Hypotheses and Research Directions for ME/CFS

[Dude]

If e.g. Daratumumab works for ME/CFS, then that study alone will be enough to tell us that something that Dara affects is involved. We don’t need all of the info, just enough.

Yes, that’s mostly the case in ME/CFS, and science in general. Not because science is useless, but because there are too many scientists doing useless stuff.

Not at all. By dissecting the individual pieces of evidence we get a much better understanding of where the solution might lie. And if the researchers had bothered with the discussions beforehand, they might have been able to design studies that could have provided meaningful data.

I think that by far the most important contribution by S4ME is that people are willing to assess the evidence and not get too caught up in hypotheses.

And I think there is a general misunderstanding among both laypeople and scientists about what science is. You’re supposed to propose a testable hypothesis, figure out what would confirm or refute it, and then gather the data. Far too many pick a hypothesis and go out only looking for data the confirms it, completely neglecting anything that disproves it.

So when someone says «the mitochondria are not producing enough energy», and someone else says that «if that was the case, you’d expect to see symptoms X and Y like in other diseases where the mitochondria are faulty, but you don’t see those in ME/CFS», you’ve already got good data against the hypothesis.

Or pointing out that if ME/CFS is neurodegenerative, then we’d expect to see the symptoms of Alzheimers, Parkinson’s etc., but we don’t. And people have gone from being severe to healthy, so whatever ME/CFS is, it’s probably reversible.

And you don’t have to be a scientist to ask those kinds of questions or make those observations.

That’s exactly my point. If Fluge and Mella had asked in this forum back then whether they should test this, many people here would probably have advised against it, saying the evidence was too weak.

The idea that we first need to finish all discussions and only then design studies is unrealistic. Especially in poorly understood diseases, good studies often come from competing and even incomplete hypotheses.
Without hypotheses, there is no meaningful data collection. Data are not neutral, they are always shaped by assumptions.

I never said that science is useless. What I meant is that, in discussions like these, hypotheses from well-known researchers are often dismissed simply because the existing studies don’t confirm them 100%. I think some hypotheses now have enough support to be tested properly. B-cell depletion is one example. The mitochondrial hypothesis is another.

What I’m trying to say is that we may need to let go of the idea that we must fully understand the disease before trying therapies. Instead, we should test solid hypotheses and see whether they lead to treatments. Otherwise, I honestly don’t see how we’ll get effective therapies anytime soon.

Remissions do not rule out a biological cause. Even autoimmune diseases can partially or completely go into remission.

Saying “you don’t need a scientific background” sounds appealing, but it’s risky. Intuition cannot replace methodological understanding, especially in highly complex biological systems.

Critical thinking means more than saying “this isn’t proven.” It also means knowing that a lack of clear signs doesn’t necessarily disprove an idea.

 

[Jonathan Edwards]

You should stick around @Dude and not be afraid to ask awkward questions and fight a corner. Lots of people here, as Utsikt has said, have no science background but make a big contribution to the discussion just by using their instincts and intelligence.

 

[Utsikt]

That’s exactly my point. If Fluge and Mella had asked in this forum back then whether they should test this, many people here would probably have advised against it, saying the evidence was too weak.

No, they would have asked for their reasoning for trying X, assessed the reasoning, and asked if there are alternative ways to get good data that is cheaper, faster and/or safer.

The idea that we first need to finish all discussions and only then design studies is unrealistic.

Nobody has claimed that. But if patients here manage to poke serious holes in a hypothesis in a matter of days, then there are serious questions that should be asked of the researchers. We’re not asking for perfection, but for the bare minimum.

What I meant is that, in discussions like these, hypotheses from well-known researchers are often dismissed simply because the existing studies don’t confirm them 100%.

No, that it not why they are dismissed. They are dismissed because there is good reason to think they are wrong. It’s possible to prove that something is wrong without knowing what the truth is. Like how I can know that adding two even numbers will always produce an even number, so any odd answer is wrong. I don’t have to know the numbers, just some properties.

What I’m trying to say is that we may need to let go of the idea that we must fully understand the disease before trying therapies. Instead, we should test solid hypotheses and see whether they lead to treatments. Otherwise, I honestly don’t see how we’ll get effective therapies anytime soon.

Nobody are claiming we need a full understanding first. Just that most people have a tendency to jump to treatments when you can get better answers sooner and cheaper with different methods.

Most people over-estimate the probability of stumbling upon a treatment, and severely under-estimate the probability of something being harmful. Experimenting willy nilly is a net negative game.

There is a long discussion about that here if you’ve got thoughts:

Post in thread 'List of diseases with a known mechanism but no cure/treatment'

Mar 30, 2025

Also I don’t think jay meant abandoning mechanistic work in favor of trialing treatments, just that treatment trials even without an established mechanism shouldn’t be discounted. I think that this path has about as much chance at getting us answers and progress as mechanistic studies

One objection to this approach is that we have a limited amount of resources and drug trials are expensive as heck.

• Utsikt

• 

Remissions do not rule out a biological cause. Even autoimmune diseases can partially or completely go into remission.

I said reversible, not non-biological. We’re in agreement here.

Saying “you don’t need a scientific background” sounds appealing, but it’s risky. Intuition cannot replace methodological understanding, especially in highly complex biological systems.

I didn’t say in general. I said for the kinds of questions I gave examples of, questions that scientists somehow don’t seem to consider that often even though they are very basic.

Critical thinking means more than saying “this isn’t proven.” It also means knowing that a lack of clear signs doesn’t necessarily disprove an idea.

Nobody here are claiming that. They’re claiming that the presence of clear negative signs probably disproves the idea.

 

[Kitty]

Maybe Kitty s referring to making sure we are trying to explain the right thing - is a proposed thing-to-explain real or misidentified?

Yessss...both the research and patient communities have wasted a lot of time trying to explain things without asking if they're really there.

Look at the PEM factsheet threads. We discovered we thought we were talking about the same things, but often we weren't. Thinking we had a thing to define when we didn't, not really. It was repetitive and wearying and took far too long, but it's essential and not enough of it happens. Being sure you know nothing is an achievement.

I don’t think it’s necessarily an uncommon skill

I might take issue with that slightly. I worked in the performing arts, and saw how knowledge and experience and training and ego and expectation and reputation all got in the way of the truth. I think it could be the case in science too. It strikes me that people are allowed something of an open mind as undergraduates, but after that many don't get to ask really stupid questions like "What is wet?" again. They're stuck in a machine that doesn't allow it, and tend to lose the will or the ability.

 

[jnmaciuch]

I might take issue with that slightly. I worked in the performing arts, and saw how knowledge and experience and training and ego and expectation and reputation all got in the way of the truth. I think it could be the case in science too. It strikes me that people are allowed something of an open mind as undergraduates, but after that many don't get to ask really stupid questions like "What is wet?" again. They're stuck in a machine that doesn't allow it, and tend to lose the will or the ability.

Sure, I can see that to an extent. But just as often as I see that attitude, I see tons of examples of the opposite. Every time I’m in a meeting with multiple PIs at least half the time is spent on questions of “are we sure X means Y? Have we checked Z? What are we missing here?”

Just a few weeks ago I was at a meeting where we were talking about several examples of drugs that ended up working even though parts of the underlying logic got disproven or the foundational research could not be replicated (and, sometimes, the replication to the replication showed that the original findings were real after all).

Is it good to be as meticulous as possible? Absolutely. But the reality of science is that we will be constantly overturning even the most basic interpretations we thought we could safely make.

Taking a leap of faith on a theory where parts of it probably won’t hold up is where all science starts by necessity—the good as well as the bad. It’s good to spend time hammering out details so the theorizing doesn't go completely off the deep end of plausibility, but the hammering-out-of-details tends not to actually move things forward without the leap-of-faith theorizing alongside it.

 

[Formerhuman]

There are several studies (with limitations) that point to altered hemodynamics in ME/CFS, particularly decreased ventricular filling pressure, decreased stroke volume, and decreased cerebral perfusion. These abnormalities can contribute to such symptoms as exercise intolerance, brain fog, dyspnea, and orthostatic intolerance. Therefore, I would be glad to see more studies with invasive and noninvasive measurements of orthostatic and exercise hemodynamics.

 

[Jonathan Edwards]

but the hammering-out-of-details tends not to actually move things forward without the leap-of-faith theorizing alongside it.

I agree with Kitty here. It is not an issue of hammering out details. It is an issue of completely misunderstanding what you think you are trying to explain. The obvious example for me is the behaviour of complement. Everyone thought that complement was inflammatory but we already had evidence in the 1980s that it was also anti-inflammatory. It depended on whether you were inside or outside blood vessels. I could not get any immune complex experts to explain why lupus was different from rheumatoid. But it was staring them in the face. I moved forward because I realised Henry Kunkel, despite all his brilliance, had made a very simple mistake in trying to explain RA.

The same happened to me when studying synovial fluid dynamics. The books talked about rates of net flux of fluid into the synovial space across the synovial membrane and deduced rates of clearance out of the joint. What was staring them in the face is that the way in to the joint and the way out are the same - the synovial membrane. So the net flux is zero by definition. Once you get that sorted out you can explain why hyaluronic acid provides a perfect passive homeostatic mechanism for fluid volume involving a very specialised phenomenon known as solute polarisation.

And much the same applied to understanding why metalloproteinase inhibitors do nothing in RA - despite Roche having spent many millions on the premise that they would, using an animal model system I had developed ten years earlier that I told them would produce an artifectual result! The irony being that at the same time they refused to try their rituximab for RA because they knew that the rheumatoid factor antibodies were just an epiphenomenon because Av Mitchison had said so.

Getting your basic ideas straight to a first approximation is what matters and people completely fail to do that most of the time.

 

[Jonathan Edwards]

There are several studies (with limitations) that point to altered hemodynamics in ME/CFS, particularly decreased ventricular filling pressure, decreased stroke volume, and decreased cerebral perfusion. These abnormalities can contribute to such symptoms as exercise intolerance, brain fog, dyspnea, and orthostatic intolerance.

Decreased ventricular filling pressure might reduce exercise capacity and you might call that exercise intolerance but in ME/CFS the exercise intolerance of interest is PEM, which is feeling terrible much later. If the problem with ME/CFS was just feeling a bit feeble on an exercise bike nobody would be too bothered.

In well recognised situations with decreased cardiac output - old fashioned heart failure - you get problems with standing up and you get dyspnoea but not brain fog much and the patterns of symptoms don't look much like ME/CFS. Exercise physiologists like to make all these things add up but as a clinician who has looked after extreme cases of haemodynamic failure I find it hard to see how these accounts actually work for ME/CFS. There has also been a lot of confusion over 'POTS'.

People will always tend to find what they think they should be fining.

 

[Sean]

in ME/CFS the exercise intolerance of interest is PEM, which is feeling terrible much later.

Any hypothesis must explain the delayed component of PEM. It is a distinct and core feature, and the main clue, I think.

It is not fatigue, tiredness, deconditioning, DOMS, etc. It is something different to all those.

 

[Formerhuman]

In well recognised situations with decreased cardiac output - old fashioned heart failure - you get problems with standing up and you get dyspnoea but not brain fog much and the patterns of symptoms don't look much like ME/CFS.

I believe in well recognised conditions with persistently decreased CO such as heart failure or aortic valve stenosis quite a few people experience cognitive decline.

Well, people with heart failure probably don't have PEM. Nevertheless, some people with ME/CFS report that HR control help them to avoid PEM. Yes, definition of POTS is problematic but before COVID my upright heart rate was usually around 60–70 bpm. During acute COVID something changed and since then it’s been more like 100–150 bpm. The more time I spend with my heart rate around 150, the more likely I am to get PEM.

I don’t think studying hemodynamics in ME/CFS should be stopped. Besides orthostatic and exercise intolerance there might be some hints to PEM. If not, it would be great to have at least some objective diagnostic tests to prove disability which is of great importance for many.

 

[Jonathan Edwards]

I believe in well recognised conditions with persistently decreased CO such as heart failure or aortic valve stenosis quite a few people experience cognitive decline.

We all experience cognitive decline with time. I don't think there is much evidence for cardiac failure or aortic stenosis affecting thinking to be honest. People with cardiac failure often have problems with multiple organs for some other common causal reason.

I don’t think studying hemodynamics in ME/CFS should be stopped.

I am not suggesting that. But we need studies with systematic recruitment and blinding of controls to avoid bias and what I have seen so far is pretty hard to interpret in that context.

During acute COVID something changed and since then it’s been more like 100–150 bpm.

There is no doubt that both post-Covid and in ME/CFS people get tachycardia but the question is where that fits into a causal mechanism. I don't think we have much idea at present. Presumably there are changes in autonomic drive but that occurs in almost any situation of being ill. We want to have some idea what is behind it in this case.

 

[Utsikt]

Is it good to be as meticulous as possible? Absolutely. But the reality of science is that we will be constantly overturning even the most basic interpretations we thought we could safely make.

Isn’t the problem that sometimes you think you’re overturning every stone, but you’re missing something?

I struggle to believe that scientists in general are regularly challenging every assumption when even I’m able to poke hole in lots of the studies that are published. Meaning that some of the flaws have to be fairly obvious because I don’t have any depth of knowledge at all in this field.

 

[jnmaciuch]

I struggle to believe that scientists in general are regularly challenging every assumption when even I’m able to poke hole in lots of the studies that are published. Meaning that some of the flaws have to be fairly obvious because I don’t have any depth of knowledge at all in this field.

No, certainly not claiming every scientist is perfect on this front—just that we can’t chalk up lack of productive science in certain domains to a complete failure to challenge assumptions once scientists get to a certain level of seniority. I think that trend, where it exists, does play a part. I even agree with @Jonathan Edwards about making sure that we’re not completely backwards in basic assumptions.

I guess I just see that as part and parcel with the leap-of-faith theorizing—realizing that a fundamental assumption might be wrong and exploring a different possibility of making the pieces fit. The latter part has to move alongside with the skeptical deconstruction to move things forward. Otherwise we end up somewhat paralyzed, since even the thing that didn’t replicate might still be replicated in a different circumstance (I’ve seen pretty consequential examples) and the thing we thought was repeatedly validated might still be disproven in another circumstance (I’ve seen pretty consequential examples).

I’ll leave it here, since I think we might be straying too far into hypotheticals and are saying the same thing to an extent. Mostly I’m just trying to make the point that theorizing is just as necessary as stringent skepticism

 

[Creekside]

I think it might help if we had more challenging and rating of assumptions. For example, I think far too much effort has been wasted on the assumption that we have Chronic Normal Fatigue. If we can't clearly differentiate between normal fatigue and ME's fatigue-like symptom, at least give "fatigue" and official rating as "we're not sure exactly what this symptom is, but it doesn't seem to be normal fatigue, so assume that it's not normal fatigue". I'm sure there are plenty of other examples involving PEM and various other symptoms.

Statistical information about how many people with ME (by the latest, best criteria) have certain symptoms would be helpful too.

 

[Madbeggar]

I think we probably can. It is a bit like saying the car goes slowly because there isn't enough petrol. If there isn't enough petrol the car stops, it doesn't go slowly.

I think a better analogy is that the petrol tank is full, but the petrol filter has become dirty, allowing only a trickle of petrol to get through. It's not an on/off situation - rather a reduced rate of flow.

Or, imagine that the injectors for each engine cylinder have their own filters - some of those filters may get dirty or even completely clogged up, allowing power production from some cylinders, but not so much from others.

Apply that idea to substrate (e.g., oxygen) trying to make its way to each cell in the body, where micro-capillaries act as filters to the RBCs that deliver it; misshaped or overly large ones might do that (in my mind, at least (and in both senses of that clause )). Some cells may have access to full flow, others only some or none.

As those vessels get plugged up, they eventually die and get replaced - along with the fossilized RBCs trapped within them. That process requires resources and creates waste products - including excess bilirubin (which has almost always been high in my blood tests). And it would require time. Could that help to explain PEM?

 

[Jonathan Edwards]

I think a better analogy is that the petrol tank is full, but the petrol filter has become dirty, allowing only a trickle of petrol to get through. It's not an on/off situation - rather a reduced rate of flow.

That was my point. You need an analogy that fits the system and makes sense in that system. The explanation you have a try at following the quoted bit simply isn't real biology. It may sound as if it is but pathologists are familiar with all the various bits of the story and they don't fit together like that.

 

[Madbeggar]

That was my point. You need an analogy that fits the system and makes sense in that system. The explanation you have a try at following the quoted bit simply isn't real biology. It may sound as if it is but pathologists are familiar with all the various bits of the story and they don't fit together like that.

I apologize for my unhinged speculation. I'm more of an idiot than pathologist.

Still... I'm going to belabor my wild pathologist-unsupported hypothesis a bit further.

I stopped recovering from excercize normally in about 1983. And developed a slew of other problems, which I later began calling ME.

In 1989, I first noticed regular "finger nail splinters" [subcuticular hemorrhages] on my hands. In a casual conversation, a cardiologist acquaintence noted that those are a symptom of a specific heart defect, which I clearly didn't have (because I was still active).

Still, if 1% of my fingernail revealed blocked capillaries (where they are easily seen), what if that phenomenon was occurring across my body in occult fashion - in my muscles, my organs, my brain...

Some years later I read the 1989 work of Leslie Simpson, where he discussed finding stiff or misshapen RBCs in people with CFS.

Ron Davis followed up on that idea about 5 years ago, with an artificial capillary bed measuring slow blood perfusion (and thus slow O2 delivery) from patients. Another idea was that something in the blood was orchestrating the changes in RBC structure that might lead to such an effect.

In the meantime, metabolic shifts within patient cells were noted in another stufy, perhaps driven by low O2 in the cell.

So, I'm still enamored with this particular vein of MECFS ore. It's obviously not the whole story; perhaps it doesn't apply to every patient. Maybe it only applies to me. (I am indeed very special .)

But you say it's all hogwash, that 5 out of 5 pathologists concur that these things never happen. That cells operate at either 100% or 0%.

You're crushing my already-tattered ego.

 

[Jonathan Edwards]

You're crushing my already-tattered ego.

I am aware that I may dent egos a bit with sceptical comments, although I suspect those egos are stronger than it might seem. I post critical comments partly because the field of ME/CFS is awash with pseudoscientific theories that fringe physicians use to exploit patients with and what I think nobody wants is for this forum to become a swap shop for such theories, extending the financial exploitation even further.

I would also argue that there is no reason for your ego to be dented by the suggestion that one theory is better than another. Everyone here believes that somewhere out there is a theory that explains why ME/CFS destroys people's lives. The aim is to get that theory right. People's egos do not need to depend on any one particular theory surely?

But let me try to answer specifics because the line of argument is not crazy. It is just that in the face of what we have learnt from 150 years of clinical and pathological analysis, it doesn't look, at least to me, as if it will fly.

Splinter haemorrages occur in normal people but a lot of them - say four at the same time, without having been chopping wood - suggest that there may be microembolisation. That is historically associated with bacterial endocarditis, as you say. But similar capillary blockage, or micro-infarction, is recognised in a number of autoimmune diseases like lupus and polyarteritis, and also in blood disorders like macroglobulinaemia. These diagnoses sometimes get missed but they nearly always have abnormal blood tests that do not occur in ME/CFS.

Of the dozen or so conditions that produce splinters, each has a different pathology in severe cases but the pathology is well described. Tissues suffer necrosis or inflammation or indeed ischaemia. And we know the clinical symptoms that go with those. None of them are seen in ME/CFS. Histology is normal. Rob Wust has recently suggested that local necrosis may occur but this is out of line with forty years of previous histology. The symptoms of ischaemia or significant capillary blockage are either claudicating or rest pain, of a sort that people with ME/CFS do not have, or trophic changes where the tissues become discoloured, puffed up with fluid, ulcerated or mummified.

If these things were going on in ME/CFS then of the several million people with the condition who have consulted a doctor in the last fifty years at least one or two would have been shown to have some ischaemic pathology. And they haven't.

 

[Jonathan Edwards]

Some years later I read the 1989 work of Leslie Simpson, where he discussed finding stiff or misshapen RBCs in people with CFS.

Ron Davis followed up on that idea about 5 years ago, with an artificial capillary bed measuring slow blood perfusion (and thus slow O2 delivery) from patients. Another idea was that something in the blood was orchestrating the changes in RBC structure that might lead to such an effect.

In the meantime, metabolic shifts within patient cells were noted in another stufy, perhaps driven by low O2 in the cell.

The problem here is that these are isolated findings over about half a century. People have tried to repeat Simpson's findings and nothing consistent has been reported as far as I know. In addition, we know the clinical presentation of conditions where red cells are stiff or misshapen and it isn't particularly like ME/CFS.

Slow flow in an artificial capillary system does not translate to low oxygenation in any direct way. Ron Davis has put a lot of energy into ME/CFS research but we have not seen any very organised studies over the last ten years and pretty much nothing in the way of formal replicated data.

A few people have noted metabolic shifts but not related to oxygen lack as far as I know - more to do with amino acid usage.

The underlying concern for me is that this 'particular vein of ore' is very much what a lay person without much idea of clinical physiology would go for as plausible. People have been attracted to it for decades. But those who are familiar with muscle physiology don't see it as very plausible after all because it does not add up, in the way I have described. And my old boss Richard Edwards (no relation) had a team of good people put on to muscle in ME/CFS in the 1980s and they found nothing.

I think it is hard for lay people to appreciate just how much medical research is reporting artefacts and irrelevances, particularly in the last 20 years. And if everyone continues to plough on studying these things that don't really add up the likelihood is that they won't scratch their heads and realise that something else might fit. I guess in a way that is what this forum is all about, scratching our heads to see if something else might fit, and keeping on wide-angled spectacles to pick up every bit of information that might just bear on that.

 

[Madbeggar]

I am aware that I may dent egos a bit with sceptical comments, although I suspect those egos are stronger than it might seem. I post critical comments partly because the field of ME/CFS is awash with pseudoscientific theories that fringe physicians use to exploit patients with and what I think nobody wants is for this forum to become a swap shop for such theories, extending the financial exploitation even further.

I appreciate and applaud yr efforts! (And my ego will surely survive to fight another day!)

...let me try to answer specifics because the line of argument is not crazy.

That's what I wanted to hear!

...people with ME/CFS do not have, or trophic changes where the tissues become discoloured, puffed up with fluid, ulcerated or mummified.

Fortunately, I am not yet fully mummified.

I really appreciate the reply. My life went completely off the rails a couple years ago. I haven't followed the research or been to this site since then. I don't even have a functioning computer. I lost my home, lived in a truck bed with my very aged cat for 5 months, finally settled into a senior apt building that I hate, and I'm suffering really bad dementia. But it's good to see you're still here, fighting the good fight.