Visual hypothesis of ME/CFS dysregulation, combining multiple patient-led hypotheses.

[Sebastiaan]

What made you think there was inflammation in ME/CFS? The Twitterati again?

Thanks @Jonathan Edwards, I appreciate the clear reply. I'll come back to some of it in a more general response. But to answer this question specifically: I do honestly think patients can be forgiven to think that inflammation is involved somehow. Quite some of the researchers with high online visibility are highlighting (chronic) inflammation in their research and presentations lately. And since peer-reviewed studies are overboard, here's a selection of videos from just the last year that made me think so, complete with PET images and all:

dr. Jarred Younger -
dr. Michelle James -
Prof. dr. Scheibenbogen -

I don't mean to share these as proof, just as examples of how one could get to believe that inflammatory mechanisms play such a central role. As a patient I'm inclined to see these as credible sources. It'll take time, but I'll try to go through the forum and do my homework to make up my own mind.

 

[Sebastiaan]

Thank you so much for the feedback so far. Based on these, I just wanted to add some reflections and pose a question.

I understand the concern about the quality of peer-reviewed literature, and it's sobering to discover that only so few of the studies on ME/CFS stand their ground. I wasn't aware, but I have the deepest respect for everyone here spending their time and effort critically re-interpreting the data. But I'm afraid I cannot contribute much there, as that's where I think a PhD in immunology does come in handy.
Indeed I'll have to spend quite some time reading up on the forum, and the DecodeME work is next on my list. But if each of the over 60 peer-reviewed studies linked in the hypothesis-figure disqualify as latest or dependable science on this forum, then a newcomer like myself would indeed be in dire need of a primer or simply a list of studies I'd be 'allowed' to quote here. The fact-sheets are fantastic! But they do not seem to serve this purpose. I appreciate the links to discussions about that as shared by @ScoutB.

I can also appreciate the need for precise wording, which seems to play a role in addressing what I have labeled as 'inflammation'. The truth is, indeed I do not know what precisely that means. I come from this from a slightly different angle. I'm comfortable with the fact that I may not understand the details regarding which cytokines, interleukins, microglia or interferon signals are at play in the case of ME/CFS.
I'm simply taking a step back and approach these as a black-box, for whatever amplifying immune-response at play (happy to adopt more appropriate wording). While I can only wait for someone smarter and more qualified to figure out the hard part 'under the hood'.
Unfortunately - based on what I read here - it seems that that may still take quite some time, let alone for those insights to lead to an effective treatment or cure.

My hope here was that - in the meantime - taking a birds-eye view on how some of these black-boxes or mechanistic domains may interact and even amplify each other may still have value in helping to understand the complexities of the illness, if not for researchers than at least for patients. I believe that this level of abstraction is where the research naturally connects to patient experience and symptoms, so perhaps it is an appropriate basis to exchange and learn from each other.

But it does raise a genuine question: Do you think this forum is an appropriate place for attempts at connecting hypotheses like this? Because even when building only on 'good' studies and avoiding vague terminology as much as possible, connecting existing hypotheses on disease mechanisms in an overview like this requires a level of abstraction, perhaps even conjecture and it may indeed invite boldness to fill in some blanks, or jump to conclusions. And I can see how there is little room for that on a science4 forum. I never meant to present this as the solution to the puzzle, but rather as a tool that could help shape some intermediate understanding. Hypothesizing away is admittedly the easy part, that builds on the hard evidence-driven work done here and in research more broadly. I'm very open to some pointers or reflections on whether this is the right time and place, or not. It could save me some spoons. Much appreciated!

 

[Jonathan Edwards]

But to answer this question specifically: I do honestly think patients can be forgiven to think that inflammation is involved somehow.

They certainly can if they take what scientists say as reliable, without making sure that they see the evidence for reliability for themselves. And I guess that is the main message I have tried to put across to patient over the last ten years.

It is easy to see that there is no inflammation because the reliable tests we have for inflammation, both clinical and lab/imaging based do not show any. Michelle James's pictures are intriguing but very preliminary and in the absence of any rise in creatine kinase or CRP the weight of evidence must be that there is no muscle inflammation.

How come peopl devoting their research to ME/CFS do not see this and claim there is inflammation? That is a good question but I have seen that sort of thing in research into chronic disease all my life. It has always puzzled me that people follow the fashionable dogma without checking the basics.

The reason why researchers thin they should be finding inflammatin is presumably because of the name myalgic encephalomyelitis (brain and cord inflammation). But that name referred to an acute epidemic illness, not to the chronic condition we now call ME/CFS, which has no evidence of inflammation.

 

[Utsikt]

I’ll give my two cents:

But if each of the over 60 peer-reviewed studies linked in the hypothesis-figure disqualify as latest or dependable science on this forum, then a newcomer like myself would indeed be in dire need of a primer or simply a list of studies I'd be 'allowed' to quote here.

You’re allowed to quote anything, but people here are going to question if it’s any good. That happens to everyone here.

My hope here was that - in the meantime - taking a birds-eye view on how some of these black-boxes or mechanistic domains may interact and even amplify each other may still have value in helping to understand the complexities of the illness, if not for researchers than at least for patients.

Trying to figure out a problem like this is like being handed a semi-trailer of tiny puzzle pieces, and being asked to assemble a puzzle of an unknown size and with an unknown motif.

99 % of the pieces are not from your puzzle, so if you don’t do a good job at sorting out which are yours (by doing very, very good experiments), you’re not going to stand a chance at getting the puzzle right.

I don’t understand how stringing together vague words and dubious data is going to make anyone wiser.

But it does raise a genuine question: Do you think this forum is an appropriate place for attempts at connecting hypotheses like this?

Of course it is a place for trying to connect hypotheses, that’s the entire point of the forum. Getting closer to the answer somehow. But some ways of doing that are more likely than other to be fruitful.

Because even when building only on 'good' studies and avoiding vague terminology as much as possible, connecting existing hypotheses on disease mechanisms in an overview like this requires a level of abstraction, perhaps even conjecture and it may indeed invite boldness to fill in some blanks, or jump to conclusions. And I can see how there is little room for that on a science4 forum.

There is plenty of room for leaps of imagination and, conjecture and abstraction. But we’re not going to understand the pathology and figure out how to treat it unless we then ask: what would it look like if this was true? How could we test it? Is there any evidence against this hypothesis? How would it fit with what we already think we know?

Science is mostly about figuring out what’s not the case until you’re left with something you can be reasonably sure actually reflects the underlying reality. Brutal and endless scrutiny of everything is the only way forward. Being wrong isn’t failure - it’s valuable learning.

But we still require something to scrutinise, and to figure out how everything we know actually fits together - and that requires every ounce of imagination and creativity we can muster.

 

[Jonathan Edwards]

But I'm afraid I cannot contribute much there, as that's where I think a PhD in immunology does come in handy.

You should not be too hesitant. There are loads of members here who started off with no relevant biological knowledge and within a year or two are now producing sharp critiques of detail. Inflammation and tissue pathology in general is tough because it has such a complex three dimensional and compartmental aspect. It is easier to attack the genetics or pharmacology maybe. But most of the issues are retty easily understood with common sense.

newcomer like myself would indeed be in dire need of a primer or simply a list of studies I'd be 'allowed' to quote here.

You are allowed to quote whatever you like. All sorts of stuff gets looked at here - a bit like Antiques Roadshow. A lot wouldn't fetch more than a fiver but every now and again someone picks up something worth ten grand that nobody was expecting.

taking a birds-eye view on how some of these black-boxes or mechanistic domains may interact and even amplify each other may still have value in helping to understand the complexities of the illness,

The trouble is that most researchers publishing are focused on black boxes where they think something should be wrong but there probably isn't. There is so far no reliable evidence for anything wrong with circulation or blood flow in ME/CFS. There are a few hints at perfusion changes but very far from proof of anything clinically relevant and the clinical picture is hard to square with vacular changes (at least to my mind).

Looking for things in the wrong place is bog standard in medical research. There may be more research looking in the wrong place because of course you go on forever looking if it is the wrong place. The great thing about DecodeME was that it looked everywhere equally and for signals that had to be part of the cause (genes, which cannot just be side-effects). It found as some signals. Now is probably the time to clear away the table completely and start cooking afresh.

 

[Jonathan Edwards]

Because even when building only on 'good' studies and avoiding vague terminology as much as possible, connecting existing hypotheses on disease mechanisms in an overview like this requires a level of abstraction, perhaps even conjecture and it may indeed invite boldness to fill in some blanks, or jump to conclusions.

A couple more thoughts. Firstly, all these 'bad studies' we trash are often very good at demonstrating a negative, even if the authors fight tooth and nail to find a grain of positive. Building a hypothesis for a disease mechanism is 90% discarding blind alleys using negative data. So these studies are not necessarily useless.

I am not sure what you mean by abstraction. I have spent my life building theories of chronic disease, with significant success in translational terms. I always take a new step based on something specific that looks as if it might fit. That of course is helped by a huge amount of background knowledge of specifics but sometimes it is something in the student textbooks that everyone has discarded for the wrong reason. Conjecture is certainly part of it and that is a huge part of what S4ME is about. People throw up theories every day. They usually get trashed but maybe that leads to a better idea.

The bottom line for me is that the sort of discussion we have here is exactly the sort of process I used in developing B cell depletion therapy for autoimmune disease. Exactly the same free argument where anyone can say whatever they like and nobody is in authority. Everyone has to argue their case. And if you have a wide range of personalities with a wide range of skills you are pretty well guaranteed to make more progress than the standard po-faced research circuit.

 

[richie]

Hi @Sebastiaan,

I am afraid to say that none of that makes much sense to me. You have joined together a lot of fashionable buzzwords

but rather than these being

they are not something I recognise as an inflammation scientist.
Lack of oxygenation does not trigger inflammation, unless there is overt damage and in ME/CFS there is neither inflammation nor damage (nor evidence of insufficient blood flow).

As @ChronicallyOverIt says, you might like to read various threads here on ideas of this sort. Unfortunately there is an awful lot of half-baked quasi-science around ME/CFS on social media.

You have to make sure that what he means by inflammation is what you mean by it! Though it seems from the posts that this point has been grasped.

 

[Concentric_Spiral]

I think the level of engagement in this thread is amazing. As someone who used to enjoy independent research, I would be overjoyed for my current thinking to be picked up seriously by people immersed in the topic. Happy hunting!

 

[Sebastiaan]

sometimes it is something in the student textbooks that everyone has discarded for the wrong reason.

Thanks for the encouraging perspective. The above 'student textbook' situation was precisely what made me think the Itaconate shunt hypothesis might be connected to the supposed Cortisol issues. Just for fun I'll share a picture of the figure in the book ("The endocrine system at a glance", Greenstein & Wood):


This shows 4 regulators of CRH and thus of Cortisol: Serotonin (5HT), Acetylcholine, Sodium and GABA. The text mentions a 5th, Nor-epinephrine/Noradrenaline as an inhibitor of CRH. I can see how the Itaconate shunt affects GABA directly as it becomes the new 'fuel' to close what's left of the Krebs/TCA cycle. This GABA shunt 'detour' however skips some of the steps in the TCA cycle, one being the Succinyl CoA Synthethase step which creates GTP. Less GTP (during the Itaconate/GABA shunt situation) means less biopterin/BH4 (which is synthesized from GTP and may already be limited in people with lower GCH1 activity, like myself, I'll have to look up if the gene shows up in the DecodeME study), which means that synthesis of both Serotonin and Noradrenalin may in turn be lowered. Acetylcholine may be affected by the lower availability of AcetylCoA during Itaconate shunting, and/or simply by the hypothesised Phosphatidylcholine deficiency as detailed by the hypothesis of @TamaraRC of (the overview figure draws heavily on all 3 versions of her work, which also further explains how noradrenaline may be impacted). Finally, I don't know if Sodium is directly affected by the Itaconate shunt. But the overview figure does provide a link in the box on ion-imbalaces, discussing the potassium pump and possibilities of Sodium overload at the cell-level in ME/CFS (which I assume would affect CRH).

Long story short: Possibly all 5 of the CRH/Cortisol regulators listed in this good-old textbook may be affected by the Itaconate shunt. I cannot say that I understand which ones would typically be up- or -downregulated, but when the known regulators of a hormone cycle are affected I think that's at least some substantiation to use the term 'dysregulation' in the context of Cortisol.

 

[ScoutB]

But it does raise a genuine question: Do you think this forum is an appropriate place for attempts at connecting hypotheses like this?

Sort of yes and no : )

As others have said, a lot of us skeptics are expecting most papers/results to be wrong, just because science is hard, most ideas turn out to be wrong etc. So an attempt to take all the ME/CFS theories and build a coherent story out of them is probably going to have more of an uphill battle on S4ME than it would in other communities.

On the other hand, we are constantly curious and speculating about possible connections and theories. Some examples of what that looks like on here:
- What can the science on the impact of acute infections on cognition tell us about ME/CFS?
- The symptom signaling theory of ME/CFS involving neurons and their synapses
- How do we know that common immune suppressants don’t work in ME?
- Interferons as mediators in ME/CFS
- Loss of CRH neurons and other neural changes in ME/CFS autopsy study - University of Amsterdam

Also, while a big connecting hypothesis might not get as much traction here, I think *you* would fit right in : ) Before I found S4ME I would have had the exact same instinct you have had to try and construct a synthesis of all the ideas. You've clearly put a lot of effort into it, and responded very graciously to our rather wet-blanket feelings about the state of ME/CFS research.

 

[Jonathan Edwards]

You have to make sure that what he means by inflammation is what you mean by it!

Well, what I mean by it is what has been in the textbooks for at least a century.
And it is well-defined rather than mixing up different steps in a causal chain!!

 

[richie]

Well, what I mean by it is what has been in the textbooks for at least a century.
And it is well-defined rather than mixing up different steps in a causal chain!!

I understand. I am not advocating for or against your usage, but other usages are now so common in the medical community that you can easily be misunderstood by people who might have a good deal of sympathy with your views overall. My own position is that there are grounds for alternative usages and that they can be helpful. We differ. Anyway, you have made it clear to me what you mean and why - partly, I think, thanks to my well meant pestering!
I do find it vexing when people who may agree about a lot end up at cross purposes over vocabulary, Ironically this is one your own central concerns, I would think, and why you demand precision. But while there are two or more competing usages the "disapproved" usages need to be recognised as existing and conversation conducted with that in mind, which does not entail concession to the validity of the usage you/I/ another person contests.

 

[Jonathan Edwards]

But while there are two or more competing usages the "disapproved" usages need to be recognised as existing and conversation conducted with that in mind, which does not entail concession to the validity of the usage you/I/ another person contests.

I fully recognise the other usages of inflammation but they are misleading and invalid and so I constantly point that out when we constantly hear them invoked.

Having spent my life in medicine surrounded by people who do not know what they are talking about (there are some prominent exceptions, but rather few) I feel that in retirement, having made use of terms the way they were intended to generate treatments of clinical value running in to hundreds of billions of dollars I feel entitled to blow off a bit of steam. If these people who use terms differently and confusingly can show that doing so provides translational progress at a similar level I will concede their point. Otherwise I call a spade a spade.

I am not sure why I should be 'misunderstood'. Yes, I do think most academics have no real idea what they doing; there is no misunderstanding there. If the problem is that I might be considered some conservative stick in the mud who likes terms to be old-fashioned I might point out that I seem to be about the only UK physician to have moved on to taking ME/CFS and ME/CFS research seriously. The fuddy-duddies all think it is biopsychosocial and that people with ME/CFS should be allowed to die of starvation with a bit of psychotherapy to help them along!

My approach may be uncomfortable. People don't like their favourite ideas torn down, but the thread poster's diagram shows just how desperately we need to tear these things down. Otherwise they just become mantras that stop any progress. Nevertheless, the thread poster seems well on the ball, and completely unphased, so I will keep at it.

 

[Nightsong]

You can cite whatever you'd like; there's no list of allowed studies, and not all members here will have the same opinion; there's no settled "S4ME position". The problem is that in the absence of reliable data and (until quite recently) the absence of many serious researchers there have been a lot of niche theories circulating, most of which don't make a great deal of mechanistic sense or simply don't match the clinical picture.

With most illnesses there is some specific pathology to grab onto that can give you leads, some lesion that can be studied - but with a clinically defined syndrome it has been difficult, until recently, to know where to begin, and in that vacuum & amidst such desperation all manner of spurious ideas and third-rate researchers have flourished. S4ME could in some ways be seen as an attempt to bring some measure of order to the chaos, although of course we discuss advocacy and care and lots more besides as well.

We are in all likelihood not looking for some imbalance between systems at a macro level in the "systems biology" sense but something very specific - a particular pathway or group of interacting pathways. Any theory or model of ME/CFS also needs to demonstrate how it can be so very debilitating yet at the same time doesn't produce classical signs of immune activation or inflammation or organ damage.

One of the reasons the DecodeME results are particularly valuable is that it avoids a lot of the biases that inhere in much other research in this area. Anything it throws up is a potential lead. Most of everything else that has been done to date has been more telling us where the problems aren't than where they are. Some academics & researchers will try to hype trivial, irrelevant or artefactual findings; that's just the way of things these days, unfortunately.

The cell-type analyses that have been performed on the DecodeME summary statistics to date seem to suggest a predominantly neural picture, and other genetic work such as Zhang seems congruent with that. There are some potential clues from MRS & PET studies. There have been a number of hints that lipids may play a role. A few pieces of the jigsaw are starting to fit together, but it's far from clear what the eventual picture will turn out to be.

My suggestion? Stick around; read the threads that interest you for a while, or the News in Brief if you can't. While we have a number of researchers, and a few patients with a scientific or medical background, I think most members here are ordinary patients & carers. If you can put together visualisations like that you have skills that would come in useful.

 

[MrMagoo]

A look at the ME/CFS Science blog is also a good introduction to mythbusting “accepted” and “well-known” symptoms and the faulty research behind them

ME/CFS Science

A critical view into ME/CFS research

mecfsscience.org

 

[Utsikt]

Long story short: Possibly all 5 of the CRH/Cortisol regulators listed in this good-old textbook may be affected by the Itaconate shunt. I cannot say that I understand which ones would typically be up- or -downregulated, but when the known regulators of a hormone cycle are affected I think that's at least some substantiation to use the term 'dysregulation' in the context of Cortisol.

When all you have to go on is a hypothesis, saying that there is «dysregulation» isn’t warranted. And by the looks of it from the thread on cortisol, there is a fairly strong evidence for there not being anything abnormal with the cortisol measurements.

And like you say, words like «dysregulation» are uninformative. They just say that something is off, but nothing about what’s actually abnormal. There’s seemingly a trend in medicine (and all of science in general) to use substitute words that just lead to confusion. And a lot of times the words require some previous interpretation of the underlying data, but the interpretation might very well be wrong.

That being said, I agree with everyone else that you should stick around. I’ve also been in the «trying to tie everything together» mindset, and I get why you’re thinking that way. But I think you’ve taken on a tremendously difficult task because of the poor quality of most of the stuff that’s out there. I’d be curious to see what the graphic looks like if you only kept the things we’re reasonably sure of. Perhaps you’ll be able to spot a new angle with that view because it can be pretty overwhelming to keep track of what’s going on across all the different approaches.

 

[SugarSquared]

Hello and welcome Sebastiaan! I really appreciate the discussion you sparked off. Before I joined this forum, this model of inflammation you raised fit right in with what I thought was going on. You've found the research a lot of us new to the ME/CFS research field find and hold onto. As others have said, it was a rude awakening for me to find out how they're not as well founded as I thought. I think that's where this forum comes in handy.

But I'm afraid I cannot contribute much there, as that's where I think a PhD in immunology does come in handy.

That's (thankfully) incorrect. I'll speak as a newer member of the forum here. Don't be fooled by my senior member status, I've only been here for a month and a half. (But I talk a lot, so I have posted enough messages to count haha.) You can contribute a lot more than you think you can. Even just asking "basic" questions can spark off meaningful discussion. The thread you started has gotten me to learn more about my blind spots Also, you already know a lot more biology than me, so I think you'll contribute a whole lot.

I started looking at this forum when the International ME/CFS Conference was taking place. Some of the research you linked was discussed there, so you may enjoy reading through the whole thread.

Before joining this forum, I felt powerless to affect research and disheartened at how poor quality a lot of it is. I now feel a lot more hopeful and have discovered I have more power than I thought. Researchers without ME/CFS are here to learn more from us and learn from the collective knowledge on this forum. It's also really cool to see how many researchers with ME/CFS there are. You've already identified some of the researchers who are on this forum. I won't @ anyone in case I leave some people out, but I recommend you look through the (members only) Introduce Yourself section to learn more about the people here. You'll learn how many fellow patients here have not completed a PhD but have knowledge on the same level of the researchers and scientists who have joined us.

Welcome once again. I'm happy to see you here.