Community symposium on molecular basis of ME/CFS at Stanford Discussion Thread

[Roy S]

https://twitter.com/i/web/status/1046192344524083200

 

[Sushi]

Ron Davis himself issues a big warning on not trying to manipulate your own cellular tryptophan. You could give yourself brain damage or die. They think there could be an easy cure but they want to test it properly and are very worried about patients hurting themselves.

!!! One person who self-experimented died!

 

[wigglethemouse]

Wild variance (and I mean wild, check out the graphs below) obscured a distribution that was not really very different.

I believe NAD has a short half life. So that could cause a large variance due to processing differences.

 

[raghav]

I woke up and saw Ron Davis' and Phair presentations. Did any researcher talk about the effect of leaky gut and / or microbiome and whether or not it plays a role ?

 

[lindaso1]

I believe it's more complicated than supplementation. He said the IDO1 route is inhibited and needs to be activated.. he also mentioned a cancer drug. Could it be Indoximod? My guess is that he's theorizing a short trial of a drug that activates the IDO1 gene could fix the cellular imbalance between tryptophan and kynurenine & change the expression of the gene.

https://www.sciencedirect.com/science/article/pii/S2452336417300201

 

[lindaso1]

@raghav

None of the speakers focused on gut microbiome but you might find this interesting as it relates to Phair's hypothesis.

https://www.frontiersin.org/articles/10.3389/fimmu.2017.01374/full

 

[IThinkImTurningJapanese]

Should we be losing our minds with excitement? because I think I am.

You know, sometimes your eyes are just too dry. Tears of joy are a welcome change.

 

[Sidereal]

The role of tryptophan in central fatigue has been discussed for decades.

The role of tryptophan in fatigue in different conditions of stress.
Review article
Castell LM, et al. Adv Exp Med Biol. 1999.

Authors
Castell LM1, Yamamoto T, Phoenix J, Newsholme EA.
Author information
1
University Department of Biochemistry, Oxford, UK. cat@bioch.ox.ac.uk
Citation
Adv Exp Med Biol. 1999;467:697-704.

Abstract
Tryptophan is the precursor for the neurotransmitter 5-hydroxytryptamine (5-HT), which is involved in fatigue and sleep. It is present in bound and free from in the blood, where the concentration is controlled by albumin binding to tryptophan. An increase in plasma free tryptophan leads to an increased rate of entry of tryptophan into the brain. This should lead to a higher level of 5-HT which may cause central fatigue. Central fatigue is implicated in clinical conditions such as chronic fatigue syndrome and post-operative fatigue. Increased plasma free tryptophan leads to an increase in the plasma concentration ratio of free tryptophan to the branched chain amino acids (BCAA) which compete with tryptophan for entry into the brain across the blood-brain barrier. The plasma concentrations of these amino acids were measured in chronic fatigue syndrome patients (CFS) before and after exercise (Castell et al., 1998), and in patients undergoing major surgery (Yamamoto et al., 1997). In the CFS patients, the pre-exercise concentration of plasma free tryptophan was higher than in controls (p < 0.05) but did not change during or after exercise. This might indicate an abnormally high level of brain 5-HT in CFS patients leading to persistent fatigue. In the control group, plasma free tryptophan was increased after maximal exercise (p < 0.001), returning towards baseline levels 60 min later. The apparent failure of the CFS patients to change the plasma free tryptophan concentration or the free tryptophan/BCAA ratio during exercise may indicate increased sensitivity of brain 5-HT receptors, as has been demonstrated in other studies (Cleare et al., 1995). In post-operative recovery after major surgery plasma free tryptophan concentrations were markedly increased compared with baseline levels; the plasma free tryptophan/BCAA concentration ratio was also increased after surgery. Plasma albumin concentrations were decreased after surgery: this may account for the increase in plasma free tryptophan levels. Provision of BCAA has improved mental performance in athletes after endurance exercise (Blomstrand et al., 1995, 1997). It is suggested that BCAA supplementation may help to counteract the effects of an increase in plasma free tryptophan, and may thus improve the status of patients during or after some clinically stressful conditions.

 

[Cam Newton]

I believe it's more complicated than supplementation. He said the IDO1 route is inhibited and needs to be activated.. he also mentioned a cancer drug. Could it be Indoximod? My guess is that he's theorizing a short trial of a drug that activates the IDO1 gene could fix the cellular imbalance between tryptophan and kynurenine & change the expression of the gene.

https://www.sciencedirect.com/science/article/pii/S2452336417300201

I believe that drug inhibits IDO, we want to upregulate it.

 

[bertiedog]

One is to supplement with kynurenine;

Not sure if this fits at all, doesn 't appear to but my Kynurenate on the last Organix test for organic acids was towards the top end of the range.

Pam

 

[MEssias]

How can the metabolic trap theory explain the epidemic ME outbreaks? Is a metabolic trap infectious?
I prophesy here that this will not be the solution. Think of me, if you realize that someday. sorry for being pessimistic

 

[Snow Leopard]

Tryptophan levels in the blood reflect the level of catabolism and in part reflect activity levels. In that sense the finding may simply be due to poor matching between patients and controls.

Exercise increases Tryptophan levels and this increase has also been hypothesised to be a cause of fatigue associated with exercise:
https://www.ncbi.nlm.nih.gov/pubmed/16424146

 

[Hopeful1976]

Does anyone know when the talks will be available on YouTube? I missed Ron's and Robert Phair's

 

[RWP (Rest without Peace)]

Can anyone post the handouts that were available this morning? I didn't get a chance to download them, and now I can't see them anymore. I DID find the agenda and Dr. Davis's letter, but I assume there's more, like there was last year.

RWP

 

[S-VV]

Regarding Tryptophan from the link that talks about the microbiome:

"Stimulated by interferon gamma, IDO acts as a tolerogenic, immunosuppressive enzyme to attenuate allergic responses by the induction of the KYN-IDO pathway, resultant depletion of TRP, and elevation in KYN metabolites"

Could that be why Th1 inmunostimulants work for some?

 

[Tally]

In that sense the finding may simply be due to poor matching between patients and controls.

That just doesn't sound like something that Dr. Phair, Dr. Davis or anyone on their team would miss. They said it themselves that it needs more testing, and it might turn out to be a fluke, but forgetting to match controls properly? I don't think so.

 

[FMMM1]

I think 'quiet hope' might be appropriate right now

But you're right, he sure didn't skimp on details


B

Hi Ben.

When will these presentations be available on YouTube? Missed most of them yesterday.

 

[Murph]

That just doesn't sound like something that Dr. Phair, Dr. Davis or anyone on their team would miss. They said it themselves that it needs more testing, and it might turn out to be a fluke, but forgetting to match controls properly? I don't think so.

@snowleopard

Also, If I remember correctly the measurements were of production of kynurenine from tryptophan in the cellular cytosol, not the amounts floating round in blood. Possibly they even said the blood measurement can go back to totally normal (but will need to watch again and check my recollection on this.)

 

[sb4]

TBH I'm not really excited about the tryptophan hypothesis. Having said that, insulin/carbs seem to increase Tryptophan influx to the brain. This could potentially explain some of the benefits of going keto in regards to CFS symptoms.

 

[FMMM1]

@Murph - Did you understand Ron's explanation of how this relates to ATP production? If so, can you tie that in with an explanation like the one above that is easily digested?

I haven't watched the presentation yet; I'm hoping that it will be available on YouTube (soon).

Regarding the link to ATP production Fluge and Mella's paper states that "[proposed upstream cause] ultimately causes metabolic dysfunction and induction of secondary rescue mechanisms". Specifically your body tries to "rescue" the situation by switching from producing cellular energy/ATP from glucose (normal) to using amino acids (such as phenylalanine) [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/]. You produce much less energy/ATP once you make this switch from using glucose (normal state) to amino acids (ME/CFS state). Naviaux said that this energy conservation state was similar to "dauer" [http://www.pnas.org/content/113/37/E5472].

So what Phair's proposing is (I assume) that the upstream cause is a problem with clearing/managing tryptophan levels. I.e. this is what causes the switch to using amino acids for your ATP/energy production -- "secondary rescue mechanism".

Here's a proposed blood based diagnostic method which is based on the measurement of one of the amino acids (phenylalanine) most people with ME/CFS are using for cellular energy/ATP production:
1) abstract: https://pubs.rsc.org/en/content/articlelanding/2018/an/c8an01437j/unauth#!divAbstract;
2) full paper: https://sci-hub.se/10.1039/C8AN01437J.

I've written to the European Union (EU) Committee on the Environment, Public Health and Food Safety (ENVI) to see if they would support a study to see if this can be used as a diagnostic test. The Committee is currently lobbying for increased funding for research into Lyme disease, including the development of a diagnostic test. The EU has already funded the development of a diagnostic test for Lyme disease [2 million euros/dollars]. The EU has not funded any research into ME/CFS. If you wish to write to your elected representative, e.g. requesting that they fund the development of a diagnostic test for ME/CFS, then you might find something useful on the thread [https://forums.phoenixrising.me/ind...h-theyre-working-for-you.61516/#post-1001161].

Ron Davis goes through other potential diagnostic methods in his talk. I caught a few minutes of this and recall the Seahorse was one of the methods discussed.

I wonder what Ron's explanation of the link between Phair's proposals and cellular energy/ATP was?