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

[JES]

I haven't had the time to digest everything from this conference yet, but one thing that interests me is whether the metabolic trap finding by Phair relates to the Norwegian findings in ME/CFS, i.e. that pyruvate dehydrogenase and glucose metabolism is impaired. It just made me wonder whether people with ME/CFS potentially have multiple metabolic issues or whether these two issues are related.

 

[raghav]

Robert Phair said during his talk that there were some more metabolic traps also to be looked into. Any idea what it could be ? It will be nice if Ron or Rob can say what they are. I suddenly feel like a child reading a Hardy boys mystery novel.

 

[Ben H]

Hi guys,

I've been fortunate enough to converse with Prof. Phair and these are his words which will hopefully clarify some things :

-----------

IDO1 is substrate inhibited, not substrate limited.

According to the metabolic trap hypothesis:
Yes, serotonin could be low or high depending on which isoform of tyrptophan hydroxylase is present in a given cell.
The IDO2 mutations (there are 5 of them) uncover a bistability that is built in to human metabolism.
Only Ron made the point about decreased NAD. We disagree on this. I think there is plenty of dietary niacin to support NAD production.
It's low kynurenine that results in a hyperactive immune system (clonally expanded Teff cells).

Also the thread self-corrected about the cancer drug. The drug was an inhibitor of IDO1. Fatigue was the most common adverse effect in Phase I trials. But the trials were in terminally ill cancer patients where fatigue is extremely common. I do not know whether adverse effect reports report differences compare to pre-drug or absolute measures.

A final thing worth emphasizing is the difference between intracellular and extracellular tryptophan. We are measuring intracellular concentrations. Extracellular concentrations (such as plasma) are unlikely to be altered much.

It might be worth reminding people of Ron's point about cherry-picking literature data in support of a theory. The point of science is hypothesis TESTING. It's fine to build a hypothesis based on support you find in the literature, but your obligation as scientists (no matter whether professional or not) is to make a testable prediction and be willing to reject the hypothesis if the prediction is not borne out in a well-controlled experiment.

-----------

Very wise words and important points indeed.


B

 

[Mel9]

At the 2017 Symposium Neil McGregor proposed genetics play a role in which symptoms patients have

Transcript:
https://www.melbournebioanalytics.o...mecfs-by-neil-mcgregor-written-transcription/

Fascinating!

 

[Sushi]

Did he describe how to do it does anyone remember?

talks about a Cryohelmet: http://www.cryohelmet.com/

Here is another one, though there is the question as to whether cooling the scalp will actually cool the brain? Whether it does or not, the wearer definitely doesn't look cool! https://www.arcticheatusa.com/cooling-cap.html

 

[nandixon]

I guess the most obvious way to attempt to upregulate IDO1 (i.e., increase its gene expression) and break the hypothetical metabolic trap proposed by Prof Phair would be to use intravenous interferon gamma (IFNγ). This seems likely to cause a person to feel much worse initially before they feel better, though.

I'd be curious to know if the effect of IFNγ in Ron Davis's nanoneedle device has been looked at?

 

[Murph]

Hi guys, I've been fortunate enough to converse with Prof. Phair and these are his words which will hopefully clarify some things :
-----------
IDO1 is substrate inhibited, not substrate limited.

Someone on Reddit called Pun_In_Ten_Did just gave this excellent explanation of substrate inhibition:

> "IDO1 is subject to substrate inhibition -- the enzymatic reaction stops when there is too much substrate (tryptophan). The substrate is competing with each other to get to the active site of the enzyme. So much fighting to get in, the enzyme just sits there waiting for something "to get in its belly!"... meanwhile, substrate level continues to rise and rise.

> (I know this because my wife and I had lunch with Bob Phair yesterday and he explained as such ) We're up here from San Diego for the symposium and to see some of her doctors."

EDIT: do not ask me about lunch with Dr Phair! I did not have lunch with him. The person from reddit did.

 

[bthompsonjr1993]

Hi guys,

I've been fortunate enough to converse with Prof. Phair and these are his words which will hopefully clarify some things :

-----------

IDO1 is substrate inhibited, not substrate limited.

According to the metabolic trap hypothesis:
Yes, serotonin could be low or high depending on which isoform of tyrptophan hydroxylase is present in a given cell.
The IDO2 mutations (there are 5 of them) uncover a bistability that is built in to human metabolism.
Only Ron made the point about decreased NAD. We disagree on this. I think there is plenty of dietary niacin to support NAD production.
It's low kynurenine that results in a hyperactive immune system (clonally expanded Teff cells).

Also the thread self-corrected about the cancer drug. The drug was an inhibitor of IDO1. Fatigue was the most common adverse effect in Phase I trials. But the trials were in terminally ill cancer patients where fatigue is extremely common. I do not know whether adverse effect reports report differences compare to pre-drug or absolute measures.

A final thing worth emphasizing is the difference between intracellular and extracellular tryptophan. We are measuring intracellular concentrations. Extracellular concentrations (such as plasma) are unlikely to be altered much.

It might be worth reminding people of Ron's point about cherry-picking literature data in support of a theory. The point of science is hypothesis TESTING. It's fine to build a hypothesis based on support you find in the literature, but your obligation as scientists (no matter whether professional or not) is to make a testable prediction and be willing to reject the hypothesis if the prediction is not borne out in a well-controlled experiment.

-----------

Very wise words and important points indeed.


B

Doesn't this directly clash with Ron's findings that whatever is causing CFS is in the plasma, not the cells?

 

[alex3619]

Doesn't this directly clash with Ron's findings that whatever is causing CFS is in the plasma, not the cells?

Actually Ron has found that whatever is causing the impedance problem, probably energy related, is in the plasma. However what causes that?

We just don't know enough yet.

 

[wingate]

The conference was fantastic! @AshleyHalcyoneH and the team planned a flawless day (along with some great weather!). Linda, Ashley, and @Janet Dafoe (Rose49) shared some touching remarks before the researchers dove into the talks. Many thanks to all those involved in putting together such a remarkable day.

It made all the difference to hear from the researchers in person. The talks demonstrated that the researchers have made great progress in the past year and are learning a lot more all the time. Important strides are being made in key areas- better understanding the disease itself, developing an accurate diagnostic tool, and looking for effective treatments.

Just as encouraging was seeing how many new people Ron has brought on board since last year's conference. It renewed my hope to see that more smart and caring people are entering the field. (Very enthused to see a young face there with Michael Sikora as well!) And, as Ron pointed out, this is a team effort with patients and treatments at the center rather than a competition for publications. That's an important distinction.

Finally, this was also the first time I had the chance to meet other patients in person. It was nice to have a physical reminder of our passionate, hopeful, and dedicated community and that we're all in this together.

 

[Sing]

I had a quick chat with Dr. Bateman and later Dr. Lily Chu, asking them if their effort to improve the ICD 10 coding for us will continue now that CFSAC was discontinued. Dr. Bateman said that Dr. Chu is working on it. Later I saw Dr. Chu at the coffee stand and she told me she had participated remotely in the last meeting, calling in during their afternoon session. She said I could find this on youtube (NCHS, ICD10? Will search around. They know it is very important that we have the most appropriate, specific code we can get, but we may only succeed in an improvement at this point.

Dr. Bateman shared a guess about why they discontinued CFSAC, (using my words) because it was starting to have more traction. In the past year (two years) other departments and government agencies had to report back after CFSAC had addressed them with our needs. In its long, early years, when CFSAC would list our needs and requests, other government departments would not necessarily even answer and certainly not give us what CFSAC had asked for.

I have a rotten memory so if any of you recognize any errors, please correct me.

 

[bthompsonjr1993]

This is so interesting. https://www.uniprot.org/uniprot/Q6ZQW0 In the "miscellaneous" section on this page for IDO2, it specifically notes that "50 % of Caucasians harbor polymorphisms which abolish IDO2 enzymatic activity."

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

 

[Murph]

This is so interesting. https://www.uniprot.org/uniprot/Q6ZQW0 In the "miscellaneous" section on this page for IDO2, it specifically notes that "50 % of Caucasians harbor polymorphisms which abolish IDO2 enzymatic activity."

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

IDO2 variants are more common among white than black people in America.

Norway is pretty much the global epi-centre of ME/CFS in many ways, not least by google search activity. (We should acknowledge the feedback loop from awareness to diagnosis frequency in Norway, but not at the expense of acknowledging the feedback loop from symptom frequency to awareness!)

I'd like to find out if IDO2 variants were especially common in Norway.

 

[CFS_for_19_years]

I wish there was a way to cool the whole head and cool it just a tiny bit.

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).

 

[bthompsonjr1993]

IDO2 variants are more common among white than black people in America.

Norway is pretty much the global epi-centre of ME/CFS in many ways, not least by google search activity. (We should acknowledge the feedback loop from awareness to diagnosis frequency in Norway, but not at the expense of acknowledging the feedback loop from symptom frequency to awareness!)

I'd like to find out if IDO2 variants were especially common in Norway.

Amazing! can you interpret this for me? What do these percentages mean exactly? (the ones next to the ethnicities)

 

[Murph]

Amazing! can you interpret this for me? What do these percentages mean exactly? (the ones next to the ethnicities)

Those percentages aren't too useful (they sum to 100 vertically) but if you look at the proportion of white people with no genetic mutations in the gene it is about 13% compared to about 30% of black people. And the share of white people with two matching mutations (homozygous) is 30% compared to 15%.

(of course this is a special population - people with Crohn's disease - so it might not apply.)

 

[wastwater]

IDO2 links on gene cards to foxo1a

 

[Sing]

IDO2 variants are more common among white than black people in America.

Norway is pretty much the global epi-centre of ME/CFS in many ways, not least by google search activity. (We should acknowledge the feedback loop from awareness to diagnosis frequency in Norway, but not at the expense of acknowledging the feedback loop from symptom frequency to awareness!)

I'd like to find out if IDO2 variants were especially common in Norway.

Dr. Berquist, who is Swedish, was the only Scandinavian I could catch for my question which was nearly the same. I asked if it had been his impression that there could be more people with ME/CFS in Scandinavian or at least with Northern European backgrounds. He said we don’t have the data yet (epidemiological information), but also indicated that he wonders as well what the comparative prevalence is in different parts of the world. I said, in effect, that I wonder if the adaptations that enabled our essentially tropical/subtropical African species to live in the cold far north could also carry some special biological vulnerabilities.Just as they recently found that Neanderthal genes, while also probably making humans fitter for life in the colder north, also are associated with certain downsides.

So I am right on your wavelength, @Murph

 

[Cam Newton]

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.

 

[Snow Leopard]

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.

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