The Power and Pitfalls of Omics: George Davey Smith’s storming talk at ME/CFS conference
Read about the talk that stole the show at a recent ME/CFS conference in Simon McGrath's two-part blog.
Discuss the article on the Forums.

ME/CFS Collaborative Research Centers & Data Management Center Announcements

Discussion in 'General ME/CFS News' started by AndyPR, Sep 27, 2017.

  1. user9876

    user9876 Senior Member

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    I'm not sure any studies thus far are large enough or consistent enough to be more than potential clues to look at further. The problem as I see it is to run a large scale collection and analysis takes a lot of money - I think its also necessary to look at samples over time from the same patient as this may help pull out signal from noise (or random upstream perturbations). That is one of the nice things that the Biobank has just got funding to do.
     
  2. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    I tend to agree with the mitochondrial expert Mike Murphy that if mitochondria are involved it will be in terms of signalling, not defective metabolism. I have not seen evidence that would make me think it likely that there is a metabolic basis for symptoms. The symptoms sound to me much more like the sort of danger-signal induced effects we see in infection or autoimmunity.
     
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  3. greeneagledown

    greeneagledown Senior Member

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    What do you make of the metabolic studies that have been done so far -- by the Norwegians, Naviaux, Hanson, etc.? Are those consistent with a disorder involving the mitochondria and impaired signaling but not involving defective metabolism per se?
     
  4. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    Unfortunately, I do not hold all these studies in my head but I do not remember yet having come across convincing evidence of metabolic changes in cells of a sort that would explain core symptoms. I may miss stuff and am always ready to look again. Which findings were you thinking of in particular?
     
  5. greeneagledown

    greeneagledown Senior Member

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    How about your boys in Norway? https://insight.jci.org/articles/view/89376
     
  6. greeneagledown

    greeneagledown Senior Member

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    The Norwegians think pyruvate dehydrogenase is being blocked.
     
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  7. greeneagledown

    greeneagledown Senior Member

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    And based on his research, Ron Davis thinks glycolysis is shut down. (His findings are mostly unpublished, though.)
     
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  8. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    If basic cell respiration was blocked the expected clinical picture would be of a primary failure of ability to do work - in muscle or heart or brain for instance. That clinical picture is seen in severe cardiac or renal failure, various forms of poisoning and other things that get people to the intensive care unit. The symptoms of ME do not seem to be like that at all. Exertion leads to feeling ill later. And studies of muscle function and respiratory capacity seem to show reasonable results on first testing and then less good results later.

    So I think if there are blocks in pathways such as these would have to be linked in to some sort of danger signalling that is the real cause of symptoms. So far I am not aware that any of these findings has been replicated to an extent that it looks like solid evidence.
     
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  9. BurnA

    BurnA Senior Member

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    Would severe patients nor present like that?

    It's kind of obvious but it reinforces the importance of post exertion studies.
    Maybe that is where the secrets will be found.
     
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  10. greeneagledown

    greeneagledown Senior Member

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    But it seems like most of us (myself included) feel crappy most of the time, not just after exertion. I always struggle to do physical (or mental) work. The crashes are the worst times, but I never feel normal no matter how little I am doing or have been doing and I think that is the case for most of us. And I'm not even severe.
     
  11. greeneagledown

    greeneagledown Senior Member

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    I believe that is the exact hypothesis Ron Davis and Robert Naviaux are pursuing. Blockways in metabolic pathways linked to danger signaling, without any damage in the mitochondria themselves.
     
    Last edited: Oct 5, 2017
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  12. PinkPanda

    PinkPanda Senior Member

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    Couldn't it be that the signaling and energy metabolism are somehow related in ME/CFS? In the Community Symposium Naviaux talked about finding G protein related mutations in ME/CFS patients.

    For example G proteins play an important role in calcium signaling and calcium stimulates the energy metabolism in places like the glycolysis, the fatty acid oxidation or the pyruvate dehydrogenase. So maybe certain defects in signaling could impact the energy metabolism, but with another clinical picture than the typical energy metabolism dysfunctions.
     
    Sing likes this.
  13. FMMM1

    FMMM1

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    I think this paper, by scientists RIKEN Center in Japan, may support your views i.e. "Metabolic shift induced by systemic activation of T cells in PD-1-deficient mice perturbs brain monoamines and emotional behavior" [published in Nature Immunology 23 October 2017].

    From the abstract "these data indicate that excessive activation of T cells causes a systemic metabolomic shift with consequences that extend beyond the immune system".

    I think I asked on my first post on this site how we could identify the causes of the activated immune system (autoimmune response?). The question appears to have come around again.

    Also, does/why does retuximab work for activation of T cells?
     
  14. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    I would be careful about drawing conclusions fro this paper. This is a genetically engineered mouse that may have ten times as many T cells as it should. I cannot see any chance of human T cells altering metabolic balance except in gross t cell lymphomas.

    Rituximab does not work for T cell driven illnesses. We do not yet know it it works for anyone with ME. it is does it will be through removing B cells.
     
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  15. FMMM1

    FMMM1

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    Thank you for your reply.

    We aren't mice; people with ME/CFS have T cells with PD-1 receptors and they have (possibly) 10 times fewer T cells.
     
  16. leokitten

    leokitten Senior Member

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    Posting again here as there is a duplicate thread...

    IMO I don't think Lipkin's work is that compelling and I do not believe they will find much of anything that is actionable. The Microbe Discovery Project is interesting work from a research perspective but I highly doubt it will lead to absolutely anything actionable.

    What important work has Lipkin published on ME/CFS in the last 5 or more years? Really nothing other than the cytokine work. Hornig and Lipkin's paper on cytokines was interesting but only somewhat validated what we already knew, nothing new and nothing that we could do anything with. Just like with the cytokine study, searching in our microbiome for abnormalities will not really lead to any treatment, it will just be somewhat interesting research to gain some knowledge and that's that.

    I believe only two groups, Fluge/Mella and Davis/Naviaux, are looking directly at what is causing the key debilitating symptoms of this disease and have hypotheses that will lead to actionable knowledge and treatments within the next 5 years. It's a total shame that they didn't get funded by NIH and Lipkin did.
     
  17. neweimear

    neweimear Senior Member

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    Lipkin has all the data he needs collected, he just needed the funds to analyse it. He did not get enough funding of course. His aim is to find treatments for us, after hearing his recent presentations, I believe he wants to find solutions plus he is one of the world's top scientists.
     
  18. leokitten

    leokitten Senior Member

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    I promise you this, when we all see the results published from his work investigating the microbiome of ME patients comparing to healthy controls it will be just like the cytokine paper. Somewhat interesting results, likely not that reproducible, and possibly finding some subsets, but will do literally nothing to push the needle forward on actionable knowledge that can be used to develop effective treatments.

    Of course he says his aim is to find treatments, but what treatment will they find from looking at the microbiome? There isn't going to be one or two standout organisms that are different between ME and HC, it's going to be this very complicated picture that will just produce many more questions than answers.
     
  19. Alvin2

    Alvin2 If humans were rational...

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    Whatever you say Doctor
     
    Last edited: Oct 28, 2017
  20. A.B.

    A.B. Senior Member

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    A lot of research is like that. Knowing what is not particularly abnormal is still valuable, as long as the work is of good quality.
     

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