List of diseases with a known mechanism but no cure/treatment

[EndME]

Were any of them big enough? Even for a homogeneous condition. My memory is that they have been small?

Looks like you're right, to my own suprise they have all been small. I can only find one larger one (52 000 cases - self identified and recruited via 23andME) with all others being of miniscule size.

I'm unsure how much work is happening in the background. At least it seems that there are/were 7 genetic Long-Covid studies happening in Germany alone (genomLC, BoSCO, long non-coding RNAs in Long-COVID, The role of genetic risk profiles in the development of post-COVID symptoms, Genome-wide association study to identify genetic risk factors for Post-COVID Syndrome, Influence of genetic background in COVID-19- and Long-COVID phenotypes, Is there a connection between the severity of COVID-19 disease, the development of long-COVID syndrome and a specific genetic cell variant in carbon metabolism?).

Given what I had misremembered myself, I think it may be a decent idea to keep an overview of the different genetic work in Long-Covid. I'll make a thread later.

 

[Andy]

Can you say whether the planned GWAS collaboration with Lipkin/Columbia was going to be in ME or LC?

ME/CFS. Grant details can be found here, https://reporter.nih.gov/project-details/10878255

 

[V.R.T.]

ME/CFS. Grant details can be found here, https://reporter.nih.gov/project-details/10878255

That seems like a worthwhile project in terms of replication. Beyond frustrating that funding has been pulled. I hope that the government sees sense but not holding my breath. Perhaps there are alternative funding sources that could be explored, as discussed in the SequenceME thread?

 

[poetinsf]

You need more, including basic scientific plausibility and an assessment of the likely reliability of reports.

If we sat on the scientific plausibility, bloodletting or geocentric theory is precisely the kind of things we would end up with. We have things like the relativity, evolution, or even the control of communicable disease spread through water because some people observed and then went out of the way to investigate rather than getting limited by the scientific plausibility de jour.

Painting your toenails with parsnip juice might work for ME/CFS, but I can't imagine anybody volunteering to fill in the paperwork!

If many people are reporting that painting the toenails with parsnip improve ME/CFS, there could be something in it even if we don't know what it is yet. Why not investigate rather than dismissing it as implausible, right?

 

[poetinsf]

I am intrigued as to what trial that was?

Here is one. I thought there was a large European study, but I don't seem to be able to find it.
Glucosamine, Chondroitin Sulfate, and the Two in Combination for Painful Knee Osteoarthritis | New England Journal of Medicine

 

[poetinsf]

You’re essentially asking a mechanic to try and fix a car by going to a general hardware store and picking an item randomly.

And that's what you would do if you had an opaque gadget you don't know anything about. You kick it around, see how it responds, and try some random stuff. You incorporate what you learned and then try the next random stuff, revising your theory about it on every step, till you fix it.

It doesn’t seem like you’re considering how many possibilities the black box contains.

You don't really have to know what it contains. You just need to know how it responds to some (random) inputs to hypothesize about it. If you think about it, we don't really know anything about anything. All we know is how something behaves in certain situations, which translates to predicting how it will respond in some other situations.

 

[poetinsf]

How do you figure out potentially useful repurposed drugs if you have no idea what to figure?

You figure it out by trying it? It ain't no use to sit and wonder why the roof is leaking. Somebody should jump on the roof and start poking around.

That has been quite useful over the years. Several drugs have com into use because they were by chance found to help.

Wouldn't it be great if we have one like that for ME/CFS? Why not systematically scour through them all to see if any clicks rather than leaving it to chance?

 

[Eddie]

And that's what you would do if you had an opaque gadget you don't know anything about. You kick it around, see how it responds, and try some random stuff. You incorporate what you learned and then try the next random stuff, revising your theory about it on every step, till you fix it.

That would be an incredibly inefficient way to go about it. Given you know nothing about the issue there are literally an infinite number of things that might fix it. If you try something and it doesn't work all that tells you is that you can rule out that one specific thing, assuming you did that one thing correctly. If what you try works to some extent that can tell you something. But that assumes you know enough about the thing to recognize when you actually helped and when it was factors outside of your control that helped.

Wouldn't a significantly better approach be to take apart the gadget looking for clues as to what is wrong. Keep breaking the gadget down into smaller parts and observing these parts until you get to a level at which some understanding exists. Then once you have an understanding of how the gadget works you will know what kinds of stuff might work and don't have to try everything.

 

[Utsikt]

@poetinsf we’re going in circles here.

I believe your suggested approach is about the most inefficient way of solving a problem that we barely know anything about.

We all want treatments, preferably yesterday. But we have to think long term and go for the approach that on average takes the least amount of time. And that’s trying to figure out the core of the problem.

Your approach has a minuscule chance of succeeding in the short term, and only a slightly better chance long term. But you’re still suggesting to gamble on getting incredibly lucky.

Trying to figure out how ME/CFS works will not be able to get us any solutions short term. That’s difficult to accept when we’re suffering so much.

 

[Jonathan Edwards]

Here is one.

Well that one didn't seem to settle a question since they got no rest but still suggested it might work in a subgroup!!!

 

[Jonathan Edwards]

You figure it out by trying it?

Er?

The question was how to figure out which one to try.
So which was it? And why?

 

[Jonathan Edwards]

Why not systematically scour through them all to see if any clicks rather than leaving it to chance?

Because if you actually tried them in doses adequate to know if they would work and ranges of protocols that you would need to check to know if they worked you would almost certainly kill at least 100 people through adverse reactions.

I get the impression that you have no experience with choosing drugs to try on diseases! I spent my life doing that. I am telling you what I learnt. We had deaths even when we picked things on the basis of some decent rationale.

 

[Andy]

That seems like a worthwhile project in terms of replication. Beyond frustrating that funding has been pulled. I hope that the government sees sense but not holding my breath. Perhaps there are alternative funding sources that could be explored, as discussed in the SequenceME thread?

I guess there could be alternative funding sources but that would be down to Columbia to explore.

 

[Creekside]

Wouldn't a significantly better approach be to take apart the gadget looking for clues as to what is wrong.

Whose brain are you offering for this taking apart? Also, human brains don't work very well when you take them apart, so you can't see the malfunctioning bits in operation. Technology for studying brains in operation is advancing, but for a lot of purposes, the brain is still a black box. My engineering background directs me to study this by applying various inputs and seeing what the outputs do.

We simply can't try all existing drugs for their effects on ME. We don't know what dosage would be required to have a noticeable effect, so you'd have to try maximum doses, which is risky, while some drugs have only a narrow range of dosage that is effective. I'm hoping that someone stumbles--through self-experimentation--across something that provides a reliable effect (positive or negative) for a significant number of PWME. Then someone can try to figure out how it's doing what it's doing.

 

[Kitty]

Why not systematically scour through them all to see if any clicks rather than leaving it to chance?

The same reason you don't try to read the British Library's 13 million books in the hope of finding the one you want. It's not a rational way to go about it.

 

[Eddie]

Whose brain are you offering for this taking apart? Also, human brains don't work very well when you take them apart, so you can't see the malfunctioning bits in operation. Technology for studying brains in operation is advancing, but for a lot of purposes, the brain is still a black box. My engineering background directs me to study this by applying various inputs and seeing what the outputs do.

We simply can't try all existing drugs for their effects on ME. We don't know what dosage would be required to have a noticeable effect, so you'd have to try maximum doses, which is risky, while some drugs have only a narrow range of dosage that is effective. I'm hoping that someone stumbles--through self-experimentation--across something that provides a reliable effect (positive or negative) for a significant number of PWME. Then someone can try to figure out how it's doing what it's doing.

The analogy was to a gadget. In humans we would have to use imaging or blood samples to see what is going wrong. That can be done while the malfunctioning bits are in operation.

How do you know we have to try maximum doses? There might be some non-linear dose dependent response.

If you think there is a realistic chance that someone will stumble on the correct drug and dose to treat ME/CFS than I understand why you would take this position. But people have already tried the drugs where there is some (questionable) rationale and those that aren't particularly dangerous. There are also plenty of treatments that people have claimed have a reliable effect on ME/CFS. Of the list below do you think we should sink significant resources into running trials on each one?

 

[Creekside]

In humans we would have to use imaging or blood samples to see what is going wrong. That can be done while the malfunctioning bits are in operation.

That doesn't work if the problem is hidden deeply inside brain cells. It could be the contents of vesicles that only travel from one part of the cell to another part of the same cell. Blood samples won't reveal that. We may not yet have the technology that would reveal ME's core dysfunction.

How do you know we have to try maximum doses?

The problem there is that you can't rule out a treatment until you do try it at all dosages, including maximum dosage. Add in the possibility of critical cofactors in various dosage. The combinations to completely test a treatment quickly reach improbable numbers. If you say "Well, just test the most likely ones at the most likely dosages.", how do you determine which ones are most likely and what dosage is most likely? That's what has been done for decades, with each researcher deciding what they think is most likely based on their pet theory ... and we've seen the result.

Someone may have already stumbled across a useful treatment, but it's someone in some undeveloped region who tried a local material, but they never heard of ME, so they haven't reported it to anyone who doesn't know about ME.

When I was shopping yesterday, I noticed a package of "Carom seeds (ajwain)", which I'd never encountered before. $1.69 is a cheap gamble, so I bought some. I think it's unlikely to have an effect on my ME, but I would have rated cumin similarly unlikely, yet that proved to be amazing for me.

That's a good counterexample for "test the most likely ones": cumin probably wouldn't have made the list. Neither would 3-5 diiodothyronine. The treatments that someone decided were "most likely" are probably the equivalent of choosing stocks based on which were most popular at the moment, rather than a deep understanding of the businesses.

 

[Eddie]

That doesn't work if the problem is hidden deeply inside brain cells. It could be the contents of vesicles that only travel from one part of the cell to another part of the same cell. Blood samples won't reveal that. We may not yet have the technology that would reveal ME's core dysfunction.

I completely agree, and I think the problem might be something like that. I would argue that makes it all the more important not to use money on treatment trials without a good justification and instead in developing new research tools.

The problem there is that you can't rule out a treatment until you do try it at all dosages, including maximum dosage. Add in the possibility of critical cofactors in various dosage. The combinations to completely test a treatment quickly reach improbable numbers. If you say "Well, just test the most likely ones at the most likely dosages.", how do you determine which ones are most likely and what dosage is most likely? That's what has been done for decades, with each researcher deciding what they think is most likely based on their pet theory ... and we've seen the result.

Someone may have already stumbled across a useful treatment, but it's someone in some undeveloped region who tried a local material, but they never heard of ME, so they haven't reported it to anyone who doesn't know about ME.

When I was shopping yesterday, I noticed a package of "Carom seeds (ajwain)", which I'd never encountered before. $1.69 is a cheap gamble, so I bought some. I think it's unlikely to have an effect on my ME, but I would have rated cumin similarly unlikely, yet that proved to be amazing for me.

That's a good counterexample for "test the most likely ones": cumin probably wouldn't have made the list. Neither would 3-5 diiodothyronine. The treatments that someone decided were "most likely" are probably the equivalent of choosing stocks based on which were most popular at the moment, rather than a deep understanding of the businesses.

That's why I don't think testing treatments in this way is likely to be successful. Without a good idea of where to look you have to try all treatments at a range of doses to ensure you haven't missed it.

I am glad you found something that works for you. But what is your criteria for deciding what to spend money on and test? What makes cumin more likely to work than any other of the drugs above?

 

[poetinsf]

@poetinsf
We all want treatments, preferably yesterday. But we have to think long term and go for the approach that on average takes the least amount of time. And that’s trying to figure out the core of the problem.

I think the main difference between you and I on this topic is that I'm way more pessimistic about the "basic science". Normally, things tend to converge as science make progress. In ME/CFS, it's been going in circles at best, or more like a random walk. There has been zero convergence.

Given the circumstance, even the attempt at a lotto will be worthwhile if we can approach it safely enough somehow. I don't see it being more expensive than the basic science that, according to @Jonathan Edwards, is wasted 95% of the time and fails to move the needle 1 nm after spending over a $1b.

 

[poetinsf]

The question was how to figure out which one to try.
So which was it? And why?

You could try the likely ones first and then move down the list. In the absence of other indicators, accumulation of anecdotes is one way to assess the likelihood.

Because if you actually tried them in doses adequate to know if they would work and ranges of protocols that you would need to check to know if they worked you would almost certainly kill at least 100 people through adverse reactions.

The safety profile of known compounds are known, aren't they? Just try safe compounds with safe dosage. It's going to be semi random anyway, so no point trying to figure out the right dosage for ME/CFS. I think one concern is making your ME/CFS is worse. Each patient should decide the risk they are willing to take.