Yep, I think we agree that we disagree. To me ME/CFS is like trying to find a sunken ship in open ocean. We have no idea where it is, and no amount of passive observations will get us near it. You need hit random locations (with educated guess) with sonar, learn from it and then move on to the next location, etc. The "basic science" of ME/CFS has been the process of trying to turn the black box into white through passive observation, and I think it's time that we give the science of black box a try.
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List of diseases with a known mechanism but no cure/treatment
- Thread starter Jaybee00
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wastwater
Senior Member (Voting Rights)
https://en.m.wikipedia.org/wiki/CADASIL
CADASIL or CADASIL syndrome, involving cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, is the most common form of hereditary stroke disorder and is thought to be caused by mutations of the NOTCH3 gene on chromosome 19.[1] The disease belongs to a family of disorders called the leukodystrophies.
The underlying pathology of CADASIL is progressive hypertrophy of the smooth muscle cells in blood vessels
https://academic.oup.com/jnen/article-abstract/72/5/416/2917596?redirectedFrom=fulltext&login=false
Brain Microvascular Accumulation and Distribution of the NOTCH3 Ectodomain and Granular Osmiophilic Material in CADASIL
CADASIL or CADASIL syndrome, involving cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, is the most common form of hereditary stroke disorder and is thought to be caused by mutations of the NOTCH3 gene on chromosome 19.[1] The disease belongs to a family of disorders called the leukodystrophies.
The underlying pathology of CADASIL is progressive hypertrophy of the smooth muscle cells in blood vessels
https://academic.oup.com/jnen/article-abstract/72/5/416/2917596?redirectedFrom=fulltext&login=false
Brain Microvascular Accumulation and Distribution of the NOTCH3 Ectodomain and Granular Osmiophilic Material in CADASIL
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If you want to organise/fund a good quality investigation of whether ibuprofen makes a meaningful difference to ME/CFS symptoms, I'm sure many of us here will cheer you on. Or perhaps there is some other drug that you are making an educated guess about that you would like to see tested properly? Abilify?
Kitty
Senior Member (Voting Rights)
The word "we" seems to be doing a lot of work.
Presumably "we" would need to be warned of the substantial risks and tiny likelihood of success. Once the unusually high susceptibility to food intolerances and drug side effects in ME/CFS was also factored in, it wouldn't be surprising if "we" largely refused to go near it. It's a type of gambling, but without any of the fun.
Utsikt
Senior Member (Voting Rights)
As far as I can tell, nobody except for maybe the person that wrote the compiler, knows how computer programs really work. They frequently crash, require constant maintenance and often just do the bare minimum they have to do in ways that really were not intended. When you fix a bug, you often have no idea why it occurred in the first place, and even less of an idea of why the new thing worked.
The human body is so much more complex that it would be exceedingly unlikely to stumble upon any useful information or insigth by trying things randomly or even semi-informed.
We can’t even figure out how AI models work, and we created them. They are far less complex than the human body.
Utsikt
Senior Member (Voting Rights)
A ship is glaringly obvious to spot if you end up searching its location. Our ship might be inside a rock that looks perfectly normal from the outside. No amount of sonar is going to find the ship in that case.
I really don’t think the basic science has been done yet.
But what does any of that mean? You would have to figure out dosage and duration and how will you do that without knowing anything or are you just going to select those randomly as well? And how would you know what has not been tried, what does "been tried" constitute for example in relation to dosage and duration and how will interactions be handled?
You could have 5 people that say that they feel good after doing CBT for a week or you could have 5 people that report feeling horrible, we know there are plenty reasons for either and we know why neither matter. How would you select what constitutes a success when you're purely relying on subjective reports were some people might be more prone to believe in something rather than something else and you'd likely end up picking those that are more likely to believe in something? I just don't think you'll get to learn much by feeding 5 people a compound at an unknown dosage for a few days and then asking them how they feel. How would that be a rule-in or rule out sign perhaps the compund had to be given at a higher or lower dosage or there were interactions or the duration wasn't right?
It seems almost as useful as just feeding one person all the thousands of compounds at once and asking them how they feel afterwards.
It is of course plausible that one can stumble upon a treatment via luck, similar to how things happened with Rituximab, even though it didn't work in the end, but I don't see this approach being a very fruitful one at getting there but there are probably meaningful approaches how one could increase ones luck (for example by setting up long-term patient registers).
I think a lot of this is down to funding. If there were similar funding to other conditions, people would be much less opposed to semi random drug trials.
In many ways I think this conversation is premature. If DecodeME and SequenceME point to something specific, trialing drugs that affect that specific thing, even if we don't understand 100% how it's involved, becomes a lot more plausible.
I really hope the basic science progresses in the next couple of years, and we have some decent leads to go off.
In many ways I think this conversation is premature. If DecodeME and SequenceME point to something specific, trialing drugs that affect that specific thing, even if we don't understand 100% how it's involved, becomes a lot more plausible.
I really hope the basic science progresses in the next couple of years, and we have some decent leads to go off.
Jonathan Edwards
Senior Member (Voting Rights)
I am not sure which way you are trying to argue. As I pointed out earlier, the random 3 million patient strategy is likely to produce at least 200 unnecessary deaths.
But that is the other strategy - basing choice on reasonably plausible theory.
Trouble at the moment is that we don't have any very plausible theories. We have quite a lot of implausible ones that could lead to vey dangerous suggestions - like Nath interfering with checkpoints.
Jonathan Edwards
Senior Member (Voting Rights)
This is the bottom line as of April 2025.
Even that might be useful. If one person's ability to switch PEM off by eating strawberries is a unique mutation, it's still affecting the PEM mechanism, which could help trace the PEM mechanism. Looking for the answer when you have a reliable before/after comparison is much easier that looking for the answer when you don't have that comparison.
The current crop also include the BPS garbage. There are hypotheses that involve specific molecular pathways, but at present we have no way to judge their quality. Judging by researcher's credentials isn't very useful. Judge by how many really scientific-sounding words are in the proposal?
Anecdotes about how brain retraining or GET cured hundreds of people?
There may also be a way to build viable fusion reactors ... but we're still waiting for someone to figure out what that way is. If we did know of a way to select potential treatments that would be most likely to work, that might be worth doing, but so far we lack that way.
I see testing of random treatments as not likely to result in an effective treatment, but rather as possibly providing useful data on what's going on in that black box of ME. Negative effects are valuable too. If 80% of PWME reliably got worse symptoms from caraway, that would be useful for further research. As a government-managed project, it would likely be an expensive failure, but as a crowd-tested project (What foodstuffs or drugs make you reliable feel worse?), maybe it would be worthwhile.
So it comes down to money. I'm sure there are patients who tried everything and nothing worked. But there are also who tried everything and found something. It may be tempting to write them off as anecdotes and insist on the frequentist approach only. Given the lack of progress however, and the prospect of progress, it would be prudent to make some fund available to make it easier for people to explore on their own instead betting the farm on the "basic science" that may never come through. Who knows, the individual exploration may add up to a breakthrough that "basic science" may never reach.
Sure, Abilify would be a good example. There are people who improved as well as those who got worse. Why not make it easier for people explore if it works for them? At some point with enough data, we may know why it works for some and doesn't for others.
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I'm not sure about that. Stat says that about 25% are severely ill and they are more likely the group that nothing works. Some in the rest have found something that works. Even experimenting when/how you walk may have effect for some. I don't think it's a good idea to generalize one way or another. I'd just leave it as "nothing works for some and something works for some". I'm advocating making it easier for those who are willing to experiment.
The risk is for individuals to decide. Sometimes strict safety, like a sticking to routine day in day out to avoid PEM, for example, can makes the condition worse for some because it's no fun.
Well, let's just say we disagree on that. Despite of lack of fund on the scale of cancer or AIDS, there still have been plenty of poking around and nothing is converging. It's been the process of blind men feeling out the elephant, over and over.
If X works for those 5 people, why take X off the table for all? One obvious reason is the cost. But if you have an objective way (time spent lying down, for example) to measure that X indeed improved condition for some, placebo or otherwise, it would be just about as criminal to make it inaccessible for all as it is to impose harmful treatment on all.
No we won't learn heck of lot. But there still could be information that moves the needle a bit after a large number of tries, which may point to areas to look deeper. That's still better than nothing. I still think it'll be more profitable to dissect (no, not literally) why some people, like those with IH, improve/recover after certain treatment than doing the muscle biopsy to look for anomaly.
I'm proposing to consider different approaches because the "basic science" approach hasn't been fruitful either. I think the ad hoc Bayesian approach has as much chance at being fruitful as the disciplined basic science way.
So, will it still produce 200 unnecessary deaths if we make available drugs that's been proven safe enough in general? That certainly will be an argument against making compounds available for experiments.
What I said was: try plausible ones first and then go down the list. I wouldn't get boxed in by the plausibility in this semi random experiment.
Do we know for sure that BPS, GET or brain retraining doesn't work for everybody? There could be one or two out there with anecdotes. Their improvement could even be real. As much as I think they don't work, I wouldn't take it off the table for all. I'm proposing to make it easier for people to experiment, however esoteric or implausible it may look. And the collective data may tell us something.
Utsikt
Senior Member (Voting Rights)
Re: if the basic science has been done.
If the researchers on here says that we’re at least a decade behind other diseases, then I would be fairly confident in saying that the basic research has not been done properly and at a sufficient scale yet.
Of course we know it doesn't work for everybody as this has been shown in multiple trials. The existence of this website is proof that it doesn't work for everybody. I think what you're trying to say it doesn't work for anybody. But there no argument there. The trials have shown there is no worthy benefit to it. I really don't see what you are trying to argue here. Whether or not something works is not a question of whether someone believes it works but depends on the evidence. It seems you don't seperate "works" from placebo-effect, regression to the mean, natural recovery, Hawthorne like effects, adapted behaviour, selection bias, subjective outcome measures, no long-term follow-ups, reporting bias and all other things? Is that a meaningful definition of "works"?
Would you argue similarly by saying that cutting off someone fingers "works" against Alzheimers because that person afterwards responds to a questionnaire by answering they don't remember having Alzheimers because they aren't able to remember much? Does ice cream "work" against MS because someone says they are feeling good after they had one. Is that your definition of "works"? You cannot establish what "works" or doesn't without solid evidence. That is the whole point of clinical trials.
What do you mean one or two with anecdotes? We know far more than that with anecdotes. There's studies on them and there's also other studies on supplements such as Patient-Reported Treatment Outcomes in ME/CFS and Long COVID. There's also websites to collect all thses anecdotes (Eureka Health for example). The problems with such anecdotes have been discussed at depth.
Are you suggesting one should ignore evidence and doctors should treat someone with cancer with voodoo because they read on facebook that it would work and because they believe in it, rather than chemotherapy?
Nobody is arguing that people with ME/CFS can't improve or that there aren't instance where improvements can't be real. We know they can. It has been seen in trials of medications without efficacy as well.
I'm really not sure what your argument is. People can do all sorts of esoteric things they want, they already do it and nobody is hindering them. Most people try GET because it's natural to think that one just has to do some exercising, apart from that the rest which is anyways typically forced into doing it. Offering services without evidence to ill people is the problem.
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