Central Hypothesis for Chronic Fatigue Syndrome: The Role of the Metabolic Trap in Fatigue
By Ronald Davis
 
We have proposed the existence of a metabolic trap that could be the causative event leading to ME/CFS (“Myalgic Encaphalomyelitis/Chronic Fatigue Syndrome”). This disease is initiated by an infection, usually from a number of viruses. A short time after or during this infection, patients can experience persistent fatigue or extreme fatigue. This fatigue usually lasts a lifetime. On rare occasions, patients spontaneously go into remission and appear to be totally normal. There does not appear to be any permanent damage in these patients, and they can return to full activity including heavy exercise, like jogging. This switching between a disease state and a healthy state is what has led to the proposal of a metabolic trap (or the deficiency and/or surplus of a critical metabolite that is stable and resistant to reset, generating a bistable state between health and disease). The first metabolic trap being explored is the tryptophan to kynurenine reaction.
Kynurenine is produced from tryptophan (an amino acid necessary for life) by an oxidation reaction using the enzyme produced from the IDO1 gene. This IDO1 gene product can be inhibited by high concentrations of tryptophan (substrate inhibition) resulting in the lack of production of kynurenine. Kynurenine appears to be a critical factor in the regulation of the immune system and could account for all of the unusual symptoms found in patients of ME/CFS. As explained below*, the inhibition of the IDO1 enzyme by tryptophan has only been observed in test tube reactions. It is essential to explore if this can take place in living cells. Experimentation is now underway to explore the metabolic trap in human cells.
 
In this talk, I will discuss our current understanding regarding ME/CFS, and the role of metabolic trap in fatigue.
 

Ronald Davis Biography
Ron is Professor of Biochemistry and of Genetics at Stanford University School of Medicine, Director of the Stanford Genome Technology Center, and Director of the Chronic Fatigue Syndrome Research Center at Stanford University. Ron is a member of the National Academy of Sciences. Throughout his career he has made numerous seminal discoveries that have accelerated genetics, genomics, and bioengineering, including over 70 patented technologies that have launched numerous successful companies. His contributions have been recognized by the Gruber Genetics Prize, the Genetics Society of America Medal, the Warren Alpert Prize, and the Personalized Medicine World Conference Luminary Award. In 2013, he was named one of the 7 World’s Greatest Inventors by The Atlantic. He now is devoted to finding a cure for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).
 
*Regarding the text tube reaction inhibiting IDO1 by tryptophan, the first test for this in vivo activity was conducted in Baker’s yeast. This organism is easily genetically manipulated. Kynurenine can lead to the production of NAD, and NAD is essential for growth. The Human IDO1 gene under yeast control was placed in yeast such that it can make kynurenine. All other methods of making kynurenine and NAD were removed, including all known genes that can consume or export tryptophan. The level of growth can now be assessed as a function of the level of tryptophan. This strain grows with a normal growth rate at low tryptophan but ceases growth at high tryptophan. This growth at high tryptophan can be rescued by the addition of kynurenine. This experiment demonstrates that the metabolic trap is operational in living cells. This ability to inhibit yeast also gives us the basis for finding a compound that can unblock the tryptophan metaboli

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