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

[Dr Who]

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. Indeed, zinc and magnesium deficiency can compromise our endogenous production of niacin from tryptophan (itself an essential amino acid, that is, consumed not made by our metabolism) I would also hope that, particularly at the relevant pathway steps, they do not confuse the analysis by routinely adding copious amounts of zinc or magnesium thus activating in vitro enzymes that are inactive or sub-active in vivo.

The unusual kinetics of the IDO1 enzyme, namely that ever increasing concentrations of its substrate start to inhibit then extinguish its activity, may be protective given that some of the metabolic intermediates and their off-shoots of the Kynurenine pathway are extremely toxic.

The raised Tryptophan may simply be a previously unrecognised "symptom" rather than a "cause". It may point to, or at least hint towards, the direction of the underlying pathology. I suspect a few more "Tryptophanoids" will be identified later. When enough "Tryptophanoids" have been identified, perhaps the underlying cause(s) can be triangulated and pin-pointed.

However, I must confess I am excited and hopeful that this is the start of getting on the right track to finding the cause, and cure, for this disease. Keep it going and many thanks.

 

[dreamydays]

Did two weeks on low tryptophan diet. No change at all and after investigation found out that half the stuff I was eating inhibited IDO. This is what they call evolution I presume! Anyway the diet is so limited its boring out of your mind especially when food is the only luxury in your life you get to sample. Anyway no side effects. Next step will be to try Sirolimus and then Kagocel.

 

[FMMM1]

Keep in mind that it matters where you measure the tryptophan. Ron is measuring it in CELLS, not in plasma. The results are different.

Thank you very much for all you and your family are doing/have done.

Currently researchers are using Raman spectroscopy to measure intracellular phenylalanine*; intracellular phenylalanine appears to be elevated in ME/CFS. On the face of it this method might also work for measuring intracellular tryptophan.
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 think that I read somewhere that OMF are looking at developing a mass spectrometry test (MS Test) for intracellular tryptophan. If a MS Test is delivered then readers in the United Kingdom may be interested to know that the UK Government laboratories (Fera Science & AFBI) carry out MS Testing. I think the prices the UK Government pays these laboratories is as low as 200 UK pounds per MS Test. However, I expect that testing for intracellular tryptophan, using MS, will require very sophisticated MS equipment [MS-MS] and would therefore be more expensive.
Most other governments have state laboratories which currently carry out MS Testing; typically they monitor food etc.

The European Union Committee on the Environment, Public Health and Food Safety (ENVI Committee) is currently lobbying for funding for research into Lyme disease and the development of a diagnostic test. I've written to the ENVI Committee asking that they also lobby for funding into ME/CFS research and the development of a diagnostic test [https://forums.phoenixrising.me/ind...h-theyre-working-for-you.61516/#post-1003111].
Consider asking your elected representative to lobby for funding into ME/CFS research and the development of a diagnostic test.

 

[JES]

Found this blog post from a few years ago that discusses the kynurenine pathway and issues it may cause in ME/CFS. It may well be that the kynurenine pathway is dysregulated in ME/CFS and would cause the changes observed in intracellular tryptophan and kynurenine concentrations. But I have some doubts on whether this is from the IDO2 metabolic trap or from something else going wrong.

 

[Martin aka paused||M.E.]

On Saturday, when I arrived to the Symposium, Dr. Naviaux pulled me aside immediately to tell me that when tested in the Nanoneedle Copaxone did indeed change ME/CFS blood to healthier blood. The only two drugs that have ever shown that result are Suramin, and Copaxone. I spoke to Ron Davis who also confirmed that. Later in the day, I ran into Rahim, the developer of the nanoneedle, who further confirmed that was the case."

If this post deserves its own thread, admin is welcome to move it

Is there any chance to get an update from Genome Center on this? Because I read in another thread here that Davis was looking into Cooaxone in April! So I’m asking myself whether it really worked with the nano needle... because this would be great news especially for the very severe ones like me giving me much hope that there will be something in the next months that I can try... and not in the Next years

@Ben H maybe via a science Wednesday update? I think this is an information that is worth to be shared...

When did you talk to Naviaux abou the nano needle, @Rachel Riggs ?

Thank you

Martin

 

[alex3619]

I would like to see a full analysis of the full Kynurenine pathway in ME/CFS patients versus healthy controls.

Not just kynurenine but serotonin, and an analysis of overlap between serotonin synthesis and IDO2 expression, given its limited tissue range.

 

[alex3619]

Do you think the thing about tryptophan is the key of ME?

I think the concern of high tryptophan might be that it drives excess serotonin synthesis ... but again, in what tissues?

 

[alex3619]

Does anyone have an idea how high TRYP, low KYN can cause low serotonin

I suspect it might drive serotonin synthesis, not lead to low serotonin, but the tissue range would be small at best.

 

[alex3619]

I think without this trigger we don’t expect the IDO2 variants to cause any noticeable problems.

I think that is one of the major points ... this is a backup enzyme, and only in exceptional circumstances is it needed. If about half of the population has one of the snps or the stop codon, then what other factors determine if the problem arises, given that maybe 10% of very sick patients get ME? Other traps? Deficiencies? Pathogen strains? Mold? Activity? Nutrition?

 

[babeng]

Is there any chance to get an update from Genome Center on this? Because I read in another thread here that Davis was looking into Cooaxone in April!

I think many of us would welcome more news regarding Copaxone. Very frustrating to know that there may possibly be a drug that can help us already out there, and not get more details..

 

[Ben H]

Is there any chance to get an update from Genome Center on this? Because I read in another thread here that Davis was looking into Cooaxone in April! So I’m asking myself whether it really worked with the nano needle... because this would be great news especially for the very severe ones like me giving me much hope that there will be something in the next months that I can try... and not in the Next years

@Ben H maybe via a science Wednesday update? I think this is an information that is worth to be shared...

When did you talk to Naviaux abou the nano needle, @Rachel Riggs ?

Thank you

Martin

Hi @MartinDH

I'll try and get an update.


Ben

 

[Ben H]

I think many of us would welcome more news regarding Copaxone. Very frustrating to know that there may possibly be a drug that can help us already out there, and not get more details..

Hi @babeng

It is frustrating, however it is inevitable because this is still very preliminary, as is the nano needle. If Copaxone attenuates the signal or restores it to somewhat 'normal' looking (I'm glossing over the massive complexity here), it still doesn't mean it will work irl. We don't know yet that the nano needle is a bio-marker, however the results are looking very good so far.

There is a duty of responsibility on the researchers as well to do no harm/pass no potentially harmful information out, because of ramifications and legality. Let alone adhering to the scientific method.

I'll try and get an update on this, but just some things to bear in mind.

The rate limiting step for this is always funding.


B

 

[Moof]

There is a duty of responsibility on the researchers as well to do no harm/pass no potentially harmful information out, because of ramifications and legality. Let alone adhering to the scientific method.

Very true – we've had enough bad science to last us all several lifetimes! The fact that this research is even happening is immensely cheering. The team must be acutely aware how many times our community has been let down, and will be keen to dot every I and cross every T before releasing any information or results.

The biomarker, when it is found, has to be reliable enough to convince doctors worldwide, including some of the rank sceptics – a necessity which hasn't weighed nearly so heavily on people working on other diseases. In that sense, our researchers are also victims of the sorry history of ME, along with the patients.

 

[alex3619]

including some of the rank sceptics

Sceptics can be convinced with good enough science. Those in denial, due usually to some other favoured theory, will most likely not be convinced.

 

[FMMM1]

Hi @babeng

It is frustrating, however it is inevitable because this is still very preliminary, as is the nano needle. If Copaxone attenuates the signal or restores it to somewhat 'normal' looking (I'm glossing over the massive complexity here), it still doesn't mean it will work irl. We don't know yet that the nano needle is a bio-marker, however the results are looking very good so far.

There is a duty of responsibility on the researchers as well to do no harm/pass no potentially harmful information out, because of ramifications and legality. Let alone adhering to the scientific method.

I'll try and get an update on this, but just some things to bear in mind.

The rate limiting step for this is always funding.


B

I think that this is a longer version of Ben's post i.e. if there's funding then you could check whether Copaxone works + in the meantime, don't try this at home.
I've tried to influence potential funders i.e. the European Union [https://forums.phoenixrising.me/ind...h-theyre-working-for-you.61516/#post-1003111]. Why not ask your elected representative to lobby for funding for research into ME/CFS including the evelopmen of a diagnostic test?

This is from Wikipedia:
[Copaxone] "It is a mixture of random-sized peptides that are composed of the four amino acids found in myelin basic protein, namely glutamic acid, lysine, alanine, and tyrosine. Myelin basic protein is the antigen in the myelin sheaths of the neurons that stimulates an autoimmune reaction in people with MS, so the peptide may work as a decoy for the attacking immune cells".

I assume that the nano needle testing is using peripheral blood mononuclear cells (PBMCs).
This is from Wikipedia:
"A peripheral blood mononuclear cell (PBMC) is any peripheral blood cell having a round nucleus. These cells consist of lymphocytes (T cells, B cells, NK cells) and monocytes, -----. In humans, lymphocytes make up the majority of the PBMC population, followed by monocytes ----."
The Seahorse analyser appears to show altered cellular energy metabolism in PBMCs in people with ME/CFS [https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186802]. The nano needle testing appears to show the same thing i.e. altered cellular energy metabolism in PBMCs in people with ME/CFS.

Fluge and Mella proposed that the altered cellular energy metabolism in muscle cells in people with ME/CFS tracks with the plasma [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/]. I.e. muscle cells from someone with ME/CFS plus healthy plasma = muscle cells with normal cellular energy metabolism. The reverse is also true i.e. muscle cells from someone with ME/CFS plus ME/CFS plasma = muscle cells with altered cellular energy metabolism. Maybe Copaxone provides a means to understand what is altering cellular energy metabolism in ME/CFS.

Does Copaxone lower the (intracellular) levels of tryptophan i.e. in PBMCs/muscle cells [Phair]?

All very complex but testable i.e. if there's funding.

 

[babeng]

It is frustrating, however it is inevitable because this is still very preliminary, as is the nano needle. If Copaxone attenuates the signal or restores it to somewhat 'normal' looking (I'm glossing over the massive complexity here), it still doesn't mean it will work irl. We don't know yet that the nano needle is a bio-marker, however the results are looking very good so far.

Thanks for your feedback Ben! I'm very aware of the responsibilities the researchers have with regard to giving to much information to soon. On the other hand more positive information gives patients hope. So it's a balance. In addition, more positive info is probably correlated with more donations. Just see the last symposium as an example.

Would love to hear how many patients cells they've tested it on, how long does it take before the response in the nano needle compared to Suramin, what the next steps are etc.

To your point of translating this to real life, this is exactly why I'm more encouraged with regard to Copaxone than Suramin, given that two people with CFS that we know of have had very good responses from Copaxone. Suramin has not had the same effect in real life from what I've understood.

Btw, do you know if they ever tested Rituximab in the nano needle?
Or if this was even possible with the working mechanisms of the drug?
I'm interested since Copaxone and Suramin are the two substances they have found that work in the nano needle.

 

[raghav]

Frankly speaking OMF should focus maximum on copaxone and metabolic trap. Other than these OMF is at least 5-7 years away from a treatment. I am stating this because Ron Davis himself said in the symposium that they are in the exploratory phase. So this phase will continue for at least 2-3 years. Then if they identity any promising treatment (existing drug) then they have to generate funds to do Phase 1 , Phase 2 and Phase 3 clinical trials. This will take 3-4 years. Hence my exstimate of 5-7 years. Of course if Nancy Klimas' phase 1 trial of Etanercept and Mifepristone yields positive result then it might reduce the waiting time.

So all the more the reason to try to bring copaxone into clinical trials. If OMF can generate sufficient funds to do a pilot trial consisting of 20 to 25 patients with copaxone then it can reduce the waiting time. But even that will take 3 - 4 years.

Forgot to add Cortene. If cortene gets positive response then it will take 3 -4 years to get it to market, assuming it sails through smoothly in phase 2 and phase 3 trials.

 

[FMMM1]

Frankly speaking OMF should focus maximum on copaxone and metabolic trap. Other than these OMF is at least 5-7 years away from a treatment. I am stating this because Ron Davis himself said in the symposium that they are in the exploratory phase. So this phase will continue for at least 2-3 years. Then if they identity any promising treatment (existing drug) then they have to generate funds to do Phase 1 , Phase 2 and Phase 3 clinical trials. This will take 3-4 years. Hence my exstimate of 5-7 years. Of course if Nancy Klimas' phase 1 trial of Etanercept and Mifepristone yields positive result then it might reduce the waiting time.

So all the more the reason to try to bring copaxone into clinical trials. If OMF can generate sufficient funds to do a pilot trial consisting of 20 to 25 patients with copaxone then it can reduce the waiting time. But even that will take 3 - 4 years.

Forgot to add Cortene. If cortene gets positive response then it will take 3 -4 years to get it to market, assuming it sails through smoothly in phase 2 and phase 3 trials.

Really don't know much about drugs but if it's a drug which is already approved (for another condition) then presumably you can rely on some of the current trials. E.g. is Phase 1 (safety) necessary if the drug is used extensively? I assume that the key issues would be (1) if it works (efficacy) and (2) dosage level.

Other thing is talk of refeeding i.e. no drug just clear the cellular tryptophan (Phair) using nutrients not drugs.

Can you not just use currently approved drugs i.e. provided they are known to be effective and you can get a doctor to prescribe them?


Funding would be a great step forward.
I've written to the European Union Committee on the Environment, Public Health and Food Safety (ENVI) requesting that they lobby for funding for research into ME/CFS including the development of a diagnostic test [https://forums.phoenixrising.me/ind...ch-theyre-working-for-you.61516/#post-1003111].
Currently the ENVI Committee is lobbying for increased funding for research into Lyme disease and the development of a diagnostic test.
In 2016 the European Commission [European Union civil service] said [regarding Lyme disease] that "Both basic research and the development of new diagnostics, treatments and vaccines for Lyme borreliosis are funded by EU research and innovation framework programmes. The total EU contribution to such projects since 2007 amounts to EUR 33.9 million [US dollars]" [http://www.europarl.europa.eu/doceo/document/E-8-2016-008631-ASW_EN.html].

ME/CFS received no funding from the European Union [http://www.europarl.europa.eu/doceo/document/E-8-2017-006901-ASW_EN.html].

 

[Martin aka paused||M.E.]

To your point of translating this to real life, this is exactly why I'm more encouraged with regard to Copaxone than Suramin, given that two people with CFS that we know of have had very good responses from Copaxone.
.

Two? Who is the other one?

 

[babeng]

@raghav good reflections. Although it is not the correct way to do it, I feel that OMF and Ron could pay more attention to patients that have experimented with Suramin/Copaxone on their own. For example, if it’s the case that three patients have already tried Suramin without success, why fund the upcoming study? It could be a waste of time and money, especially if a couple of more patients tried it without success. I know it’s not the correct way to do things. But the same can be said about Copaxone, where you have the opposite situation, with two patients having responded to the drug. At least they should do a pilot study with 3-4 patients before funding a larger trial. That's a must the way I see it.

Two? Who is the other one?

Cort mentions two patients in this recent article
https://www.healthrising.org/blog/2...ion-finding-could-open-new-treatment-options/