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Question collection thread for S4ME Q&A with Dr Karl Morten, University of Oxford, Sept 2019

Discussion in 'Researcher Interactions' started by Andy, Aug 15, 2019.

  1. Andy

    Andy Committee Member & Outreach

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    Friday 6th Sept, I will be having another of my video Q&As, this time with Dr Karl Morten of University of Oxford. So post your questions for him below and I will ask him as many as possible. Questions posted up until end of Monday 2nd Sept will be considered.

    If you need reminding of Karl and his work, click here for his University of Oxford profile, and here for his Researchgate profile.

    For forum threads that are relevant:

    Click here for my thread reporting as a patient representative with his collaborative research group (includes discussion of his rejected application to the MRC for funding).

    Click here for the thread on the paper that attempted to validate the findings of the mito function test that Sarah Myhill uses. (Karl and Julia Newton were joint authors).

    Click here for the thread on his talk in New Zealand (includes link to YouTube video of the talk).

    Click here for the thread on Simon McGrath's blog that discussed the research from various groups, including Karl's, that have found evidence for "something" in the blood of patients.

    ETA: To view our previous Q&As with other researchers see https://www.youtube.com/playlist?list=PLueHKJtiq09dtfqte4pcFkEbFaeWSQqRD
     
    Last edited: Aug 15, 2019
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  2. wigglethemouse

    wigglethemouse Senior Member (Voting Rights)

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    Q1. In the NZ presentation Karl Morten showed a 6 fold increase in Glutamate and a reduction in Glutamine. What needs to be done to validate this possible key finding?
    GlutamineGlutamate_KarlMorten_SlidesPage59.JPG

    Q2.How do Glutamate levels in the blood correlate to Glutamate levels in the brain?


    Elevated Glutamate is thought to be involved in Catanonia (Wikipedia) and Catatonia symptoms share many elements with very severe ME.
    https://en.wikipedia.org/wiki/Catatonia

    Some quotes from Wikipedia:


    Here is a recent Twitter thread that is worth a read on Catatonia by Dr. Mark Guthridge from Australia (tweets a lot about ME/CFS)
     
    Last edited: Aug 15, 2019
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  3. wigglethemouse

    wigglethemouse Senior Member (Voting Rights)

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    Q3. In the NZ presentation 2 unidentified VIP metabolites were significantly elevated in a subset of patients. What work has been done to identify those metabolites and to verify in a additional small cohort?
    GlutamateGlutamine_KarlMortenSlide60.JPG

    Q4. Is Karl Morten in communication with other groups doing metabolite work such as Lipkin, Naviaux, Davis, Hanson to dig deeper into these results. For example could Metabolon/Others program their Mass spec to look for these particular unidentified metabolites in other ME/CFS cohorts as those samples are processed?
     
    Last edited: Aug 22, 2019
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  4. wigglethemouse

    wigglethemouse Senior Member (Voting Rights)

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    Q5. The oxygen consumption plasma swap that Karl Morten reported on was fascinating, corroborating others findings that something in the plasma is inhibiting the energy pathways. Could Karl elaborate on ideas/experiments he could perform given adequate funding to take this further to try and narrow down the causes of the changes. What needs to be done.
    KarlMortenPlasmaSwap.JPG

    EDIT: In the Stanford nanoneedle paper published this year they described the procedure for applying a salt solution to the cells plus plasma and observing a membrane impedance change in cells with ME/CFS plasma. It would be very interesting to retry your experiment with the addition of the same concentration of salt solution to see what you observe with oxygen consumption.
     
    Last edited: Aug 22, 2019
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  5. wigglethemouse

    wigglethemouse Senior Member (Voting Rights)

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    Q6. Paul Fisher presented detailed work into Mitochondrial function in ME/CFS plasma cells at the Australia conference hosted by Emerge. Has Karl had a chance to brainstorm and discuss findings with Paul why cells seem to be in a high energy overdrive but then the end output seems reduced - both Karl and Paul are well respected Mitochondrial experts.
     
    Last edited: Aug 15, 2019
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  6. wigglethemouse

    wigglethemouse Senior Member (Voting Rights)

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    Q7. How much beer money would it take to visit Accumen Labs in Devon and jointly perform an experiment with John McLaren-Howard to resolve the differences on the Mitochondrial Function test so that both parties can be satisfied. I'm sure Norman Booth would have welcomed this. Combine with a long weekend Vacation perhaps?
     
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  7. wigglethemouse

    wigglethemouse Senior Member (Voting Rights)

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    Q8. In your NZ presentation and in the Tomas et al Mitochondrial Function test paper, you expressed the importance and relevance of timely processing of blood drawn from study participants for some studies. If I remember right you showed an example of substrate exhaustion when blood is left in the tube for an extended time.

    For the studies you would like to perform, would you be able to use the UK ME Biobank samples, or would you have specific blood draw process requirements needing processing on site at your lab? How could patients help you with this if needed?
     
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  8. wigglethemouse

    wigglethemouse Senior Member (Voting Rights)

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    Q9. I'm a sucker for personal stories. He touched on this in the NZ presentation.. I'm sure many of us would like to understand his path to becoming involved in ME/CFS and why and how he wants to make a difference.
     
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  9. strategist

    strategist Senior Member (Voting Rights)

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    I am very interested to hear what he thinks about Fisher's findings.
     
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  10. strategist

    strategist Senior Member (Voting Rights)

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    I would like to know what other illnesses have similar metabolite profiles, and whether he feels confident to say anything about metabolism in ME/CFS yet.
     
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  11. strategist

    strategist Senior Member (Voting Rights)

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    How far away is a diagnostic test? Even one that merely shows something is wrong and is usable in practice by physicians would be a nice step forward.
     
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  12. richie

    richie Established Member (Voting Rights)

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    Seconded.
    Plus should we be seeking diagnostic or informative testing (lupus is (often) diagnosed by test panels). IS atest invalid just because it is not diagnostic?
    Can we see Mc's claims as to integrity of his procedues taken seriously (incl possibility of refutation, of course). Is it good enough to just claim that timing issues must have played a role?
    What does KM have to say about alledged improvements in mito score and clinical improvements after interventions?
     
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  13. Annamaria

    Annamaria Senior Member (Voting Rights)

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    Thirded.
     
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  14. Aroa

    Aroa Established Member (Voting Rights)

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    You found that cellular phenylalanine is increased in ME patients.

    Do you have any hypothesis on why this may be happening ?

    Dr. Phair is studying Metabolic Traps . One of them could be the Tyrosine trap in which tyrosine hydroxylase may be substrate inhibited . Any thoughts on this and how this could be related to your findings ?
     
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  15. FMMM1

    FMMM1 Senior Member (Voting Rights)

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    @Andy
    Q1: Can the change in oxygen consumption, i.e. when ME plasma added to muscle cells versus normal plasma, be used to diagnose ME?
    [see graph - courtesy of @wigglethemouse ]

    Currently people with ME do not know if they have this "abnormality" [change in oxygen consumption/nano-needle response], many may not [NIH study shows high rate of false ME diagnosis approx. 30%?], and that might be relevant - e.g. show that they may have another known/treatable disease.
    Q2: Are these tests [change in oxygen consumption/nano-needle response] potentially useful even if we do not know precisely the underlying disease process is?

    Q3: Can we skip the protracted process (years/decades) of understanding the underlying disease process and use the existing diagnostic tests (nano-needle/oxygen consumption --) and drugs e.g. using copaxone/SS-31?
    That might improve the quality of life of people with ME now. Also, it might force funding of research since people have an disease which responds to treatment -- they can no longer be dismissed as having a psychological illness.

    Q4: Any progress/ideas on how to identify what is in the exosomes which causes this response (change in oxygen consumption) - any other known/similar effects in other diseases such as Parkinson's [exosome mediated signalling]?



    [​IMG]
     
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  16. strategist

    strategist Senior Member (Voting Rights)

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    I think we concluded that this was a misunderstanding.
     
  17. FMMM1

    FMMM1 Senior Member (Voting Rights)

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    I'd like to see some data i.e. from the NIH study and possibly from Julia Newton's group at Newcastle University. How many people tested positive using something like Karl's oxygen consumption test/nano-needle i.e. have this reversible change in cellular energy production? How many people were found to have another disease?

    We shouldn't assume that we can currently diagnose other diseases, such as MS, with 100% accuracy -- Ron Davis pointed out that so far the nano-needle is unusual since it's 100% accurate. On the plus side misdiagnosis has lead to the identification of a potential treatment i.e. copaxone which was used in a patient who was misdiagnosed with MS but who had ME.

    I expect that the data from the NIH study & Julia Newton's group will highlight the difficulties in diagnosing some diseases -- even relatively common diseases such as MS --- it may even point to some more potential treatments.

    @Andy can I squeeze in a further question for Karl - any update on the Raman spectroscopy (potential diagnostic) test for ME?
     
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  18. Barry

    Barry Senior Member (Voting Rights)

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    Would be very useful also presumably for the NICE guideline development. Anything that shows a biomedical differentiation from both healthy controls and from people who are solely deconditioned, could make all the difference between a fudge and a fix.
     
    Last edited: Aug 26, 2019
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  19. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    [​IMG]

    Does anyone understand what this graph shows? It has always puzzled me.

    Where do the readings start? Are they all at 13 or higher or where? The first red reading is way lower than the other two. What is happening when the level dips. Was the plasma added at 0? If so why do the cells only go down as well if nothing has been added to them? What is the box between 1 and 2? Are the rows of dots just from a single sample each or are there lots of samples shown? Why are the data shown as dots rather than lines? Maybe Karl knows all the answers.
     
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  20. Amw66

    Amw66 Senior Member (Voting Rights)

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    Graph reminds me of something but upside down. Most of graphs I relate a similar but inverted shape to are either climate systems/ crop CO2 / cell cycle . I think it's an inverse of photsynthesis CO2 for C4 plants, which have a different response to C3 due to rate limiting effect of CO2 - could this be similar?
    If axes are logged what does it look like?
    Why does the rate of change for ME cells differ between 0-2 so much - is this compensatory systems being out of whack ?

    Sorry, not too much sleep last week so this may be nonsense
     

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