TGF beta might be. But the methodology has to be good enough to produce a solid answer and that has often not been the case.
 
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