Ron Davis Summary of ME/CFS Working Group At Stanford Meeting Sept 8-10, 2021

Janet Dafoe

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ME/CFS Working Group at Stanford Meeting September 8-10, 2021

Summary, by Ronald W. Davis, PhD, and Janet L Dafoe, PhD

This was a great meeting and showed a lot of activity and progress in ME/CFS in an ever-growing number of groups. Researchers presented unpublished and often preliminary results. This style of scientific meeting can greatly accelerate research because scientists learn new information much earlier. It can often take a year or more to get a research paper published. Because of the preliminary nature of the results, it is essential that they remain confidential and not made public. Therefore, this is a summary without too many details. The speakers are listed at the end.

There is continued search for a pathogen(s) that can sustain ME/CFS. Most studies look for DNA or RNA from a pathogen.In addition, EBV and HHV6 have gained renewed interest for researchers due to evidence of activation of these viruses in the absence of DNA replication and amplification.

There were a number of talks about the metabolomics of ME/CFS. This work is moving from finding lists of metabolites involved in the disease to investigating various metabolic pathways. A major focus is on the nitrogen and BH4 pathways. There is a new focus on pathways in the mitochondria. This is difficult to study because of the small amount of mitochondrial metabolites in blood samples. However, this focus may be at the heart of what’s wrong in ME/CFS.

There was new work presented regarding autoantibodies and immune dysregulation. It is believed this dysregulation is what is causing autoantibodies to be present. The next question is, “What is causing the immune dysregulation?” There was also new work on neuro-inflammation, which also might result from the immune dysregulation.

There was a preliminary report of the molecular changes occurring with PEM. This will be a major endeavor.

A major effort was reported of an extensive genetic analysis from published and unpublished DNA sequence data looking for single genes and combinations of genes and any correlations with phenotypes. This is the first attempt to put together these previously disparate groups of data, and it was exciting to see. Thus far, the results are preliminary, but this is a very important investigation.

We heard an update on red cell deformability. In previous work, some labs have found a difference in red cell deformability between patients and healthy controls, and one lab found no difference. However, it was recently discovered that oxygen levels in the blood have a major impact on deformability. New instruments are being developed to measure deformability under controlled oxygen levels. There is a clear difference in deformability between patients and healthy controls under low blood oxygen levels. Thus, this continues to provide promise for a fast and inexpensive biomarker and diagnostic test.

New results on metabolic traps were presented. It is possible that there are many different metabolic traps and that these traps may be the cause of a number of chronic diseases. The tryptophan to kynurenine trap has been the first to be explored as an underlying cause of ME/CFS. This trap was first demonstrated in a test tube using purified enzymes, but does it exist in vivo in isolated cells? Yes! It was demonstrated that yeast with the Human IDO1 gene inserted into it became trapped when tryptophan was increased in the medium. Work is now progressing to determine if Human cells can be trapped. Using the yeast system, screening is proceeding for an FDA approved drug that will reactivate the Human IDO1 enzyme and get the cell out of the trap. In addition, a new trap or energy bypass in mitochondria was presented that could explain the low energy in patients and PEM.

In between the presentations, there was a significant amount of time for questions, discussions, brainstorming and the forming of collaborations. It felt like the research on ME/CFS has reached a new level, and it engendered an ever growing spirit of hope for eventual treatments and a cure.

Particiipants:
Christopher Armstrong, Rahaf Assil, Lucinda Bateman, Jonas Bergquist, Joseph Breen, Lily Chu,Jane Collins, Laurel Crosby, Janet Dafoe, Mark Davis, Ron Davis, Kenny de Meirleir, Mary Dimmock, Donna Felsenstein, Jennifer Frankovich, Keith Geraghty, Arnaud Germain, Anna Gil, Ludovic Giloteaux, Eric Gordon, Michael Gresser, Andrew Crimson, Paul Guyre, Rebecca Hamlin, Maureen Hanson, Ashley Haugen, Craig Heller, Katrina Hong, Mady Hornig, Li-Yuan Hung, Fereshteh Jahaniani, Michael Jensen, Sharada Kalanidhi, David Kaufman, Betsy Keller, Ryan Kellog, Vinod Khosla, Seoyeon Kim, Nancy Klimas, Kevin Kramer, Crystal Lantz, Joshua Leisk, Susan Levine, Alan Light, Kathleen Light, Ami Mac, Jessica Maya, Roya Mazrouei, Neil McGregor, Alain Moreau, Karl Morten, Adam O’Neal, Anna Okumu, Robert Phair, Bhupesh Prusty, Anand Ramasubramanian, Amit Saha, Carmen Scheibenbogen, Liisa Selin, Jaime Seltzer, Amrit Shahzad, Peidong Shen, Richard Simpson, Michael Snyder, Rivka Solomon, Franziska Sotzny, Linda Tannenbaum, Ronald Tompkins, David Tuller, Marielle van Kooten, Vanessa Velasco, Jiandi Wan, John Whiting, Vicky Whittemore, Julie Whilhelmy, Wenzhong Xiao, Sitong Zhou


We are all extremely grateful to all the funders of this research, including, NIH, OMF, Vinod Khosla, international funders, and the awesome generosity of patients and their loved ones. As usual, the progress of this research is always slower than it potentially could be due to limited funds. Donations are so deeply appreciated!
 

Shanti1

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Yes, thank you for the update. These two points were of particular interest to me:
In addition, EBV and HHV6 have gained renewed interest for researchers due to evidence of activation of these viruses in the absence of DNA replication and amplification.
Yes! It was demonstrated that yeast with the Human IDO1 gene inserted into it became trapped when tryptophan was increased in the medium. Work is now progressing to determine if Human cells can be trapped.
 
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A major effort was reported of an extensive genetic analysis from published and unpublished DNA sequence data looking for single genes and combinations of genes and any correlations with phenotypes. This is the first attempt to put together these previously disparate groups of data, and it was exciting to see. Thus far, the results are preliminary, but this is a very important investigation.
Could be the key to the lock!
 

Avenger

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I have sent this message because of your new focus on pathways in Mitochondrial dysfunction; I have included evidence of Mitochondrial Dysfunction related to D-Lactic acidosis; where 'surprisingly low complexes' were dismissed because my Histochemistry was not related to this neurotoxin;

I urgently need some help and advice; Although i have a diagnosis of D-Lactic acidosis supported by a Consultant Gastroenterologist, the NHS Chief Executive will not accept my diagnosis. It has been my belief that there may be others with similar problems due to similar Organic Acids, but I am not being allowed to prove this conclusively with a D-Lactic assay; that is necessary for me to have a Faecal Transplant at Birmingham QE Hospital (due to Licensing); and the Chief Executive are placing 'Chronic Fatigue Syndrome' back in my records which will place a psychological emphasis on my illness.

I need to find somewhere out of the UK to have a D-Lactic assay; I have evidence from 4 related Mitochondrial Investigations (that were performed during milder illness including abnormal fatigue, but not exacerbations or major crashes where I would develop more severe systemic symptoms including abnormal fatigue, breathing difficulty (often misunderstood as Hyperventilation), weakness, memory, high blood pressure, and cognitive difficulty).

Since 2002 (before I was diagnosed with D-Lactic acidosis) 4 Doctors requested Blood Gas Assays, when i was ill and had breathing difficulty; and since 2017 (after diagnosis of D-Lactic acidosis) a number of Consultants have asked for a D-Lactic assay when I am unwell; But No Assay has ever been performed for Arterial Blood Gasses or D-Lactic assay; I am receiving antibiotic treatment but losing antibiotics one after another due to resistance and my time is running out. I need a D-Lactic assay for Faecal Transplant due to Licensing because it has never been performed on another D-Lactic patient in the UK, but there has been fierce resistance to my being given a D-Lactic Assay in my own county. I have been having to travel 60 miles to Birmingham with transient symptoms to have a D-Lactic assay, which is impossible; are there any easier ways to obtain this evidence such as Urine Analysis or Faecal Assay or Microbiologist who can perform them. I cannot find anyone in the UK? I have not been allowed a Faecal Assay during exacerbations of symptoms and I am now wondering if this is a deliberate attempt to stop evidence of a relationship between D-Lactic acidosis and ME/CFS. At the same time Chronic Fatigue Syndrome is being placed back in my records despite my still being supported by a Gastroenterologist expert in D-Lactic acidosis; CFS in my records will undermine my diagnosis and place me in danger especially during Covid-19; and CFS has already been taken as the cause of my symptoms by nurses who are unfamiliar with D-Lactic acidosis.

I have tried to set up a 'Care Plan' to obtain a D-Lactic assay locally, but they want to put things in that are not true, such as to 'treat as Sepsis', when I do not develop and raise in temperature which will lead to further misunderstanding due expectation of a high temperature.

I had 4 Mitochondrial Investigations performed; 2 by a world leading Neurologist who after both Biopsies 4 years apart, stated that my Mitochondrial 'Complexes were unexpectedly low' on both occasions, but could not relate the low complexes to my muscle histochemistry; and had not taken into account the possibility of another component such as D-Lactate or Organic acids. The Neurologist was looking for a cell dysfunction or disease, but because that could not be explained by my Histochemistry, stated that there was no evidence of Mitochondrial Dysfunction;

The 2 Biopsies were at least 4 years apart; 1999 and 2004 and Dr. Myhills Mitochondrial and Hypoglycemia Investigations in 2005 and 2012. The results and my diagnosis of D-Lactic acidosis should speak for themselves; I have sent you copies that include the 2 Surprisingly Low Complexes. I now believe that Mitochondrial Biopsies were not understood in terms of Organic Acids. I was an athlete at the time of falling ill and my second Muscle Biopsy was put down to my increased muscle fibers due to training when I had stopped training 4 years earlier because I was so unwell!

I also had 2 Mitochondrial Investigations performed by Dr. Sarah Myhill that also show abnormality; I think that the investigations were performed through John Mclaren-Howards Laboratory and showed abnormality including Hypoglycemia although the Biopsies were not performed during a bad exacerbation.

When illness starts I have increasing Gastrointestinal symptoms; such as reflux, abdominal pain, sickness and bouts of reflux aspiration when food will not empty from my stomach; Emily Collingridge died from "respiratory arrest in an individual with clinically diagnosed ME due to the side-effects of prescription drugs and aspiration of gastric contents" during a long hospital admission. Merryn Crofts also had severe Gastrointestinal symptoms and became anorexic (one method of stopping D-Lactic acid is to withold enteral foods) but she died in hospital while give enteral foods from a feeding tube, that would have contained Carbohydrates and Sugars.

This lack of correlation between Mitochondrial Dysfunction and D-Lactate had led to further the belief that I was Somatizing. The lack of evidence due to normal blood results, that caused an 18 year delay in my diagnosis, was clearly only the evidence of absence, because of the lack training and ability to understand these issues, even from a World Leading Neurologist.

I believe that, this is why this illness has remained hidden for so long!

Mitochondrial Results Below;