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#OMFScienceWednesdays-Robert Phair, PhD + ‘Metabolic Trap’

Discussion in 'General ME/CFS News' started by Ben H, Jun 13, 2018.

  1. Ben H

    Ben H OMF Correspondent

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    Hi guys,

    On this #OMFScienceWednesday we introduce you to researcher Robert Phair, PhD, running the OMF-funded metabolic trap project. Today, Dr. Phair shares his personal connections and how he became a part of OMF’s End ME/CFS research project.


    “I was a professor of physiology and biomedical engineering at The Johns Hopkins School of Medicine for 16 years before co-founding (with Ann Chasson) Integrative Bioinformatics Inc, a scientific consulting and software development firm in Mountain View, CA. We combine basic principles from human biology and systems engineering to test complex biological theories against experimental and clinical data. Our clients are scientists at research institutions and pharmaceutical firms.


    My neighbor, Marilyn S., is a ME/CFS patient. She and I had been discussing ME/CFS at weekly neighborhood get-togethers for about two years when another neighbor, Karin Molander, gave us a copy of her Stanford Medical School alumni magazine with an article, written by Tracie White, telling the story of the Davis/Dafoe family and Ron Davis' ME/CFS research effort at the Stanford Genome Technology Center (SGTC).


    A chain of family friendships in Silicon Valley linked me to Laurel Crosby, PhD, a member of the Davis team. Laurel invited me to visit SCTC and talk with her and Ron. I spoke with them for a half hour in July 2016, and it was obvious we all thought a collaboration was a good idea.


    I worked as a volunteer for a year and a half learning everything I could about ME/CFS. The great thing about this collaboration was that, for the first time, I actually had ME/CFS data to analyze and a bunch of smart colleagues with whom to work. During this period, the first results of the OMF-funded, Severely Ill Patient Study (SIPS) became available. These data included whole genome sequencing for 20 patients, and I began to look, one gene at a time, for potential genetic predispositions. Eighty-six genes later, I found a gene for which every SIPS patient had at least one damaged copy. But because another gene provided a biological workaround, it took me all summer to imagine a theory that might explain the origin of ME/CFS based on this common mutation. This is the theory I called the "Metabolic Trap."


    When I presented my theory to the SGTC ME/CFS team, I felt definite enthusiasm. That night I got a rare text from Ron: "That was an outstanding presentation." Naturally, this made me feel great, and shortly afterwards, OMF funded the project, in February, 2018. This made it immediately possible for our company to collaborate with SGTC scientists, Curt Fischer and Julie Wilhelmy (also OMF-funded).


    We're doing experimental tests of the metabolic trap hypothesis by applying the techniques of tracer kinetics and mass spectrometry to white blood cells from ME/CFS patients and people who are healthy. The first experiments are well underway. The reason I want to work on this disease, the reason I've invested so many days and nights, will be obvious to anyone who is or cares for or knows a victim of ME/CFS.

    Anyone who has read Hillary Johnson's Osler's Web or has seen the moving documentary films, like Jen Brea's Unrest, knows why we are working. Anyone who has attended a Millions Missing rally and listened to Ron Davis and Janet Dafoe speak so eloquently about the tragedy and the courageous hope of their son, Whitney, has felt in their hearts the reason this work is so important to me. We've seen Whitney's Plea. We won't give up.”


    Thank you Dr. Phair for being a part of our stellar team. Read more about Dr. Phair’s metabolic trap project.


    B

    @Janet Dafoe (Rose49) @AshleyHalcyoneH @marilynbsg
     
  2. Neunistiva

    Neunistiva Senior Member

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    Really great to read about this hypothesis more.

    Can someone more knowledgeable than me explain what this means?

    Eighty-six genes later, I found a gene for which every SIPS patient had at least one damaged copy. But because another gene provided a biological workaround, it took me all summer to imagine a theory that might explain the origin of ME/CFS based on this common mutation.
     
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  3. raghav

    raghav Senior Member

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    just a nagging doubt. Does the team have to test all the 300+ cell types in the human body or is it sufficient to test the wbc only ?
     
  4. Ben H

    Ben H OMF Correspondent

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    I don’t believe so, but I am pretty sure it will be tested on more than one cell type at somepoint. It may already have been but @Janet Dafoe (Rose49) may be able to clarify.


    B
     
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  5. Ben H

    Ben H OMF Correspondent

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    I am not saying I am more knowledgeable than you @Neunistiva :) but what part would you like explaining more so?

    The basic premise is that in the Severely ill patient study, every single patient had a copy of a gene that was ‘damaged’ per se. In this case as Prof. Phair states there is another gene that can provide a biological workaround to the possible effects of that ‘damaged’ gene. However a theory still emerged despite this and that is part of the ‘metabolic trap’ hypothesis.


    B
     
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  6. Neunistiva

    Neunistiva Senior Member

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    Feel free to do so :)

    This part was confusing to me. I am clueless about genetics, so I don't understand how one gene "knows" the other is faulty and jumps in to do the same thing in a different way, nor how did we despite this backup gene fall into the trap.

    It doesn't matter, as long as Dr. Phair understands it, I don't have to :p
     
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  7. Ben H

    Ben H OMF Correspondent

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    There is ‘gene redundancy’ which is where there are multiple copies of a gene in the genome which perform the same function. Not sure if that is the case here, maybe @Janet Dafoe (Rose49) can ask Ron!

    I think it’s important to remember at this time that it is still just a hypothesis, so we don’t actually know that patients have fallen into this potential trap. However the modelling suggests it is possible afaik and hence why it is being pursued.


    B
     
    Last edited: Jun 14, 2018 at 3:23 PM
  8. FMMM1

    FMMM1 Senior Member

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    Haven't really read your question but here goes for a reply.

    I listen to BBC Radio 4 Inside Science. I think the presenter is a geneticist. Some time ago (last year?) he review a publication based on genetic research of an Asian community in the United Kingdom. I'm wondering how to say this but they marry people from the same community so they sometimes pick up the same genetic mutations from the male and female side. Hence the interest from genetic researchers i.e. even a recessive mutation should be expressed. Somewhat surprisingly these people often present no evidence of negative effects from this mutated gene. The reason is that your body has a workaround "redundancy" or whatever you wish to call it. I can't remember an explanation of how another gene fixes the problem; possibly we can simply accept that it does (black box approach) but perhaps the mechanism could present a potential treatment/cure.

    So although Dr. Phair appears to have found a commonly occurring mutation he was wise to the existence of workaround/redundancy. Where he's gone now is intriguing. Possibly there's a non-virtuous circle; once you get in you cant get out. Check out Chris Arnstrong's webinar from December 2016. Chris was proposing a non-virtuous circle some time ago.

    I'm guessing that if Dr. Phair cracks this for even a few people with ME/CFS then (even if there are multiple causes of ME/CFS) he may help to explain a large part of the disease mechanism.
     
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  9. Murph

    Murph :)

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    This info is new to me:

    I guess when he was asking for everyone's genetic data, Phair was looking to see how common the damaged gene is in non-seriously ill patients. Suppose it is only present in the severely ill - if he can bring people like Whitney to my (mild) level it would be a huge achievement and massively improve quality of life of the worst sufferers. If the damaged gene was present in the rest of us too, then wow. That could be a very big deal.




    Phair is definitely nervous that testing the WBC only will not be enough to prove it either way. If the theory fails in wbc they are planning to do some muscle biopsies. That is harder though.
     
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  10. Rossy191276

    Rossy191276 Senior Member

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    Hi @Murph where did you hear that they were planning on doing biopsies if needed. I am a severely ill patient and I believe my biopsy is still frozen at hospital- I would gladly try to get it sent to them if it helped...
     
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  11. raghav

    raghav Senior Member

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    They are trying to reset the central pathway in white blood cells. But in the process if other cell types also get reset and if suppose they are not meant to be reset then will that cause a problem ? If all the other cell types are in the central pathway already then fine. Even then they have to ensure they dont switch off the central pathway in these other cell types. I am certain Dr. Phair with his more than 35 years experience modelling cellular biology would have thought about the ramifications of resetting just one cell type (wbc).
     
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  12. raghav

    raghav Senior Member

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    I have another layman doubt. If WBC are the culprit and their metabolism is low, does that bring down the metabolism of an entire human being ? Or is the wbc communicating with all the other cell types and asking them to shut down, as Robert Naviaux is proposing ?
     
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  13. wastwater

    wastwater Senior Member

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    I wonder which gene or genes are effected and which pathway they effect
     
    Last edited: Jun 14, 2018 at 5:03 PM
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  14. Murph

    Murph :)

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    They are not trying to reset just White blood cells (WBCs) in patients. The focus on wbc is just for the experiments in test tubes.

    Why? You get WBCs when you take blood from someone, and so those are the cells scientists do experiments on. (You also get a lot of red blood cells but they are not normal cells at all - no nucleus, really tiny, highly speicalised in carrying iron, so they're not a plausible candidate for experiments.)

    They hope that if the experiments work on wbcs then they will work on our whole bodies (or at least all those cell-types that are currently affected). I.e. they hope the WBC metabolism is a good match for metabolism in every cell. However, they are aware that it might not be. In which case they need to experiment on other cells.

    This is the best of my knowledge. I know there *is* some interplay between T-cell metabolism and the activation of the whole immune system but I don't think that is relevant here.
     
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  15. FMMM1

    FMMM1 Senior Member

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    I suspect OMF won't tell us that until they have concluded their research; currently scheduled for the end of the summer. You may wish to check with Ben H (OMF) regarding the timeline.
     
  16. valentinelynx

    valentinelynx Senior Member

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    A question... this term, "metabolic trap": was it coined by Phair to describe this particular hypothesis or is a term used elsewhere?

    When I googled "metabolic trap", I found a reference to the concept of enzymatic activity "trapping" particular types of compounds inside a cell. Or, in Wikipedia, it's described as the use of radioactivity to find how compounds are taken up and held by cells.

    Neither of these uses of the term seems to me to be applicable here, because it sounds to me like the "trap" Phair is talking about is one in which a patient's metabolism is caught in, not a molecule caught in a cell. But I wanted to be sure that I am not just making things up...
     
  17. FMMM1

    FMMM1 Senior Member

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    I think your right in your description i.e. in your last paragraph.

    A trap is something you're caught in (apologies - for stating the obvious); in this case a self perpetuating (low energy) metabolic state which may (see Janet Defoe's comments above) give rise to the immunological response observed by Mark Davis (see OMF Community Symposium September 2017) and others.

    I've commented above that if you review Chris Armstrong's work (I think it's in his webinar from October 2016); I think you'll find that he proposed that your metabolism was locked into a non-virtuous circle. So the hypothesis currently being tested (Phair) may have been proposed before; however, I think the mechanism proposed by Chris related to reduced stomach acidity, evidenced by high levels of volatile fatty acids in blood samples from people with ME/CFS.
     
    Last edited: Jun 17, 2018 at 8:00 AM
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