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Are we close to a "unified theory" of ME/CFS? If so, what is it?

Discussion in 'General ME/CFS Discussion' started by Sasha, Oct 22, 2016.

  1. Sasha

    Sasha Fine, thank you

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    It seems to be all happening on the research front, with lots of excitement about metabolomics in particular, but as someone who is definitely not a bio-boffin, I can't tell if there's convergence on the cause of our illness.

    I remember @Rose49 saying how excited Ron Davis was at the IiME conference that lots of people seemed to be thinking along the same lines, but maybe I'm reading too much into that statement!

    So, are there any elements of the mechanism of our disease(s) that are agreed on? Are we close to a "unified theory"? If we're not, what's needed to get us there, is that research already underway, and when can we expect it to be reported?

    Tagging @Simon, @znahle, @Jonathan Edwards, @ChrisArmstrong in case interested.
     
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  2. A.B.

    A.B. Senior Member

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    Someone posted this on reddit:

    1. 22 May 2015 Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients (full, pdf)
      • - Christopher W. Armstrong, Neil R. McGregor, Donald P. Lewis, Henry L. Butt, Paul R. Gooley
    2. 13 July 2016 Metabolic features of chronic fatigue syndrome (full)
      • - Robert K. Naviaux, Jane C. Naviaux, Kefeng Li, A. Taylor Bright, William A. Alaynick, Lin Wang, Asha Baxter, Neil Nathan,, Wayne Anderson, and Eric Gordon
    3. 21 September 2016 Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles (full)
      • - Emi Yamano, Masahiro Sugimoto, Akiyoshi Hirayama, Satoshi Kume, Masanori Yamato, Guanghua Jin, Seiki Tajima, Nobuhito Goda, Kazuhiro Iwai, Sanae Fukuda, Kouzi Yamaguti, Hirohiko Kuratsune, Tomoyoshi Soga, Yasuyoshi Watanabe & Yosky Kataoka
    4. 27 September 2016 Bottom-up proteomics suggests an association between differential expression of mitochondrial proteins and chronic fatigue syndromeproteomics
      • - F Ciregia, L Kollipara, L Giusti, R P Zahedi, C Giacomelli, M R Mazzoni, G Giannaccini, P Scarpellini, A Urbani, A Sickmann, A Lucacchini and L Bazzichi
    5. ? October 2016 Elevated Energy Production in Chronic Fatigue Syndrome Patients (full)
      • - Nick Lawson, Chung-Han Hsieh, Dana March, and Xinnan Wang

    Additional, yet unpublished research:

    Dr. Hanson's Metabolomics ME/CFS Study Validates Naviaux's Core Finding,

    Dr. Hanson's YouTube webinar

    Dr. Mella (as in Dr. Mella and Dr. Fluge from Norway) says they have found same metabolites as Dr. Gordon and Dr. Naviaux in their PNAS paper (2).

    PS: Naviaux and Davis have another metabolomics paper in the works if I remember right.
     
    Last edited: Oct 22, 2016
  3. Sasha

    Sasha Fine, thank you

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    @A.B. - I see a list of studies there but not an answer to my question! :)

    Hoping someone would synthesise.
     
  4. worldbackwards

    worldbackwards A unique snowflake

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    Earth

    (sorry)
     
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  5. ash0787

    ash0787 Senior Member

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    Me neither, only have A level biology, I used to be academically inclined though and I know a fair bit about science and technology as a general concept I guess.

    It might be hard to explain if you dont already naturally understand from reading the studies,
    but essentially if there is a consensus it seems to be that whatever is happening, the body is effectively
    in control of in a coordinated response, its a functional mode that is either programmed into the body to handle certain scenarios, or some sort of mistake that isn't severe enough that the body cannot compensate for,
    As opposed to something like lead poisoning from an embedded bullet that the body has no genetic knowledge of,
    and cannot metabolically compensate for its introduction.

    If it were a mode it might be something like a self fulfilling prophecy, or an environment trigger such a traces of a virus, whereas if it were a 'mistake' it might be something like a single metabolic reaction becoming permanently disrupted somehow ( gene activation maybe ? ) causing a cascade effect which then is compensated for.
     
    Last edited: Oct 22, 2016
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  6. lansbergen

    lansbergen Senior Member

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    It points in a direction but there still is a long way to go.

    It fits with what I was thinking but as always there are many variables. It can start the same in evrybody but somewhere along the line there will be differencies.

    Anyway for me it is enough informatie to keep doing what I have been doing for the last 20 years.
     
  7. Snow Leopard

    Snow Leopard Hibernating

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    No, we have a long way to go, but a key may emerge in the next few years, particularly with a (raw data) meta analysis of the recent and ongoing metabolomics studies.
     
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  8. Hip

    Hip Senior Member

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    I have just been reading through all the Myhill, Booth and McLaren-Howard papers this last week, which like the more recent metabolomic studies, identified defects in the energy metabolism of ME/CFS patients.

    While reading this Myhill et al stuff, I had in the back of my mind this concept of a "grand unified theory" of ME/CFS, and what such a theory would entail.

    It seems to me that a successful unified theory would have to tie together, in an overarching explanatory framework, at least three known cardinal features of ME/CFS:

    (1) That ME/CFS is linked to being triggered and maintained by specific viral infections, such as coxsackievirus B, echovirus and Epstein-Barr virus.

    (2) That ME/CFS involves autoimmunity: the rituximab studies indicate this, and in addition, recent studies have shown the orthostatic intolerance conditions of POTS and OH, which are frequently found in ME/CFS, quite likely have an autoimmune basis. So it certainly looks like there is autoimmunity going on in ME/CFS.

    (3) The work of Myhill et al, plus more recent metabolomic studies, indicate that the fatigue and lack of energy that ME/CFS report may really be a fundamental physical lack of energy at the mitochondrial level. There seems to be a real defect in the energy metabolism of ME/CFS patients. Myhill et al found that ME/CFS patients have defects in mitochondrial translocator protein function and in mitochondrial oxidative phosphorylation, which impact and inhibit mitochondrial energy production.


    Anyway, so when I was reading the Myhill et al papers, I found a possible connection — and a potential "grand unified theory" — that links all three of the above cardinal features into one potential explanatory framework, namely that:

    Coxsackievirus B appears to trigger a specific autoantibody that targets mitochondrial translocator protein (thus resulting in reduced energy output from mitochondria).

    That single sentence may be a "grand unified theory" of ME/CFS, at least for some subsets of patients.

    The sequence of events in that sentence, if it indeed applies to ME/CFS, would tie together all three cardinal features of ME/CFS, and provide a unified theory of ME/CFS. (For more details of this translocator protein autoantibody, see the translocator protein section of this post).

    Of course, the above is just an idea, and as far as I know, nobody has looked for the presence of translocator protein autoantibodies in ME/CFS.

    But this sort of idea is, I believe, the kind of thing needed to try to connect the diverse features of ME/CFS into an overarching explanatory theory.
     
    Last edited: Oct 22, 2016
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  9. Sasha

    Sasha Fine, thank you

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    Thanks, @Hip.

    I wonder what all those scientists at the IiME conference that Ron Davis thought were all on the same page were talking about.

    I suppose my question is really whether the researchers feel that things are coming together or whether they feel they're all blindfolded and feeling just the nearest bit of the elephant.
     
  10. Hip

    Hip Senior Member

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    To an extent, I think "feeling the nearest bit of the elephant" is a tendency among most researchers. Every scientist has their own field of interest and expertise, and their approach tends to be to apply their area of expertise to the matter at hand (ME/CFS in this case).

    I was watching an interesting documentary about pharmaceutical drug discovery and development: in pharmaceutical research, what they have found is that within any specific scientific discipline and field of expertise, most of the pharmaceutical discoveries have already been made; and in fact, these days, new discoveries tend only to occur at the boundary between two disciplines, the area where one field of expertise overlaps another.

    So, simple as it sounds, what one pharmaceutical research organization have started doing is creating strategic seating plans in their offices and laboratories, that place individuals with complementary scientific disciplines in adjacent desks. In this way, just by normal daily office banter, you get a cross-fertilization of ideas, which may then lead to the next big discovery.

    So this is one solution to the issue of individual researchers only feeling their own part of the elephant.

    And undoubtedly, this interdisciplinary cross-fertilization of ideas would be very helpful in ME/CFS.
     
    Last edited: Oct 22, 2016
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  11. Sasha

    Sasha Fine, thank you

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    We seem to be going very off topic, and perhaps that's because I didn't make it clear that I wasn't looking for speculations from non-researchers, but a view on whether researchers now feel that they're converging on something.

    If non-researchers would like to produce and discuss their own speculations (and that would make an interesting thread), would you please like to create your own, new thread for that?

    I'd really like this thread to focus on whether researchers are converging on a theory.

    Thanks! :)
     
  12. TigerLilea

    TigerLilea Senior Member

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    I think it is too soon yet to know.
     
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  13. ash0787

    ash0787 Senior Member

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    The problem is that CFS cases tend to start with wildly varying events, rather than one specific virus, everyone is coincidently getting this particular undetectable virus at the same time as those specific rare events ? doesn't seem plausible unless the multiple pathogens are somehow symbiotic.

    Maybe its impossible to just figure it out this way and they have to actually look at whats going on in the body in fine detail with metabolomics etc.
     
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  14. Hip

    Hip Senior Member

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    I would not say that ME/CFS starts with "wildly varying events"; the triggering of ME/CFS has only been linked to a small and specific range of viral and occasionally bacterial/protozoal infections, with enterovirus (coxsackievirus B plus echovirus) and Epstein-Barr virus probably being the main triggering ones.

    Occasionally ME/CFS is triggered by vaccination, or after major surgery (though blood transfusion during surgery may introduce a viral infection, so this may really be a viral trigger). And mold, pesticide exposure, corticosteroids (in very specific circumstances), and possibly stress may be risk factors. But outside of that, there are no other events that have been linked to triggering ME/CFS that I am aware of. And the viral triggers are by far the most common.

    So to my mind, any unified theory of ME/CFS will need to explain why only these specific viruses, particularly coxsackievirus B and Epstein-Barr virus, seem to trigger ME/CFS. But such a theory would also have to explain how autoimmunity arises, and how the apparent energy metabolism dysfunction arises.

    This I think is going to require an interdisciplinary approach to ME/CFS research.
     
  15. hixxy

    hixxy Senior Member

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    I disagree and I also think it's possible that many people have not reliably characterised their triggering event. Especially those with gradual or mixed onset.
     
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  16. Hip

    Hip Senior Member

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    Just saying you disagree without providing reasons or evidence is not really a scientific argument. If you assert that ME/CFS can be triggered by "wildly varying events," what is the evidence for this?

    Note that it is not really possible for individuals to characterize triggering events; that can generally only be done statistically through studies, doctor's observations, or possibly through the observations on a whole group of patients on forums (although I have never any such forum research).

    What do you mean by "mixed onset"?

    But this is getting off topic.
     
    Last edited: Oct 23, 2016
  17. hixxy

    hixxy Senior Member

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    Where is the evidence that the triggers in the quote above are more common than the triggers in the quote below? Have adequate studies even been done to substantiate such a claim?

    You've just said a few "occasional" triggers in the quote above and yet below you plough on as though these infections are the only trigger in the quote below.

    If you claimed that some other triggers happen occasionally, then a theory based on these few infectious triggers is not very unifying at all.
     
    Last edited: Oct 23, 2016
  18. Hip

    Hip Senior Member

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    @hixxy
    When in your post you refer to "triggers above" and "triggers below," what do you mean? Can you be more clear please.

    EDIT: scrap that question, I think I understand what you mean.
     
    Last edited: Oct 23, 2016
  19. alex3619

    alex3619 Senior Member

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    I think we are close to having the data for a grand unified theory of at least the core subgroup of ME. What it actually means is still elusive. There are too many possibilities. The science keeps throwing up oddities that need to be explained.

    I do think however that many old theories are extinct, especially the psychobabble.

    I also think that CFS in particular might be several diseases, and even ME might be a couple of different diseases. On the other hand with such large numbers of things that are dysregulated it might be that much or most of the variation we see simply arises from the extreme complexity of how all these things work together.

    Things are changing rapidly. The new technologies are generating new data which I think will seriously change how we think about ME and CFS. We just are not at the grand unified theory stage. We are however at a point where we can see many of the issues more clearly, as the data makes many old ideas untenable. However there may be subgroups for which different theories apply.

    The thing is that, presuming one single theory is right, then the others must be wrong, at least for any specific subgroup (as eventually determined when we figure out what the subgroups are). So the theories are nearly all wrong, all but one (or one per subgroup). So if you were to guess then the answer that would most often be right is that the theory is wrong, regardless of the theory. That answer only comes unstuck when the correct theory is found, though we might not realize until years after it was proposed, because it still takes scientific investigation to validate the theory.
     
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  20. Hip

    Hip Senior Member

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    Dr Chia published one letter detailing the probable causes of ME/CFS in 200 consecutive patients. Here you see that vaccination is the probable cause of 1.5% of cases of ME/CFS, toxic mold exposure is the probable cause 1% of cases of ME/CFS, whereas enterovirus he finds is the probable cause of 55% of cases. Surgery-triggered ME/CFS does not appear at all.

    Epstein-Barr virus seems infrequent in Chia's list, at only 3% of ME/CFS cases, but I think the percentage of EBV-triggered ME/CFS is probably more like 20% of cases (I did a calculation here that indicates this). Perhaps he does not get many EBV patients, because he is more known for his interest in enterovirus.

    And if you spend long enough reading patient stories on these forums, and other ME/CFS literature, you get you own impression regarding how common each triggering factor is. You see vaccination triggers relatively rarely on these forums, but viral triggering is very common. And I have only seen two cases of surgery-triggered ME/CFS in the 6 years that I have been reading ME/CFS forums.

    Of course, there needs to be more research looking at exactly what causes ME/CFS and how frequently it does so. And there are some other ideas about what might trigger ME/CFS, such Dr Lipkin's ideas that it is some bacteria in the gut. But there is no evidence for this gut bacteria theory at all at the moment; it's just an idea.



    If enterovirus is causing the bulk of ME/CFS cases as Dr Chia's figures suggest, then obviously you'd best try to explain that subset of ME/CFS first, because that's the subset of disease that affects the largest group of people.

    It's possible that other triggers like vaccination might create slightly different versions of this disease, which may have a slightly different pathophysiology. But you get variations on the theme in many diseases, for example, there are 4 types of multiple sclerosis. You may get variations, but there will also be core features common to all variations. So this would not affect the hunt for a unified theory of ME/CFS.



    That's not what I was talking about. What I tried to point out was that there is a strong link between ME/CFS and certain specific viruses, such as enterovirus and EBV. For the enterovirus ME/CFS research, which goes back to the 1970s and earlier, see this post.

    By contrast, there is no link whatsoever between ME/CFS and other common viruses, for example norovirus. Norovirus has never precipitated ME/CFS as far as we know, whereas enterovirus and EBV seem to do it all the time.

    Therefore a unified theory would need to explain why enterovirus and EBV can trigger ME/CFS, but other viruses like norovirus cannot.
     
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