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

[BeautifulDay]

Is it possible to not have significant mitochondrial energy issues and still have the metabolic trap? Reason I ask is because I completed some testing by metabolon and they found everything to be okay with my mitochondria.

Hi @Jackb23,

Our family has mitochondrial disease, yet, depending upon who we test with and how they analyze it - they can miss it.

For example, there is no single DNA testing company that will look for all the known mitochondrial mutations. They search for the easy low hanging fruit -- the known pathogenic variants. I've even seen a big testing company used by a hospital to sequence data for the mitochondria, have a pathogenic mutation in the mitochondria in that sequence, and yet the testing company's analysis said no pathogenic mutation was found. It's always best to go back to the raw data.

In addition to the pathogenic mutations, it takes a specialist to really dive in and look for the high risk deleterious, rare variants, that are highly conserved among mammalian.

There is also muscle biopsies. And blood/urine/CSF testing.... And then there is the exercise tolerance tests and where someone lands in comparison to known ME and mito patient tables. There are also extensive family histories that can help in the diagnosis.

Therefore, just because metabolon says they found everything fine with the mitochondria doesn't mean that they turned over all the stones.

 

[dreampop]

@Janet Dafoe (Rose49) I haven't had the chance to watch yet. But, and, it's probably been said already, but I wanted to thank Stanford and Janet and her family especially. For the symposium, but also for the endless effort they put into putting our illness on the map and bringing in the best to study it. I know it's not easy. I probably can't put into words what it means to me, maybe to say it's like knitting together forgotten sick people with the world that can help them.

I'm deeply grateful!

 

[nandixon]

I've been thinking a bit about your idea here. Assuming we can upregulate the genes that express IDO1, would launching more copies of the enzyme into an environment where they will be substrate inhibited help enough?

View attachment 29546

Looking at the above graph, yes, IDO1 can still make some kynurenine even at high levels of trp. But would it be enough?

Just eyeballing the chart, the flux produced by IDO2 can be 6 times higher than that from IDO1. Is interferon gamma enough to cause a six fold increase in expression of IDO1?

Looking at Phair's graphic of the tracer experiment showing the cellular uptake of tryptophan over 1600 minutes (27 hours), I'm thinking that even just a 50% increase in gene expression of IDO1 by interferon-gamma may be sufficient to turn things around. (I won't have a chance to listen to Phair’s presentation until this weekend so perhaps he's said something to the contrary I'm not aware of.)

This 2015 study, in Fig. 3D, is indicating that interferon-gamma can increase gene expression of IDO1 by about 3-fold in PBMCs:
Expression of the Kynurenine Pathway in Human Peripheral Blood Mononuclear Cells: Implications for Inflammatory and Neurodegenerative Disease

The authors also note that interferon-gamma not only increases IDO1 gene expression but also increases the activity of the resultant enzyme itself as well, so that’s additionally helpful if true.

Also of interest, from the study it appears that interferon-gamma increases IDO1 expression in PBMCs over about a 24 hour period, and this upregulation is maintained for several days, possibly a week.

If Phair's metabolic trap involving IDO1/IDO2 is what is really happening in ME/CFS, then we may actually already know, qualitatively, that interferon-gamma is likely to sufficiently upregulate IDO1 based on the remissions that patients apparently obtained with Dr Chia's use of interferon-alpha and -gamma.

 

[MonkeyMan]

My head is spinning after reading the comments above and watching some parts of the conference. Such an incredibly talented and dedidated team of scientists and supporters! Their efforts really give me hope. A couple of things I'm not understanding though.

Robert Phair had said earlier this year that they should know if the metabolic trap is present in the white blood cells of ME/CFS patients by the end of summer. Can someone clarrify for me (sorry if I missed it, brain fog!) if they answered this?

And Ron Davis had said a while back "We have one primary circuit that we are looking at, at the moment, we should figure out whether that is right by the end of the summer." Is this the same issue that Phair is referring to in his "end of summer" comment? And was Ron's primary circuit question answered at the symposium?

Thanks to anyone who can help.

 

[knackers323]

@theflo can you remember where this info is, or remember what the cause of the low receptors is? Genetic?
Thanks

So I'm a little heartbroken to hear about this possible metabolic trap, and the implications of possible high serotonin / reduced serotonin receptors in the brain, and the possible effect of tryp/5htp supplementation.

 

[Sidereal]

Can someone clarrify for me (sorry if I missed it, brain fog!) if they answered this?

If I understood his presentation correctly, they have tested the kynurenine/tryptophan ratio in six patients thus far and found the result to be statistically significantly lower compared to six normal controls.

 

[dreamydays]

Kagocel an antiviral drug increases interferon-gamma which could induce IDO1.

 

[dreamydays]

Has anyone had any thoughts on an ultra low tryptophan diet?

 

[MEssias]

davis said expressly "better no self-attempts!"

 

[FMMM1]

Has anyone had any thoughts on an ultra low tryptophan diet?

Yea crossed my mind. It's an essential amino acid i.e. your body cannot produce it, so you must get it from your diet.

I'm not aware of anything which would (selectively) bind it in food (i.e. maker it unavailable). I can't see why you couldn't produce a diet which was low in/eliminated tryptophan.
I don't think you need a lot of tryptophan [from the presentations?] so producing a diet with low enough levels, but well balanced for everything else, might be challenging. Risky?

You might ask someone like OMF. You'd need to know clearance rate/half life in the body.

 

[theflo]

@theflo can you remember where this info is, or remember what the cause of the low receptors is? Genetic?
Thanks

@knackers323 It's here: https://livestream.com/accounts/1973198/ME-CFS-2018/videos/180981460
The Davis/Phair presentation is at 6:24:49, and then the discussion continues in the panel.
Low / High receptors are possible because of (possible) high tryptophan = possible high serotonin, etc.

 

[Akasha]

I have no clue about genetics, totally out of my league, but maybe any of you can use this information and see if these are the ones that Phair referred to or not:

I found some info of the SNP's from this article (probably the one about the cancer drug Davis and Phair referred to). The only ones they talked about activity were R248 and Y359:

"One C-T SNP affecting R248 in human IDO2 was structurally analogous to R231 in human IDO, which makes a critical contact with the indole ring of tryptophan. The nonsynonymous substitution (R248W) reduced catalytic activity ∼90% in T-REX cells (Supplementary Fig. S5). A second T-A SNP affecting Y359 generated a premature stop codon (Y359X), which completely abolished activity"​

Don't know the difference between Y359X and Y359stop. Maybe the relevant alleles here are:

R248W - rs10109853(C,T)
Y359stop - rs4503083(A,T)​

I also found the rs of five nonsynonymous variants FOR IDO2 (in this article), the two above and these three:

rs35212142(A,T)
rs4736794(G,A)
rs35446289(?,?)​

Could those correspond to S252T, I127V and N257K? I couldn't find any information about them in SNPedia. Is it possible 23andMe doesn't sequence them? That or I don't have them.
If we can find which ones are the mutated alleles, maybe we can make a poll and see if the PR community have more than the 1.7 mutations they talked about?

Anyway, I hope this information wasn't useless...

 

[Learner1]

Phair told me 23andme is not reporting all of them, so we wouldn't be able to tell from just 23andme data.

In regard to Interferon-gamma promoting IDO1, from what I understood, the problem is related to IDO2 - if its not working properly, it doesnt matter if you increase IDO1.

I believe I may have this situation and have very high tryptophan and 5-HIAA levels. Does anyone know how to dump tryptophan?

 

[MonkeyMan]

If I understood his presentation correctly, they have tested the kynurenine/tryptophan ratio in six patients thus far and found the result to be statistically significantly lower compared to six normal controls.

Thanks, but how does this tie in with whether the metabolic trap is present in WBCs, or whether they have found the "right" primary circuit??

 

[sb4]

Yea crossed my mind. It's an essential amino acid i.e. your body cannot produce it, so you must get it from your diet.

Someone on another thread mentioned that they doubted the hypothesis as kynurinine is needed to make NAD and if people have fasted, like myself (for 30days), with CFS then they should have developed B3 deficiency, which I don't think I did. Not sure how solid this argument is. We have gut bacteria that can produce B vitamins.

I assume that during this fast I broke down muscle, and muscle contains tryptophan right?

Perhaps a low tryptophan diet would act like BCAA supplementation though you could possibly run into problems with insomnia. Think it would be hard to arrange for low tryptophan yet normal values of other AAs without something like BCAA supplementation.

 

[Learner1]

Thanks, but how does this tie in with whether the metabolic trap is present in WBCs, or whether they have found the "right" primary circuit??

I believe he said it was in the cytosol. IDO1 and IDO2 do interact with the immune system, as described in the articles posted above.

Phair believes there are other traps, too. No one said this was a primary circuit. But, as it leads to NAD production, impairment could be significant. I've found getting NAD in IVs and sublingually to be very helpful, and am wondering if they are getting around the trap.

 

[Learner1]

Someone on another thread mentioned that they doubted the hypothesis as kynurinine is needed to make NAD and if people have fasted, like myself (for 30days), with CFS then they should have developed B3 deficiency, which I don't think I did. Not sure how solid this argument is. We have gut bacteria that can produce B vitamins.

B6 can be converted to B3. A lot of biochemicals can be recycled or converted through various pathways.

I assume that during this fast I broke down muscle, and muscle contains tryptophan right?

Yes.

Perhaps a low tryptophan diet would act like BCAA supplementation though you could possibly run into problems with insomnia. Think it would be hard to arrange for low tryptophan yet normal values of other AAs without something like BCAA supplementation.

Msybe the question should be how to use up tryptophan faster. My amino acid tests have shown low everything and high tryptophan.

 

[aquariusgirl]

@Learner1

My mom had super elevated 5HIAA levels when measured years ago. Also low Red blood cell NAD!

Dr Amy Yasko & DR Rich Van Konynenburg commented on my mother’s 5HIAA levels! They couldn’t explain it.

In addition, I suspect she has iron overload ....hetero for one of the big 3 HFE genes, which unless mistaken means iron is unavailable.

Iron is the cofactor for IDO2.

Desperate to know what to do.

Phair told me 23andme is not reporting all of them, so we wouldn't be able to tell from just 23andme data.

In regard to Interferon-gamma promoting IDO1, from what I understood, the problem is related to IDO2 - if its not working properly, it doesnt matter if you increase IDO1.

I believe I may have this situation and have very high tryptophan and 5-HIAA levels. Does anyone know how to dump tryptophan?

Learner

 

[MonkeyMan]

I believe he said it was in the cytosol. IDO1 and IDO2 do interact with the immune system, as described in the articles posted above.

Thanks, so does that mean that Phair confirmed the trap is indeed in WBCs?

No one said this was a primary circuit.

To quote Davis from https://www.omf.ngo/wp-content/uploads/2018/05/Dr-Ron-Davis-MA-Dept-Pub-Health-April-2018.pdf
But we do believe that it is some sort of systemic problem probably with some central control circuit. It’s a matter of trying to find what is that central control circuit that is messed up in some way. We think there is something going on that locks the patients into this and they can’t get out of it. So if we can figure out what that control circuit is then we can figure out our strategy to unlock it. That is our major effort at the moment because that would possibly mean that we don’t need to develop a drug. There may be ways to manipulate that central circuit to get people out of the disease. We have one primary circuit that we are looking at, at the moment; we should figure out whether that is right by the end of the summer.

So ... is it right?

 

[junkcrap50]

Phair believes there are other traps, too. No one said this was a primary circuit.

Thank you! I thought I was going crazy about how everyone missed the point where Phair said this was not the only metabolic trap. There were other metabolic traps too!This is the only one he shared, for whatever reason. Maybe, this trap is the one Phair has looked at most closely.

We have one primary circuit that we are looking at, at the moment.

There are other traps they are looking at. This is just one. 1 trap for this complex disease is likely too simplistic.