Speculations about the genetics of ME/CFS and DecodeME

[Snow Leopard]

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.

Einstein's early work was all based on reinterpretations of the empirical work of others.

He was inspired by Hilbert's approach (in mathematics) to re-frame all of the important theoretical findings in physics and, well, succeeded in doing something similar...

The key point was 'standing on the shoulders of giants', something that most of the LongCOVID researchers failed to do, when they made their NIH cash grab. It's all new they said. If only they took the time to learn that it was not.

If you had $100M to spend on ME/CFS research what would you actually do with it

I am not the only one, but I have quite a list of research proposal ideas (and some idea of what techniques to use) across the spectrum, from mathematical modelling, to neuroscience, to exercise physiology, to qualitative research.

Such as theoretical modelling of the relationship between muscular blood flow and motor unit recruitment and fatigubility (and their relationship with the anaerobic threshold), further examining the neuroscience of afferent feedback from muscles and using specific new techniques in neuroscience, validating some alternatives (EEG, EMG, TMS) to maximal cardiopulmonary tests in demonstrating 2-day fatigubility and also providing an objective basis for which we could test pharmacological interventions.

I think the emphasis should be on trying to build the dart board first, rather than just throwing darts and hoping for the best.

Oh and a robust way of developing new composite (PROMs & objective measures) outcome measures that starts with qualitative research, with active participation of patients to see what doesn't work in prior scales, to see what most relevant, to develop a scale and then go back to the qualitative stage in the context of a clinical trial to ask patients whether the questions are relevant and how easily they think the scale (and other prior scales) could be biased. Doing online surveys alone is not good enough.

Rather than going oh, CFS is defined by fatigue, let's throw an bunch of 'fatigy' questions together (if anyone asks, we'll say they were generated by various experts), performing some correlation statistics (without understanding that social context biases can create false correlation) to make sure there are no odd-one-out questions, giving it to 100 consecutive attenders to a general practice and then pretending it's reliable and valid in different contexts, such as the primary outcome in clinical trials. And pretending it will have good face validity because a similar scale made by a friend was tested for face validty in a different study. She'll be right mate, I'm sure patients will love it.

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.

Neither will researchers if they keep kicking the can down the road rather than actually doing ground breaking work. There are a few diamonds in the rough, but there aren't enough people to cause a critical mass. This is why they need to be open to patient-researchers to keep them on their toes, always asking 'can you do better'.

 

[butter.]

Einstein's early work was all based on reinterpretations of the empirical work of others.

He was inspired by Hilbert's approach (in mathematics) to re-frame all of the important theoretical findings in physics and, well, succeeded in doing something similar...

The key point was 'standing on the shoulders of giants', something that most of the LongCOVID researchers failed to do, when they made their NIH cash grab. It's all new they said. If only they took the time to learn that it was not.




I am not the only one, but I have quite a list of research proposal ideas (and some idea of what techniques to use) across the spectrum, from mathematical modelling, to neuroscience, to exercise physiology, to qualitative research.

Such as theoretical modelling of the relationship between muscular blood flow and motor unit recruitment and fatigubility (and their relationship with the anaerobic threshold), further examining the neuroscience of afferent feedback from muscles and using specific new techniques in neuroscience, validating some alternatives (EEG, EMG, TMS) to maximal cardiopulmonary tests in demonstrating 2-day fatigubility and also providing an objective basis for which we could test pharmacological interventions.

I think the emphasis should be on trying to build the dart board first, rather than just throwing darts and hoping for the best.

Oh and a robust way of developing new composite (PROMs & objective measures) outcome measures that starts with qualitative research, with active participation of patients to see what doesn't work in prior scales, to see what most relevant, to develop a scale and then go back to the qualitative stage in the context of a clinical trial to ask patients whether the questions are relevant and how easily they think the scale (and other prior scales) could be biased. Doing online surveys alone is not good enough.

Rather than going oh, CFS is defined by fatigue, let's throw an bunch of 'fatigy' questions together (if anyone asks, we'll say they were generated by various experts), performing some correlation statistics (without understanding that social context biases can create false correlation) to make sure there are no odd-one-out questions, giving it to 100 consecutive attenders to a general practice and then pretending it's reliable and valid in different contexts, such as the primary outcome in clinical trials. And pretending it will have good face validity because a similar scale made by a friend was tested for face validty in a different study. She'll be right mate, I'm sure patients will love it.



Neither will researchers if they keep kicking the can down the road rather than actually doing ground breaking work. There are a few diamonds in the rough, but there aren't enough people to cause a critical mass. This is why they need to be open to patient-researchers to keep them on their toes, always asking 'can you do better'.

It's not about 'patient vs non patient researchers' though, Snowy, it's about 'knowing vs not knowing' and 'having the energy to implement that knowing vs having no or very little energy to implement that knowing.'

Arguing about and criticising research after the fact is obviously not 'wrong' but it's not very productive, very few researchers will care about that unfortunately (especially the bad ones!), and there will always be more bad research as a result. It's better to find more rough diamonds than trying to be an alchemist turning mud into gold. I think that's generally true, but it's extremely important for the ME/CFS community given the overall constraints (in money and energy) we face.

 

[FMMM1]

I recommended two things, both of which have been implemented, with the funder contributing millions to one of them

Evidently "one of them" was DecodeME - I'm wondering what the other was?

 

[V.R.T.]

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.

I do agree with a lot of what you say and I sympathise with your concern about safety for trial participants. And I'm sorry to hear about the patients that died.

As you say, drugs are toxic and can have adverse effects. But the adverse effects of leaving people to rot when there are things that could be trialled now must be considered too. I'm not going to lecture you on what it's like to be at the mercy of a hostile medical/benefits system etc because I'm sure you're aware.
But in my opinion that, and the nature of PEM, make this a much more urgent issue and tilt the risk/benefit axis somewhat.

If some of these long covid drugs have a positive signal in phase 2 against PEM/ fatigue, surely you would support an ME trial? Or if the drug the Norwegians are doing a pilot study on shows promise, for example?

And stuff like LDN and Mestinon needs to be properly tried, because people are using them anyway. But the OMF are doing that so perhaps a moot point.

In terms of the interesting papers you mention, surely if these findings might be worth pursuing then they are worth pursuing, because how else can they be verified or proven false? We have a lot of interesting studies in ME/CFS that no one has tried to replicate because of funding issues.

Could a drug to order really be made available so quickly? I was under the impression a new drug would take at least a decade to progresss through trials and reach patients. And that new drugs fail all the time. If what you say is true there is more hope than I thought.

 

[Jonathan Edwards]

In terms of the interesting papers you mention, surely if these findings might be worth pursuing then they are worth pursuing, because how else can they be verified or proven false? We have a lot of interesting studies in ME/CFS that no one has tried to replicate because of funding issues.

Yes, I am not wanting to argue that there is nothing worth doing. There are some things to follow up but the people concerned are likely to be doing that I=f they really believe their own results.

My main point was simply that I don't think forum members should be criticised of responding their time discussing science rather than raising funds. My guess is that if raising big funds for ME/CFS was really a practical option someone would have succeeded by now. And certainly not many people have any idea how todo it. On the other hand I see the discussions as hugely productive. People see different sides to an issue when they have to justify their position in debate.

Certainly for me, the discussions here are absolutely essential to the knowledge I have gained which I feed back in terms of reviewing the grant applications that do come through.

If some of these long covid drugs have a positive signal in phase 2 against PEM/ fatigue, surely you would support an ME trial? Or if the drug the Norwegians are doing a pilot study on shows promise, for example?

If anything gives a reliable positive signal then yes, but I am not very optimistic that anything being studied so far is going to provide a major breakthrough.

 

[V.R.T.]

My main point was simply that I don't think forum members should be criticised of responding their time discussing science rather than raising funds.

Certainly for me, the discussions here are absolutely essential to the knowledge I have gained which I feed back in terms of reviewing the grant applications that do come through.

We are in agreement there!

 

[Kitty]

But the adverse effects of leaving people to rot when there are things that could be trialled now must be considered too ... But in my opinion that, and the nature of PEM, make this a much more urgent issue and tilt the risk/benefit axis somewhat.

The axis may be tilted for some of us, but it has to be for the doctors and the ethics board too.

They see people with a puzzling but potentially reversible condition, who are (apart from ME/CFS) fairly healthy. It must be difficult to justify use of a risky drug whose benefits are uncertain even when the misery of living with ME is taken into account. Looking a year or two ahead, it's far more likely that we'll have a treatment for ME than one for organ damage caused by a cascade of adverse drug effects.

[Edited last sentence word order]

 

[V.R.T.]

The axis may be tilted for some of us, but it has to be for the doctors and the ethics board too.

They see people with a puzzling but potentially reversible condition, who are (apart from ME/CFS) fairly healthy. It must be difficult to justify use of a risky drug whose benefits are uncertain even when the misery of living with ME is taken into account. Looking a or two year ahead, it's far more likely that we'll have a treatment for ME than one for organ damage caused by a cascade of adverse drug effects.

I understand. I am certainly not advocating for gung ho administration of anything and everything.

I am afraid im out of spoons so cant reply further

 

[Amw66]

Einstein's early work was all based on reinterpretations of the empirical work of others.

He was inspired by Hilbert's approach (in mathematics) to re-frame all of the important theoretical findings in physics and, well, succeeded in doing something similar...

The key point was 'standing on the shoulders of giants', something that most of the LongCOVID researchers failed to do, when they made their NIH cash grab. It's all new they said. If only they took the time to learn that it was not.




I am not the only one, but I have quite a list of research proposal ideas (and some idea of what techniques to use) across the spectrum, from mathematical modelling, to neuroscience, to exercise physiology, to qualitative research.

Such as theoretical modelling of the relationship between muscular blood flow and motor unit recruitment and fatigubility (and their relationship with the anaerobic threshold), further examining the neuroscience of afferent feedback from muscles and using specific new techniques in neuroscience, validating some alternatives (EEG, EMG, TMS) to maximal cardiopulmonary tests in demonstrating 2-day fatigubility and also providing an objective basis for which we could test pharmacological interventions.

I think the emphasis should be on trying to build the dart board first, rather than just throwing darts and hoping for the best.

Oh and a robust way of developing new composite (PROMs & objective measures) outcome measures that starts with qualitative research, with active participation of patients to see what doesn't work in prior scales, to see what most relevant, to develop a scale and then go back to the qualitative stage in the context of a clinical trial to ask patients whether the questions are relevant and how easily they think the scale (and other prior scales) could be biased. Doing online surveys alone is not good enough.

Rather than going oh, CFS is defined by fatigue, let's throw an bunch of 'fatigy' questions together (if anyone asks, we'll say they were generated by various experts), performing some correlation statistics (without understanding that social context biases can create false correlation) to make sure there are no odd-one-out questions, giving it to 100 consecutive attenders to a general practice and then pretending it's reliable and valid in different contexts, such as the primary outcome in clinical trials. And pretending it will have good face validity because a similar scale made by a friend was tested for face validty in a different study. She'll be right mate, I'm sure patients will love it.



Neither will researchers if they keep kicking the can down the road rather than actually doing ground breaking work. There are a few diamonds in the rough, but there aren't enough people to cause a critical mass. This is why they need to be open to patient-researchers to keep them on their toes, always asking 'can you do better'.

So much this . Thanks for putting it so eloquently

 

[Sid]

It worked, but during the process of testing it a few people died.

Of infection?

 

[Jonathan Edwards]

Of infection?

Probably more of sterile pneumonitis. I am not sue this has ever been adequately sorted out. Cell depleting monoclonals can produce serious acute events.

 

[FMMM1]

Re the 100 Million, it's entirely possible to get that kind of money working in less than 24 - 36 months

Karl Morten attempted (crowdfund) to raise money to fund ME/CFS research but didn't succeed.

 

[FMMM1]

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.

Thanks - interesting insight.
@ME/CFS Skeptic

 

[V.R.T.]

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'd like to ask you a little bit more about this if you dont mind: Could a drug to order really be made available so quickly? I was under the impression a new drug would take at least a decade to progresss through trials and reach patients. Do you have a reasonable best case scenario for how a good result from Decode ME might play out?

 

[Jonathan Edwards]

I'd like to ask you a little bit more about this if you dont mind: Could a drug to order really be made available so quickly? I was under the impression a new drug would take at least a decade to progresss through trials and reach patients. Do you have a reasonable best case scenario for how a good result from Decode ME might play out?

The very best thing would be that DecodeME would find a link to some very obscure but crucial control protein - let us say TWEAK (it exists). Suddenly we would realise that ME/CFS might be mediated by short range interaction between TWEAK and gamma-interferon sensitising nerve endings. The task is then to produce a specific TWEAK antagonist that competed for the interferon binding site. Setting up assays for competitive inhibition of binding might take 3-6 months I guess - assuming that either a drug company or a TWEAK biology lab had the wherewithal to get going as soon as the paper is read. I don't know how long it would take to synthesise candidate small molecular mass inhibitors (simple drugs) but I think these days much of that is streamlined. The task would be similar to the generation of protease inhibitors for AIDS, which was quite quick once the target was known. If the choice was to make a monoclonal antibody to do the job you just clone out antibodies with high binding, make some cDNA and go into production. I may be oversimplifying but the biotech people do all sorts of things very quickly these days.

To make the scenario even better we could make it that it was realised that this TWEAK pathway was a key factor in 'malaise' associated with all sorts of illnesses and post-surgery and whatever and looked a really good target for a drug with wide applicability. Lots of research groups would get on to it and just like the Covid vaccines you would have a product made by several in no time at all (under 2 years). Roll-out to clinical use, if the drug was really effective, could be six months, with two phase 3 trials in parallel and accelerated approval.

That is optimistic, but the main point is that once the companies have seen something as profitable they can get it through to the clinic pretty quick. There might even be repurposable monoclonals - similar to rituixmab - but which actually work.

 

[V.R.T.]

The very best thing would be that DecodeME would find a link to some very obscure but crucial control protein - let us say TWEAK (it exists). Suddenly we would realise that ME/CFS might be mediated by short range interaction between TWEAK and gamma-interferon sensitising nerve endings. The task is then to produce a specific TWEAK antagonist that competed for the interferon binding site. Setting up assays for competitive inhibition of binding might take 3-6 months I guess - assuming that either a drug company or a TWEAK biology lab had the wherewithal to get going as soon as the paper is read. I don't know how long it would take to synthesise candidate small molecular mass inhibitors (simple drugs) but I think these days much of that is streamlined. The task would be similar to the generation of protease inhibitors for AIDS, which was quite quick once the target was known. If the choice was to make a monoclonal antibody to do the job you just clone out antibodies with high binding, make some cDNA and go into production. I may be oversimplifying but the biotech people do all sorts of things very quickly these days.

To make the scenario even better we could make it that it was realised that this TWEAK pathway was a key factor in 'malaise' associated with all sorts of illnesses and post-surgery and whatever and looked a really good target for a drug with wide applicability. Lots of research groups would get on to it and just like the Covid vaccines you would have a product made by several in no time at all (under 2 years). Roll-out to clinical use, if the drug was really effective, could be six months, with two phase 3 trials in parallel and accelerated approval.

That is optimistic, but the main point is that once the companies have seen something as profitable they can get it through to the clinic pretty quick. There might even be repurposable monoclonals - similar to rituixmab - but which actually work.

Thanks, that's very clear. Fingers and toes crossed then I suppose!

 

[MelbME]

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
Transcript :

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

Definitely interested in looking at the Decode data. Have a few things we're interested in.

Sneaky value of this type of resource is providing data for short projects to get masters students interested in this research area to perhaps do a PhD.

 

[MelbME]

I think a focus on understanding PEM is the best funding direction.

I think you need to know when patients are close to it. Knowing that accurately would be a key test to timing different intervention strategies. It's critical.

Detailed analysis of patients going through it and recovering back up close to baseline. Many different ways this could be done.

 

[Yann04]

I think a focus on understanding PEM is the best funding direction.

I think you need to know when patients are close to it. Knowing that accurately would be a key test to timing different intervention strategies. It's critical.

Detailed analysis of patients going through it and recovering back up close to baseline. Many different ways this could be done.

That’s been my intuition too. PEM is a major disease process and mechanism in itself. It is what makes ME stand out as a different clinical entity. I really think the large majority of research funding should go into understanding it.

 

[Kitty]

I think you need to know when patients are close to it. Knowing that accurately would be a key test to timing different intervention strategies. It's critical.

This isn't really the right place for this, but as I always forget when it is the right moment, here goes!

It's worth bearing in mind that food can have an impact on the likelihood and severity of PEM in some of us. And if research participants need to travel or stay away from home to take part, or will need lunch because it's a full day in clinic, they're likely to vary their eating routines.

It might not even be relevant in the type of work you hope to do, but maybe it's worth adding to the list of questions to ask at the planning stage: do we need to encourage participants to eat their usual food at the usual time, and try to make sure it's feasible for them?