The 12th Invest in ME Conference, Part 1
OverTheHills presents the first article in a series of three about the recent 12th Invest In ME international Conference (IIMEC12) in London.
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Ron Davis: Preliminary data shows problems with energy metabolism

Discussion in 'General ME/CFS News' started by Simon, Jun 5, 2016.

  1. Simon

    Simon

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    New blog :
    Ron Davis: Preliminary data shows problems with energy metabolism | #MEAction

    I'm posting in its entirety, since it's largely based on tweets from PR - big thanks to @Kina for those. Thanks too for help from @JaimeS and Alex Anderssen.



    Professor Ron Davis presented new findings from his Big Data study at Friday’s Invest in ME 2016 conference. Davis’s preliminary data show serious problems with the biochemical processes needed to convert sugars and fats from food into energy the body can use. If these findings are replicated, this could prove a major step forward in understanding ME/CFS.

    Davis’s study is unusual: it’s small with just twenty patients and ten controls, yet generated two billion data points; in fact, the researchers’ biggest problem is dealing with so much data.

    [​IMG]
    Cellular metabolism is incredibly complex, requiring and producing a wide variety of chemicals to function, day to day. Click for full-size image.

    The strategy for the study was to focus on severely ill patients because their biology would show the greatest differences compared with healthy controls. In the past, bedbound, severely ill ME/CFS patients have often been viewed as simply too difficult to study, rather than as key to making progress.

    The purpose of the study was to collect a prodigious amount of data and use it to identify biomarkers. The study examined a huge number of aspects of patient biology including immunology, proteomics (the production and interplay of proteins), and gene expression. But the main finding revealed at the conference related to metabolomics, the “systematic study of the unique chemical fingerprints that specific cellular processes leave behind”. Metabolomics can help to reveal what’s going on, and what’s going wrong in cells.

    Metabolomics is very expensive because it needs some very high-tech equipment, and that limits sample size. The study was only possible because the work was done at cost by new company Metabolon. In fact, Ron’s son Whitney Dafoe was the first person ever studied using Metabolon’s new process. So far, just three sick patients were studied, and were compared with 43 controls.

    Tiny sample, huge differences
    To find a meaningful difference in such a small sample would usually be impossible – only an enormous difference between patient and controls could be statistically significant because so much variation could be down to the “random noise” of chance. In this case, the differences were vast enough to be considered significant; and, as Professor Davis told the audience, studying three people is not a big study but in personalized medicine, you can learn from just one patient.

    Professor Davis illustrated just how big the difference is by using standard deviations, the most common measure of differences in science. The standard deviation is a measure of how much the data within a sample varies on a particular variable, such as people’s height or blood sugar. At least one data point from Whitney Dafoe’s energy metabolism molecules was 16 standard deviations away from the average of the control group. To put that into perspective, 99.7% of all data should fall within three standard deviations away from the average in either direction, and only 0.3% beyond that boundary. The more standard deviations the data is from the average, the less likely that the difference is due to chance. Findings from ill patients that are sixteen standard deviations away from the average in healthy patients is extraordinary.

    [​IMG]
    Patients had big problems generating energy (graph by @JaimeS). Click for full-size image.

    The metabolomic data in the three patients who were examined highlighted that the main metabolic engine of energy molecule generation – the citric acid cycle in mitochondria – isn’t working properly. Glycolysis also does not look like it’s working very well in patients.

    Researchers were able to determine these errors by looking at the molecular byproducts of the cell and noting abnormalities in the compounds usually consumed and generated by these reactions. The basic biochemical process to turn sugars from food into energy molecules just wasn’t delivering for patients.

    This might not surprise many patients, but it’s big news in the world of ME/CFS research. There have been findings along these lines before, notably on the second of a two-day maximal exercise test (the day one test results look normal), and in a study on the products of glycolysis in the blood and urine of ME patients by Christopher Armstrong and colleagues.

    More research is needed to replicate these findings, and such a study is already in the works; but this could be the start of a dramatic shift in the field.

    Ron Davis, who has previously studied patients with physical trauma also noted that mitochondria “shut down” in these patients and said that a key question is why they don’t start up again in ME/CFS patients.

    Davis said that his son Whitney showed errors in B-vitamin metabolism, resulting in a very rare deficiency of biotin; this is important, because enzymes in the citric acid cycle are dependent on biotin. In another patient, tryptophan metabolism was a problem.

    Professor Davis’s talk generated excitement both at the conference and among those following the Twitter coverage. His wife, Janet Dafoe, commenting on his talk, said that his team hoped to work quickly towards tests for personal biomarkers for all patients. She said of the research, “We know it’s frustrating and that people are rightfully chomping at the bit! So am I! Every morning… when I wake up, he brings me coffee and I quiz him about what has happened that day so far. I wish you could all be flies on the wall. It’s so exciting. If everyone knew all of what he’s doing, I can’t believe he wouldn’t get big funding.”

    Donations can be made to Professor Davis’s work via the Open Medicine Foundation. Janet Dafoe has noted some confusion in regards to the OMF, the OMI, and the CFS Research Center; donating to the Open Medicine Foundation is the best way to make contributions.


    Please note that this article is based solely on tweets from Phoenix Rising’s team and Maija Haavisto, who were at the conference. Huge thanks to them: tweeting on the fly about a technical presentation is not easy. The article has not been checked with Professor Davis, and any errors are ours. Jaime S and Alex made significant contributions to this article.
     
    Last edited: Jun 5, 2016
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  2. adreno

    adreno PR activist

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    Exciting stuff @Simon. Although, problems with the krebs cycle has been suggested for decades.
     
  3. alex3619

    alex3619 Senior Member

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    I first proposed some of this in 1999. It went down like a lead balloon. People were more interested in the notion of accelerated glycolysis rather than an inhibited citric acid cycle. My model was wrong though. However my revised model, still unpublished and no longer about causation but only pathophysiology, is still viable though of dubious value considering the awesome amount of data now available.

    Further discussions as to why this might be, with Marty Pall and Rich van Konyenburg, led to Rich becoming very interested in glutathione, a path I was very much into at the time, given how it can severely impact mitochondrial function. GSH is critical in proper protein folding. I still wonder, even now, how much of the measurable enzyme quantities inside the mitochondria are properly folded. Molecules like aconitase are imported from the cell unfolded, and folded inside the mitochondria.

    I can only wish I had the kind of data we have now. Back then it would have been better than a truckload of candy to me.

    I suspect that, initially at least, what we will get is a large detailed case series showing a range of issues. Its the repeating patterns and subgroups that will make this interesting. Hmmm, its starting to sound like I might be in a candy store soon.
     
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  4. Ben H

    Ben H OMF Correspondent

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    Interesting Alex. I've always thought the Krebs cycle wasn't up to par, because of how this felt for me, coming from a place of having a huge amount of ATP etc for my athletic endeavours, to my housebound state now. It feels metabolic in nature. Specifics though I had no idea, because you can't unless you have an OAT done, or better still metabolomics.

    R.e. Your research, especially on glutathione and protein folding, may be extremely important. I'm sure Ron and team are up to scratch on this, however it may be worth your/our time if you are up to it contacting Linda at OMF and forwarding your thoughts on.

    They are extremely open to suggestions, there are no ego's at OMF, despite the world class team. It was a stipulation of Davis's.

    So in short, if you have anything to say, or any ideas, even old, they may still be relevant and may be important in the cause.


    B
     
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  5. BurnA

    BurnA Senior Member

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    Indeed, whist it is encouraging to hear Ron Davis suggest his theories, given that only 3 patients have been tested so far it might be a bit early to get too excited.

    Also given that there are only 20 patients in the big data study the level of repeating patterns and subgroups may be difficult to discern. I am hoping there is a high level of consistent abnormal results but who knows.
     
  6. Ben H

    Ben H OMF Correspondent

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    Good points BurnA.

    From what I can fathom so far, there are certainly differences in the group as mentioned above (biotin for Whitney, tryptophan metabolism for another) but there are very clear abnormalities that are shared across the board. This is insinuated by Davis, and his 'close to biomarker' remarks.

    I think there is a lot that we do not know yet, simply because it is waiting to be published. However when talking, in interviews, he has stated the TCA to be the issue for us. What's causing that he doesn't know at the moment, but it is suggested that is the issue. I can't see him stating that unless he was certain, based on the 20+ patients so far, and consistent findings. He just can't afford to. But we just need to wait for the data and publications to come out.

    The subsets are a little more difficult and I think that where the big data set comes in.

    Great points.



    B
     
    Last edited: Jun 5, 2016
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  7. aimossy

    aimossy Senior Member

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    I think Ron Davis said it's risky. But in the sense it can have big pay offs.

    I'm wondering how many groups are doing metabolomics work at the moment or are about to apart from Davis, Naviaux and Hornig.
     
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  8. RL_sparky

    RL_sparky Senior Member

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    I think I read somewhere that Dr. Maureen Hanson is also doing a study.
     
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  9. aimossy

    aimossy Senior Member

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    Oh woops. The grand challenge is also planning a extremely large study with metabolomics.
     
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  10. Simon

    Simon

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    Yes, given the problems we have with energy for both mental and physical activity, it would certainly makes sense. But there's not been a whole load of evidence. Also, a lot of the exercise studies don't seem to consistent with this, often showing relatively normal results on day 1 of a 2 day max test (as the article mentions). Some studies have found disproportionately high levels of lactate in exercising patients, but other studies haven't. It's also likely that patients in these exercise studies are at the mild end of the spectrum, compared with the severe patients in this study. That would make it easier to pick up differences (the whole idea of focusing on severely-affected patients).

    There may well be subgroups too as Alex and others have suggested.

    A hugely important point. What makes these findings interesting is how extreme they are (almost off the scale), but it's still only three patients

    Indeed. Am I right in thinking that OMF data will be made open in due course?

    Still recovering from blogging, back another day.
     
  11. user9876

    user9876 Senior Member

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    I'm wondering if they will find subgroups or whether they will find that these processes are disturbed in patients but not necessarily in a consistent way.

    The question I'm wondering is that if there is disruptions in this cycle what are causing it?
     
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  12. aimossy

    aimossy Senior Member

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    Thanks @RL_sparky It makes me wonder if klimas group is too.
    We could have a fair few looking at metabolomics. I don't know enough to know if they would use the same methods or look at the same metabolites there seems so many metabolites you can look at.
     
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  13. JamBob

    JamBob Senior Member

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    Sounds promising - I wonder how much it would cost per patient to run these kind of tests and if it is something that will ever be accessible to the general population.

    Also I would like to know how we can know if these deficits (eg. biotin or tryptophan deficiency) are caused by the disease itself or are artefacts of the impact of a disease. Eg. if someone is so sick that they are unable to eat and can only have nutrition through a tube, wouldn't that in itself lead to nutritional deficits? Or is that unlikely?
     
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  14. Ben H

    Ben H OMF Correspondent

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    Indeed. I'm hoping based on Davis 'close to biomarker' etc that there must be identical findings. Otherwise you couldn't have a biomarker. It would be scary indeed if the TCA was disturbed differently for every patient as it could make a cure very difficult. I guess we need to wait and see, but I'm hopeful.

    The CDR mechanism could potentially disrupt this cycle. It's been insinuated, and it was recently published by Dr Naviaux who is Davis's mitochondrial researcher:

    http://www.sciencedirect.com/science/article/pii/S1567724913002390



    B
     
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  15. aimossy

    aimossy Senior Member

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    I think you can pay for your own testing at metabolon.com ? Some study was offering free testing for 1500 donation.
     
  16. Marco

    Marco Grrrrrrr!

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    Are ME/CFS symptoms and epidemiology consistent with inherited or acquired defects of the Krebs cycle? Even partial defects often result in pretty unmissable signs such as developmental delay and often early death.
     
  17. RL_sparky

    RL_sparky Senior Member

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    @aimossy. Gordon Medical was offering the tests for a $1500.00 donation but I can't find that on his site anymore. He was offering it originally in an effort to raise the $400,000.00 needed for his follow up study that OMF is now funding.
     
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  18. Sasha

    Sasha Fine, thank you

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    Isn't it part of the NIH intramural study? I can't remember, but they're doing loads.
     
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  19. barbc56

    barbc56 Senior Member

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    Wonderful! Thanks @Simon. A very positive direction.

    I just made a very small donation, but every penny counts, eh?

    Thanks to @Kina @JaimeS and anyone else that helped with this.

    I've often wondered how leaving out those most severly affected would change the outcomes of studies. Not from any great insight by me, other than a few required courses in study design/statistics so long ago that I've probably forgotten more than learned, but because of the impact of wanting to participate in studies over the years and just could not make it. I'm not anywhere near disabled as those such as Whitney.

    Ron even brings Janet coffee in the morning! I'm sure well deserved. What an incredible and compassionate family. I wish them well!
     
    Last edited: Jun 5, 2016
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  20. JaimeS

    JaimeS Senior Member

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    Personally, mine was off the charts for lactate. And that was before deconditioning set in. Unlike many, I ended up getting the more complex testing early on in the illness.
     
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