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

[Tally]

I have always wondered why it seems like almost all people with CFS are caucasian. That could be the answer!!

but also indicated that he wonders as well what the comparative prevalence is in different parts of the world.

This research seems to suggest it's not more prevalent among Caucasians

The present study found adult rates of chronic fatigue syndrome (CFS) in Nigeria that were somewhat higher than rates from community-based CFS epidemiologic studies in the USA.
​

If I remember correctly Japan had a prevalence of around 1%, so similar to the US and UK.

I think at this point in time prevalence is dependent on which definition is used in research, and visibility of patients depends on how lucky they are to be in the group of people which is taken seriously by doctors, and lucky enough that at the moment they get sick they are educated, not in poverty, and have family support enough to be able to fight.

It's not that simple, it is hard to match people on activity levels etc.

Everything these researchers are doing is difficult. Much more difficult than matching controls.

I'm sorry, I just can't agree with you because wrongly matching controls for ME is such a rookie mistake that I am not worried they made it. If they couldn't find proper controls I am sure they at least took it into account.

These are not BPS researchers who will steamroll over proper methodology to promote their careers.

 

[FMMM1]

Oh, I'm so excited now to see Ron's and Robert's presentations, having read what people have said! They were in the middle of the night in the UK – the event started at 5pm our time, and I only managed to stay with it until the lunch break before I fell asleep. It all sounds incredibly positive.

I agree that this looks positive.

I watched the start of Ron's talk and he emphasised the need to develop a diagnostic test. One of the options he highlighted was the Seahorse analyser. Here's another potential blood based diagnostic test:
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) if they would lobby for funding for a study to see if this can be used as a diagnostic test. I've posted some material here [https://forums.phoenixrising.me/ind...h-theyre-working-for-you.61516/#post-1001161]. I think that we should try to lobby our elected representatives i.e. for funding to develop a diagnostic test.

At this stage individuals do not know that they have this specific metabolic problem i.e. switch to using amino acids, rather than glucose, for cellular energy (ATP) production.

If I understand it correctly, this research only relates to people who have this specific metabolic cellular energy (ATP) production problem.

I missed Phair's talk (I'm also in the UK). Is the theory that everyone has this specific genetic problem? The incidence of ME/CFS is approximately 1 million in 500 million European population (0.002%?). So the number of people with this genetic problem would need to exceed that. I think I read somewhere on this site that mutations on this gene were relatively common (greater than 1%?). Just as well we have a world leading geneticist i.e. Ron Davis!

From this site I understand that there's a potential drug treatment (cancer drug?). I assume that this strengthens the case for developing a diagnostic test i.e. you will only get access to a drug if you can demonstrate that you have this specific form of the disease.

Think about how/whether we could assist in the delivery of a diagnostic test.

 

[perrier]

Did anyone manage to pick up any references to when the metabolic trap theory might be tested on people? Or is this some years down the line? For the sick person, of course, the bottom line is: can this help, and when can it help. Thanks.

 

[perrier]

I love Core Products because they stay cold a long time without the fear of freezing your skin. Frostbite, which can stay painful for months, is avoided with this ice pack. It's OK to put directly on your skin.

https://www.amazon.com/Core-Products-Flexible-Compression-Injuries/dp/B07DW92BBP
(Same product as above.)
https://www.coreproducts.com/clover-pack.html

The pack is 11.5" x 11.5" and comes with TWO straps (length not specified).

Extra tip: Your head will stay cooler when it has no hair. There are separate threads on PR about shaving one's head (male and female).

On the market there now exists an FDA approved sleep device from Ebbs technology which consists of a headband which stays cool all night. We have the device. Hard to say yet, what its benefits are.

 

[FMMM1]

I was complaining about sample size on the nano-needle impedance study before.
This slide (which to the best of my knowledge has never been shown in public before) is pretty much enough to stop the complaining! What an amazing separation.
View attachment 29495

I'd be interesting in seeing how it compares to this potential blood based diagnostic test for ME/CFS:
1) abstract: https://pubs.rsc.org/en/content/articlelanding/2018/an/c8an01437j/unauth#!divAbstract;
2) full paper: https://sci-hub.se/10.1039/C8AN01437J.
Small study but the statistics look promising i.e. the test correctly predicted 98% of those with ME/CFS [compared to healthy controls].
The test measures phenylalanine in blood cells. The test appears to confirm findings by Christopher Armstrong, and Fluge and Mella, [OMF] i.e. that there is a switch in cellular energy production from glucose to amino acids (such as phenylalanine) in ME/CFS.
A larger study is currently underway.

Ron pointed out that they don't know what the nanoneedle is measuring i.e. it's a change in impedence but the cause is unknown.

I wonder how these tests will perform in men i.e. women may be easier to diagnose?

I've asked the (EU Committee on the Environment, Public Health and Food Safety (ENVI) if they would support a study to see if this can be used as a diagnostic test.

Maybe we should contact our elected representatives i.e. to ask if they would lobby for funding to develop a diagnostic test.

 

[FMMM1]

It seems to be me that Dr. Phairs theory goes deepest to the root cause and all the other things presented are a result of the negative affects the metabolic trap is having on the brain and the body. He also presented the most detailed and rational explanation for the disease and all the variety of symptoms. I could see it unfolding like this Metabolic trap leads to T-cell clonal expansion leads to inflammation in the brain which then sets off all of the symptoms we have.

His explanation was also the most hopeful and seemed closest to actionable results.

I hope he is correct and they can start testing some treatments. Dr. Youngers theory is compelling too, but like he said in ending still doesn't explain what is causing brain inflammation; just gives us another symptom that causes sickness feelings. Also at least a year b/f there will be any results .....too long and far away; more will die over this year. Need to work fervently on the hypothesis that can bring us results sooner. How can they get a big Silicon Valley entrepreneur to donate!!!!!!!

I haven't seen Phair's presentation yet.

If I understand it correctly there's talk of a cancer drug i.e. which may be effective (regulates the expression of these enzymes or whatever). Nancy Klimas has looked at drug repurposing i.e. taking already approved drugs and trying to apply them to gulf war illness [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495687/]. Department of Defence has funded Klimas's work. If the veterans turn out to have ME/CFS then the Department of Defence might fund the trial.

Ron Davis highlighted the need for a diagnostic test; here's a potential test:
1) abstract: https://pubs.rsc.org/en/content/articlelanding/2018/an/c8an01437j/unauth#!divAbstract;
2) full paper: https://sci-hub.se/10.1039/C8AN01437J.

The European Union (EU) funded the development of a diagnostic test for Lyme disease [2 million euros/dollars]. I've asked the EU Committee on the Environment, Public Health and Food Safety (ENVI) if they would lobby for funding for the development of a diagnostic test for ME/CFS [https://forums.phoenixrising.me/ind...ch-theyre-working-for-you.61516/#post-1001161].

So there are options for the public funding for drug trials (drug repurposing) and development of a diagnostic test for ME/CFS.

I suggest that we contact our elected representatives to see if they will lobby for/support public funding for drug trials (drug repurposing) and development of a diagnostic test for ME/CFS.

 

[Learner1]

Does anyone have the names of exact SNPs that were mentioned in the talk that disrupt IDO2? They usually start with rs. I tried googling around and found a few but I’d like to see if they match what Dr Phair found.

See attached.

If I understand it correctly there's talk of a cancer drug i.e. which may be effective (regulates the expression of these enzymes or whatever).

No, the drug did the same thing and CAUSED fatigue. We need the opposite.

 

[FMMM1]

Here's what might be a reason to stay netural on the metabolic trap hypothesis.

If the kynurenine pathway were disturbed, it would flow to NAD. Naviaux's metabolomics data was far from clear on nicotinamide. While patients differed massively from controls, it was in different directions between men and women! It showed strong results due to a few outliers. Wild variance (and I mean wild, check out the graphs below) obscured a distribution that was not really very different.

View attachment 29502
Axis on graph one goes to 4.5 million but exercise caution:
View attachment 29503

Axis on graph two goes to 60 million!

I'm not sure that I understand what you're saying but Fluge and Mella found a difference between men and women. Check out Table 1 i.e. results for phenylalanine (Phe) in this study [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/]. The results for women, with ME/CFS versus healthy controls, were highly significant [P less than 0.001] but the results for men were not significant [P 0.19]. I.e. it appears that the response in women with ME/CFS is different from men with ME/CFS .

 

[FMMM1]

See attached.


No, the drug did the same thing and CAUSED fatigue. We need the opposite.

That's really interesting i.e. appears to support the theory that people with ME/CFS not being able to clear tryptophan and that this results in fatigue. Did the drug inhibit IDO1 or IDO2 or both?

Also is there another drug they're interested in i.e. for a potential drug trial?

I should have stayed up to see Phair's presentation but I didn't know the running order for the presentations.

Thanks

 

[babeng]

The test appears to confirm findings by Christopher Armstrong, and Fluge and Mella, [OMF] i.e. that there is a switch in cellular energy production from glucose to amino acids (such as phenylalanine) in ME/CFS.

Or could the test show a different trap given that Phair says it could be several traps?
I'm no expert at the subject, but since increased cellular tryptophan showes a possible trap, maybe increased phenylalanine does the same.

My point is that increased cellular phenylalanie doesn't necessarily need to confirm Fluge/Mella/Armstrong's theory. Cause with that logic increased cellular tryptophan would confirm their theory as well, and not the possible trap?

 

[Learner1]

That's really interesting i.e. appears to support the theory that people with ME/CFS not being able to clear tryptophan and that this results in fatigue. Did the drug inhibit IDO1 or IDO2 or both?


Also is there another drug they're interested in i.e. for a potential drug trial?

I should have stayed up to see Phair's presentation but I didn't know the running order for the presentations.

Thanks

I am not sure that a drug is the answer. The trap is biochemistry altered in a malevolent way. We need to find a way to alter in a positive way. He had no answers yet.

He said there are more traps.

 

[FMMM1]

Or could the test show a different trap given that Phair says it could be several traps?
I'm no expert at the subject, but since increased cellular tryptophan showes a possible trap, maybe increased phenylalanine does the same.

My point is that increased cellular phenylalanie doesn't necessarily need to confirm Fluge/Mella/Armstrong's theory. Cause with that logic increased cellular tryptophan would confirm their theory as well, and not the possible trap?

I'm not sure I understand this.
Here are the amino acids Fluge and Mella proposed were being used as a fuel source in ME/CFS:
isoleucine (Ile), leucine (Leu), lysine (Lys), phenylalanine (Phe), tryptophan (Trp), and tyrosine (Tyr).
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/].

I.e. 6 amino acids which gives you 6 potential traps. This assumes they all behave like tryptophan i.e.:

• there is a similar 2 stage mechanism for lowering the intracellular levels of the amino acid; and
• if the amino acid reaches a high enough level fatigue (ME/CFS) sets in.

This seems to leave the question of source/cause of the problem i.e. what drives the metabolic shift to using amino acids as the energy source rather than glucose +++questions.

Not sure if the other amino acids give a strong signal using this method i.e. Raman spectroscopy. An advantage of this test may be that it measures intracellular levels (in the cytosol?) of the amino acid.
1) abstract: https://pubs.rsc.org/en/content/articlelanding/2018/an/c8an01437j/unauth#!divAbstract;
2) full paper: https://sci-hub.se/10.1039/C8AN01437J.

Way out of my league but thanks for this. I need to watch Phair's talk; thank you all for your assistance.
@Learner1

 

[bthompsonjr1993]

See attached.


No, the drug did the same thing and CAUSED fatigue. We need the opposite.

Do you think that means that every single one of the 20 severely ill patients had a mutation of IDO2? I wish they would have specified that

 

[lindaso1]

View attachment 29519

I'm not saying this is the complete solution but I do find it interesting that my OATS test from last month does show low kynurenine, low serotonin and an imbalance of quin & serotonin.

Maybe someone more experienced in this pathway can weigh in if I'm reading this correctly or if it's just wishful thinking?

As far as next steps, as I recall Davis said they'd like to test remedies but lack of funding was an issue. Maybe someone who attended the conference was able to get more info directly?

 

[Cam Newton]

See attached.


No, the drug did the same thing and CAUSED fatigue. We need the opposite.

Thanks. I have both the R248W, and the Y359stop. The other ones I’m not sure since I can’t find their corresponding rs numbers.

 

[edawg81]

Here are a (limited) collection of screen shots (from several presentations) from the symposium, so people have access to while OMF works on getting the full video online:

http://www.mediafire.com/file/v4s6itj2dyfw1x5/MECFS18.zip/file

 

[Murph]

I'm not sure that I understand what you're saying but Fluge and Mella found a difference between men and women. Check out Table 1 i.e. results for phenylalanine (Phe) in this study [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/]. The results for women, with ME/CFS versus healthy controls, were highly significant [P less than 0.001] but the results for men were not significant [P 0.19]. I.e. it appears that the response in women with ME/CFS is different from men with ME/CFS .

Let me explain:

Trp is one way to make Kynurenine which is one way to make NAD. The metabolic trap hypothesis says we're not making kynurenine from Trp. So you might also expect low NAD (nicotinamide).

But instead the results on NAD are unclear. If we showed obviously diminished NAD, the theory that we can't make kynurenine would be supported. We don't show obviously diminished NAD, so the theory we can't make kynurenine is neither supported nor refuted.

(From Ben's comment above, it seems like Phair thinks maybe we can make nictotinamide from dietary niacin, so that could be an alternative pathway.)

I didn't see a role for Phenylalanine in the metabolic trap hypothesis. Can you explain?

 

[Murph]

I'm not sure I understand this.
Here are the amino acids Fluge and Mella proposed were being used as a fuel source in ME/CFS:
isoleucine (Ile), leucine (Leu), lysine (Lys), phenylalanine (Phe), tryptophan (Trp), and tyrosine (Tyr).
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/].

I.e. 6 amino acids which gives you 6 potential traps. This assumes they all behave like tryptophan i.e.:

• there is a similar 2 stage mechanism for lowering the intracellular levels of the amino acid; and

@Learner1

If I followed this correctly, the reason he got obsessed on tryptophan -> kynurenine is that it relies on an unusual enzyme situation. Most enzymes work like this, where they work harder up to a saturation point: https://en.wikipedia.org/wiki/Michaelis–Menten_kinetics but IDO1 is subject to substrate inhibition, which is not common and (once IDO2 is broken) opens up the possibility of a trap.

You should watch the talk. It's hard enough to understand even having watched it!

 

[Janet Dafoe]

Here's the Stanford livestream on you tube. It will be up for a while. Ashley will divide it into individual talks and it will be on OMF website in a while. OMF is already busy raising funds for all those new studies! They are amazing!

https://livestream.com/accounts/1973198/ME-CFS-2018

#mecfs2018

 

[Ben H]

As Janet says here is the livestream again:

https://livestream.com/accounts/1973198/ME-CFS-2018

You may have to sign up again to view it however.




B