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

FMMM1

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I'd also add that if tryptophan is high in the cell, maybe it's high because the body needs it there. It may not be a bad thing...
Depends on whether you have a problem (non-functioning genetic mutation) with IDO2. If you have a problem with IDO2 then high tryptophan sounds like a potential problem.
 

dannybex

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Depends on whether you have a problem (non-functioning genetic mutation) with IDO2. If you have a problem with IDO2 then high tryptophan sounds like a potential problem.
I suppose that's possible. It may be worth keeping in mind however that many with MTHFR polymorphisms (just as one example) aren't sick, despite all the mthf-ing hyperbole of the past 10 years.
 

FMMM1

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I suppose that's possible. It may be worth keeping in mind however that many with MTHFR polymorphisms (just as one example) aren't sick, despite all the mthf-ing hyperbole of the past 10 years.
Yea I recall (vaguely) a study in an ethnic minority group in England, which found mutations where the individuals didn't seem to be negatively effected. From memory in this community there are marriages between relatively closely related people. They identified people who had 2 copies of a recessive genetic mutation and no negative outcome. Reason was that the system has workarounds. Not to say there are workarounds for high intracellular tryptophan combined with these IDO2 mutations though.

I was wondering if you could use tryptophan for cellular energy and if so does this use the IDO2 pathway? I.e. reduce high intracellular tryptophan by burning it as fuel.
 
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dannybex

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Before getting too excited about the raised Tryptophan, I would like to see a full analysis of the full Kynurenine pathway in ME/CFS patients versus healthy controls. The Kynurenine pathway is what Tryptophan is metabolised through on its way to be being turned into niacin and ultimately NAD. 50% of caucasians "harbor" a non-functioning IDO2 according to UniProt. What this translates to in terms of phenotypicity I am not sure as I do not know whether "harboring" is referring to heterozygosity or homozygosity but this does devalue any significance of IDO2 mutations or dysfunction in ME/CFS subjects unless it is an absolute requirement for pathogenesis in addition to other factors. I have mentioned on another thread that niacin (vitamin B3) deficiency can account for many symptoms in the symptomscape of ME/CFS and especially if accompanied by mineral deficiencies such as zinc and magnesium.
Excellent points. If one is getting sufficient niacin through diet or supplementation, then tryptophan doesn't need to be broken down to make it to provide energy in the mitochondria.
 

FMMM1

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Excellent points. If one is getting sufficient niacin through diet or supplementation, then tryptophan doesn't need to be broken down to make it to provide energy in the mitochondria.
From memory (and limited understanding) Phair/Davis discussed the issue of NAD at the Community Symposium. Robert Phair reckons diet will ensure people with ME/CFS have enough NAD i.e. even if IDO2 isn't working (leading to lower NAD production from tryptophan?). However, Ron Davis wasn't so sure i.e. that NAD levels were OK in ME/CFS. Solution would be to test for low levels of NAD; similarly you could look for zinc and magnesium deficiency. Ron Davis seemed to be sufficiently interested in NAD to look into it (money/priorities permitting).

Tryptophan use for cellular energy production was covered by Fluge/Mella in a paper published a year ago. Seems that this class of amino acids are used as cellular fuel in ME/CFS. Chris Armstrong identified this some years ago; he did a webinar on it possibly 2 years ago. Are you suggesting that tryptophan needs to converted to something else before it can be used as fuel?
 

Dr Who

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NAD (Nicotinamide Adenine Dinucleotide) is not really a fuel, although it can be metabolised when around in excess quantitities. The significance of NAD is in its faciliative role as a substrate and coenzyme in many of the enzyme reactions of extracting the energy from fuels such as glucose, other carbohydrates, fats and proteins. The NAD is one of the types of spark plugs if you like, that also can act as tiny batteries carrying energy from one reaction place to another.

Tryptophan can be a fuel also, as an amino acid released from proteins from our diet or from the breakdown of proteins in our bodies. It is also an amino acid that we cannot make ourselves so even tryptophan from the breakdown of our own proteins will have had to be consumed in our diet previously. It is in itself a "vitamin" amino acid, which are usually called "essential amino acids".

If being metabolised as a fuel, Tryptophan derived energy is very inefficient and risks the production of toxic substances that can cause harm to cells and affect metabolism in a negative way. A bit like putting spark plugs or batteries in your log burning stove or aga (or if like me you have neither, your disposable barbeque) the result would be not much heat and a nasty smell/taste of poisons.

This is probably why, if there is too much Tryptophan around. the enzyme which channels it down the common pathway which later splits into the "lets burn this" and the "lets make NAD" pathways has the unusual feature of effectively 'switchin down or off'. It might prevent burning too much Tryptophan and producing too much Tryptophanic noxious/toxic smoke, but it may have the effect of preventing us making enough of our own NAD.

Even when working normally or well. turning Tryptophan into NAD is very inefficient. From memory, I think it is around 60g of Tryptophan has to be eaten to produce 1g of NAD. Given that a whole host of other carbohydrate and amino acid fragments need to be broken up and restuck together in such a way as to make up around half of the molecular weight of NAD, in reactions dependent on essential minerals and other vitamins, the less than 1% of consumed Tryptophan that goes into making NAD could be very vulnerable to dietary deficiency or other metabolic demands such as the manufacture of Serotonin and Melatonin which Tryptophan is far more famous for!

Your comments about Dr Davis, Fluge/Mella and Armstrong are very intriguing and do raise some interesting questions. Unfortunately I am away from my what I used to call "my work" (but now call "my hobby" thanks to the belief that Davis et al will get there soon, if not soon enough). So. I can't give the molecular chapter and verse of the pathways. It does make me wonder if some essential nutrient deficiency or other metabolic block involved in the Tryptophan metabolic pathways might result in hypo-endogenous niacin/NAD and hyper-kynurenine metabolitoxaemia? I look forward to exploring that idea when I can.

I am on the mainland dealing with a very protracted, complicated and difficult family health issue. I have not even been able to see if there is any threads presenting any of the presentations of September's meeting. I missed the live feed also. When I do get back to the island my energies have been taken up catching up on things needed done there. I have not been keeping a close eye on PheonixRising until just now and I am pleased that the comments above are fairly recent. Please forgive me if I do not get back to you promptly and if I do and then strangely "go dark" please do not feel either offended or worried about having offended or having bored me!

I have forgot what I came here to do now.... oh dear, never mind, glad I saw this instead anyway!
 
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After watching the last video from Ron talking about wrong values from the mass spectrometer i have some doubts about the whole metabolic trap tbh.
 

FMMM1

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NAD (Nicotinamide Adenine Dinucleotide) is not really a fuel, although it can be metabolised when around in excess quantitities. The significance of NAD is in its faciliative role as a substrate and coenzyme in many of the enzyme reactions of extracting the energy from fuels such as glucose, other carbohydrates, fats and proteins. The NAD is one of the types of spark plugs if you like, that also can act as tiny batteries carrying energy from one reaction place to another.

Tryptophan can be a fuel also, as an amino acid released from proteins from our diet or from the breakdown of proteins in our bodies. It is also an amino acid that we cannot make ourselves so even tryptophan from the breakdown of our own proteins will have had to be consumed in our diet previously. It is in itself a "vitamin" amino acid, which are usually called "essential amino acids".

If being metabolised as a fuel, Tryptophan derived energy is very inefficient and risks the production of toxic substances that can cause harm to cells and affect metabolism in a negative way. A bit like putting spark plugs or batteries in your log burning stove or aga (or if like me you have neither, your disposable barbeque) the result would be not much heat and a nasty smell/taste of poisons.

This is probably why, if there is too much Tryptophan around. the enzyme which channels it down the common pathway which later splits into the "lets burn this" and the "lets make NAD" pathways has the unusual feature of effectively 'switchin down or off'. It might prevent burning too much Tryptophan and producing too much Tryptophanic noxious/toxic smoke, but it may have the effect of preventing us making enough of our own NAD.

Even when working normally or well. turning Tryptophan into NAD is very inefficient. From memory, I think it is around 60g of Tryptophan has to be eaten to produce 1g of NAD. Given that a whole host of other carbohydrate and amino acid fragments need to be broken up and restuck together in such a way as to make up around half of the molecular weight of NAD, in reactions dependent on essential minerals and other vitamins, the less than 1% of consumed Tryptophan that goes into making NAD could be very vulnerable to dietary deficiency or other metabolic demands such as the manufacture of Serotonin and Melatonin which Tryptophan is far more famous for!

Your comments about Dr Davis, Fluge/Mella and Armstrong are very intriguing and do raise some interesting questions. Unfortunately I am away from my what I used to call "my work" (but now call "my hobby" thanks to the belief that Davis et al will get there soon, if not soon enough). So. I can't give the molecular chapter and verse of the pathways. It does make me wonder if some essential nutrient deficiency or other metabolic block involved in the Tryptophan metabolic pathways might result in hypo-endogenous niacin/NAD and hyper-kynurenine metabolitoxaemia? I look forward to exploring that idea when I can.

I am on the mainland dealing with a very protracted, complicated and difficult family health issue. I have not even been able to see if there is any threads presenting any of the presentations of September's meeting. I missed the live feed also. When I do get back to the island my energies have been taken up catching up on things needed done there. I have not been keeping a close eye on PheonixRising until just now and I am pleased that the comments above are fairly recent. Please forgive me if I do not get back to you promptly and if I do and then strangely "go dark" please do not feel either offended or worried about having offended or having bored me!

I have forgot what I came here to do now.... oh dear, never mind, glad I saw this instead anyway!

Thank you for this post. You obviously know a lot more about this than me.

So we could have a problem with insufficient NAD. However, we could have sufficient NAD but have a problem caused by using tryptophan as a fuel (cellular energy production). Since using tryptophan for cellular energy production creates all sorts of nasty byproducts, your body can switch off the pathway which uses tryptophan for energy production (sensible) and the IDO1 & IDO2 pathway leading to kynurinine/NAD (not sensible?). Trying to think about how to say this but would that mean that tryptophan accumulates within the cell? I recall Ron Davis, at the OMF Symposium, pointing out that a potential cancer drug which inhibited IDO1/2 caused severe fatigue. He also pointed out that we should be careful about selectively picking information.

I just wondered if the transport of tryptophan into the cell should be/is regulated i.e. to transport more when need/less --. Is there an issue with regulating tryptophan "intake" into the cell?

I'll try to look at the pathway you referred to.

Thanks again.
 

FMMM1

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Tryptophan can be a fuel also

If being metabolised as a fuel, Tryptophan derived energy is very inefficient and risks the production of toxic substances that can cause harm to cells and affect metabolism in a negative way. A bit like putting spark plugs or batteries in your log burning stove or aga (or if like me you have neither, your disposable barbeque) the result would be not much heat and a nasty smell/taste of poisons.

This is probably why, if there is too much Tryptophan around. the enzyme which channels it down the common pathway which later splits into the "lets burn this" and the "lets make NAD" pathways has the unusual feature of effectively 'switchin down or off'. It might prevent burning too much Tryptophan and producing too much Tryptophanic noxious/toxic smoke, but it may have the effect of preventing us making enough of our own NAD.
According to this diagram conversion of tryptophan into acetyl-CoA, and thereby cellular energy/ATP*, occurs after the IDO1/2 dependent step -
https://www.researchgate.net/figure...n-blot-analysis-of-DDC-and-IDO_fig7_236930762

Therefore, if IDO1/2 aren't working then presumably tryptophan cannot be converted into acetyl-CoA/ATP.

This would appear to support the view that tryptophan can accumulate i.e. if IDO1/2 aren't working. I.e. there is no alternative (non IDO1/2 dependent) way of converting tryptophan to acetyl-CoA/ATP.

Does this mean that everyone with severe ME/CFS has a non-functioning form of 1DO2?



*The citric acid cycle – also known as the TCA cycle or the Krebs cycle – is a series of chemical reactions used by all aerobic organisms to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins, into adenosine triphosphate and carbon dioxide. Wikipedia
 

Belbyr

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I don't know if some of you remember but I recall this being one of Cort's most interesting blog posts from a while back. I was hoping we would have heard something on this by now. I know the POTS researchers all seem to be in agreement that autoimmunity is the problem within the last year or two, and most likely caused by molecular mimicry from an infection.

I remembered this after seeing Fluge/Mella pop up in this thread.

https://www.healthrising.org/blog/2...ity-chronic-fatigue-syndrome-alan-light-talk/
 

FMMM1

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I don't know if some of you remember but I recall this being one of Cort's most interesting blog posts from a while back. I was hoping we would have heard something on this by now. I know the POTS researchers all seem to be in agreement that autoimmunity is the problem within the last year or two, and most likely caused by molecular mimicry from an infection.

I remembered this after seeing Fluge/Mella pop up in this thread.

https://www.healthrising.org/blog/2...ity-chronic-fatigue-syndrome-alan-light-talk/
Unutmaz/Oh's recently published a paper on MAIT cells (a type of T-cells in gut lining) which (I assume) are activated in ME/CFS and a bunch of other diseases like Crohn's Disease ["Tuning of human MAIT cell activation by commensal bacteria species and MR1-dependent T-cell presentation"]. Unutmaz/Oh's paper reminds me of Mark Davis's presentation at the 2017 OMF Symposium i.e. where he presented data showing clonal expansion in T-cells.

Unutmaz/Oh don't appear to be highlighting autoimmunity but rather a change to more pathogenic gut bugs (microbiome) resulting in activation of (MAIT) T-cells i.e. immune activation rather than autoimmunity.

There's a blog on Unutmaz/Oh's paper here (including a link to the full paper) - https://forums.phoenixrising.me/ind...cies-and-mr1-dependent-t-cell-presenta.62646/
 

FMMM1

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@FMMM1 You may enjoy watching Jonas Bergquist from this years Stanford symposium sponsored by OMF at the 18 min time point discussing autoimmunity in ME/CFS
Hi I was wondering how my previous response to you post would be perceived. I've been trying to lobby for funding from the European Union for ME/CFS research; Jonas's group is one of the leading groups in Europe. My draft letter to Members of the European Parliament is included below; it specifically refers to Jonas's group. We're on the same side here.

Regarding Jonas's comments on autoimmunity in ME/CFS. At around 18 minutes Jonas discusses his study on autoantibodies to muscarinic (muscarinic acetylcholine receptors) and adrenergic receptors. Their study found that these autoantibodies were significantly increased in ME/CFS. Jonas refers to a group in Berlin who they worked with on these autoantibody tests; this group is led by Carmen Scheibenbogen University Hospital Charité. During the rituximab study Carmen's group published a study comparing the levels of these autoantibodies in the rituximab test and control (placebo) groups or similar (from memory). @Jonathan Edwards expressed concerns on this site i.e. (if the cause of ME/CFS was muscarinic/adrenergic antibodies) he would have expected a much greater difference between the two groups. So if these autoantibodies (or I assume any B-cell autoantibodies) were causing ME/CFS then rituximab would have worked. Rituximab did not work therefore autoantibodies to muscarinic/adrenergic receptors/any other B-cells autoantibodies do not appear to cause ME/CFS.
If you want to see how to improve these autoantibody tests then Ron Davis has proposed an improved method [https://www.omf.ngo/experts-blog/].
Check out Ron Davis's presentation at the 2018 OMF Community Symposium; Ron points out that there's evidence that low Kynurenine (Robert Phair etc.) increases autoimmunity. The fact that removing the autoantibodies (rituximab) didn't cure ME/CFS may be consistent with Phair's (low Kynurenine) hypothesis i.e. autoantibodies are secondary/a consequence of ME/CFS - not the cause.

Carmen Scheibenbogen's group recently published a study on the expression of three very long non-coding RNA genes; basically they are expressed at a higher level in ME/CFS ["The expression signature of very long non-coding RNA in myalgic encephalomyelitis/chronic fatigue syndrome" - https://www.ncbi.nlm.nih.gov/pubmed/30119681]. The expression of two of the three genes separated people with ME/CFS from healthy controls (possible diagnostic test).

A prominent researcher once wrote that she thought that to solve ME/CFS might require a major new scientific development. [Scheibenbogen's] Very long non-coding RNA genes are being studied in prostate cancer i.e. another difficult to diagnose/treat disease. Intracellular tryptophan (Robert Phair etc.) is another "new" area.




Please think about lobbying for more funding from the European Union [https://forums.phoenixrising.me/ind...yre-working-for-you.61516/page-2#post-1017469]. Lyme disease got 33.9 million (dollars/euros) from the European Union Horizon 2020 (science and technology) fund; ME/CFS got zero.

Here's a draft letter I'm hoping to send to Members of the European Parliament (MEPs) seeking support for research/development of a diagnostic test for ME/CFS. If you can lobby MEPs, or know others who can (e.g. those involved in the missing million campaign throughout Europe), then I'd be grateful for your assistance.

*Draft letter to MEPs:
"Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affects more than one million people within the EU. This illness is characterised by persistent and excessive fatigue, post-exertional malaise, flu-like symptoms and cognitive impairments. Most sufferers are unable to lead a normal life. Those affected are predominately women. Many people with ME/CFS feel that they are labelled as having a psychological condition and that research into ME/CFS is not prioritised as a result of this "psychological" label.

Many of the symptoms of ME/CFS overlap with those of Lyme disease and fibromyalgia.

There are no established biological diagnostic tests for ME/CFS, nor are there any treatments.

Professor Carmen Scheibenbogen, Charite, Germany recently discovered that people with ME/CFS can be separated from healthy people by measuring the expression of three genes.
Professor Julia Newton at Newcastle University found that differences in cellular energy production can be used to separate people with ME/CFS from healthy people.
These discoveries could be the basis of a biological diagnostic test for ME/CFS.

There are other excellent researchers in the European Union working on ME/CFS e.g. Professor Jonas Bergquist Uppsala University, Sweden; Professor Øystein Fluge and Olav Mella Haukeland universitetssykehus Norway.

The European Commission has funded the European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [EUROMENE] under the Cooperation in Science and Technology (COST) program. However, the Commission, in its response to a Parliamentary Question on Funding of research on ME/CFS [E-006901/2017] acknowledge that it had not funded any research into ME/CFS:
"To date, no specific projects on ME/CFS have been supported by the EU Framework Programmes for Research and Innovation."

Request:
I would be grateful if you would lobby the European Commission to ask that they fund research into ME/CFS, including the development of a diagnostic test. ME/CFS affects approximately 1 million people in the European Union; most of them are unable to lead a normal life. The development of a diagnostic test, and effective treatments, would help to reduce the suffering of these people."
 
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During the rituximab study Carmen's group published a study comparing the levels of these autoantibodies in the rituximab test and control (placebo) groups or similar (from memory). @Jonathan Edwards expressed concerns on this site i.e. (if the cause of ME/CFS was muscarinic/adrenergic antibodies) he would have expected a much greater difference between the two groups. So if these autoantibodies (or I assume any B-cell autoantibodies) were causing ME/CFS then rituximab would have worked. Rituximab did not work therefore autoantibodies to muscarinic/adrenergic receptors/any other B-cells autoantibodies do not appear to cause ME/CFS.
I'm not sure you can conclude that. They may not cause it, but those receptors are linked to dysautonomia and muscle weakness. Have a read of this regarding Carmen Scheibenbogen immunotherapy research.
Link : Recent Autoimmune Therapy Study from Ramsay 2016 & 2017 Grantee Carmen Scheibenbogen
The most recent in a series of papers from Dr. Scheibenbogen’s research group at Charité, examining a potential autoimmune treatment in ME/CFS, was published in PLoS ONE in March 2018. They used a blood purification technique called immunoadsorption (IA) that allows for the removal of pathogenic proteins from the blood in a way that is more selective than plasma exchange. ME/CFS patients were selected based on infection-triggered disease onset and elevated levels of ß2 antibodies for this proof of concept study.

The group found evidence of reduced levels of specific autoantibodies in 9 of 10 ME/CFS patients who underwent IA. These same antibodies, against M acetylcholine and β adrenergic receptors, were identified as elevated in a subset of ME/CFS patients as compared to controls in a previous study by Dr. Scheibenbogen. There was also self-reported clinical improvement in 7 of 10 study participants following the IA treatment. This was a small-scale proof of concept study without a control arm, but it demonstrated the potential for therapeutic application. A more extensive discussion of the study results and an overview of Dr. Scheibenbogen’s work were featured in a recent blog post from Simmaron Research .