Stanford Community Symposium 2018: Phair, Metabolic traps, Tryptophan trap

I had a tetanus jab (due to being attacked by a dog) shortly before getting obvious ME, but I was already unwell.

 

I reacted badly to a tetanus jab, my arm swelled up after half an hour! That was after I had been ill for 8 years. It did not make me worse, but I have never had another one.

I think vaccines for us are like getting a bug, another stress our bodies have to cope with. The balance is whether the infection would be worse on us. I get the flu vaccine and had the pneumococcus one because I am at risk of these things. It is very individual with no right answer

 

I didn't feel any difference after the tetanus or rubella shot I received on the same day , but it was after I received the first Hep B jab that my stamina and balance was off, it was subtle at first, but one month later after the second Hep B jab is when things went downhill really fast.

The viral/vertigo attack I experienced 6 months prior (to the hep b shots) came right back with a vengeance!

 

On Cort's blog, Janet Dafoe has been posting comments from Ron, including this interesting one:

They have identified quite a large number of potential traps but more investigation is needed to determine if they fit all the requirements to be traps.

The way to test if someone is in the trap is to check the tryptophan/kynurinine ratio in white blood cells, not plasma. Regular medical labs are not equipped to do this. Scientists at the genome center are working on a simpler and cheaper method for doing this. Right now it requires a $100,000 – $1,000,000 mass spectrometer!​

 

So sorry. I lost a friend ( healthy) who was on a drug trial in 1980's when he was a scientist at Glaxos....( he was short of cash)... he became ill and committed suicide when he stopped the trial..... See https://www.theguardian.com/uk/2001/may/26/sarahboseley
Prozac class drug blamed for killing Professor David Healey was involved in supporting those who took the class action.

 

Oh God - I'm so sorry.

 

This is the article I meant to upload.

https://www.theguardian.com/theguardian/1999/oct/30/weekend7.weekend1

 

Cross-posting an extract from a comment I made in another thread, members only, because of the link to the metabolic trap (https://www.s4me.info/threads/does-being-in-more-in-daylight-help-your-symptoms.6381/#post-116102).

Recently I accidentally stumbled on an interesting connection between light intolerance and the metabolic trap theory when googling 'kynurenine' to better understand the latter. What should pop up but a condition called Polymorphic Light Eruption (PMLE), something I've suffered from all my life.

Mostly PMLE manifests as an insanely itchy rash after sun exposure but some people also get a flu-like malaise. I've always been getting the rash but the flu-like malaise only arrived along with ME.

Interestingly there are some – superficial? - similarities to PEM: symptoms are delayed, and impaired T-cell function, altered cytokine production and excess formation of kynurenic acid* are thought to be involved. So I wonder if those of you intolerant to daylight could be having some sort of milder, non-rash version of PMLE? An immune-mediated reaction to UV light maybe?

*Note that kynurenic acid is a downstream product of kynurenine so an excess here appears to contradict the metabolic trap hypothesis which predicts reduced kynurenine which in turn should logically lead to reduced kynurenic acid – unless there is an additional mechanism that takes most of the little kynurenine there is for making kynurenic acid and leaving even less to make good stuff like NAD+, thereby potentially worsening the effect of the metabolic trap. Alternatively, there may be a different pathway to turn tryptophan into kynurenic acid, bypassing the kynurenine step, explained in this article (which is a bit over my head): https://www.hindawi.com/journals/omcl/2018/5272741/​

 

I have some concerns and some additional points about the IDO hypothesis.

The first is about tissue distribution. Marking pathways is fine, but IDO2 has strictly limited expression. The two primary areas are the liver and immune cells, with a few others that may be relevant. If there is a problem here, then its likely that low kynurenine is having an effect only via immune cells, which might show why immune therapies sometimes help.

On the other hand there is currently insufficient modelling and testing of serotonin synthesis. This is an escape valve for high tryptophan, but I have yet to look at matching up tissue distribution of serotonin synthesis and IDO2 expression. Phair describes potential problems not due to low kynurenine but due to excess serotonin. This needs to be tested. It does however explain why so many of us do poorly on SSRIs, but at the same time shows that boosting serotonin synthesis might be helpful .. which is not what SSRIs do. Indeed I wonder if SSRIs lower serotonin synthesis. If so, and if the IDO hypothesis is correct, then SSRIs might lead to increased intracellular tryptophan.

These questions are not just about system dynamics, but how gene expression and activation occurs in different tissues. This needs to be further investigated.

I first started talking about stable states and CFS in the 90s (I was not calling it ME back then), and it was very hard to get any traction at least in part because nobody wanted to get involved with dynamics and chaos theory. Later I talked about hypoxia, and this was in contradiction to a popular theory at the time, so again it got little traction. I am deeply interested in this approach, because they are taking it places my brain function no longer allows me to go.

We should also not forget that the IDO hypothesis is only one of several potential hypotheses. If these IDO2 problem snps are in about 42% of people, and ME occurs in about 10% of severely infected patients (with the possibility of higher percentages in some outbreaks) then other factors might help decide which patients with an IDO2 problem might get ME or CFS. This could be additional metabolic traps, or specific pathogenic strains, or cofactors like mold, nutrition, activity and so on.

We live in interesting times, but in this case the interesting stuff is not about a curse, but the way out of a curse.

 

I keep reading how a lot of the genes in the pathway are heme dependent. What if you have a problem with iron? Could it disable the genes?

 

I am not sure this is right. Do you have any links? Maybe you mean the proteins are heme dependent? Or is there a need for heme dependent activators?

If the proteins contain an heme region then they might be impacted, but not the genes. They might also be vulnerable to nitrosative and oxidative stress. It all depends on the details.

If the genes are actually heme dependent this would be new to me, and interesting.

 

Yes, I could well be wrong. Not a science buff. Just something that I thought I saw in links other folks kindly posted...

I don't have time to search for those links just now... here is what I googled.

https://www.nature.com/articles/emm201469

https://pubs.rsc.org/en/content/articlelanding/2017/mt/c7mt00105c#!divAbstract

 

It looks like the heme group is in the enzymes, and while the genes may code for it the effects are on the enzymes.

 

IDO gene expression image, showing haeme involvement -



This suggests that low iron might result in low active IDO enzymatic capacity.

 

On serotonin effects, I want to make a comment about serotonin concentrations.

When you measure urinary or serum serotonin or its breakdown product, you are measuring something averaged over time and distance/volume. It tells you nothing about localised serotonin concentration.

If we have an issue with embedded or mobile immune cells overproducing serotonin, and I am not saying we do just yet, then we need to take into account local concentrations which might have an impact on nearby cells, as well as issues with potential serotonin production or release spikes. I do not know such serotonin spikes occur, but they do with other substances. Over time and distance this impact will diminish, as the serotonin concentration will go down due to dilution.

This means that urinary and regular serum tests will likely be highly unreliable. This is one reason, I think, our researchers are focusing on intracellular concentrations in immune cells in which IDO2 is expressed.

 

I suggest emailing OMF directly and they will forward to both Researchers.

 

I've come very late to the Metabolic Trap and have some questions about it, as well as one particular concern. But just to make sure I have got this right, could old hands at this game let me know if my summary, below is accurate? Thanks


Summary: Robert Phair’s metabolic Trap idea aims to explain ME/CFS. It proposes that common genetic mutations that affect the metabolism of the amino acid tryptophan are a risk factor for the illness. Then, if people experience a relatively rare event, such as a severe infection, the metabolism of tryptophan can be pushed from a healthy state with normal levels of tryptophan in cells to an unhealthy one with permanently high levels. This is the metabolic trap.

High tryptophan levels then drive changes to the levels of neurotransmitter serotonin (which is derived from tryptophan), perhaps in the mid-brain — and this causes for ME/CFS symptoms.

​

The central idea to the trap is "bistability" where there are two alternate states for a system, but it is very difficult the system to move between the two states. See the diagram below (not the one that he showed in his Stanford talk):

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I am also posting something I started drafting for a blog that will never get written. I will spare you the full draft.


How Phair homed in on the "trap"

Phair's starting point that was that there was probably common genetic mutations at play, because he reported that, in epidemic outbreak cases, 10-25% of sick case people go on to develop ME/CFS. (I haven't seen any data, but I have seen figures for glandular fever at around 10%, and similar figures for Q fever and Giardia.)

So he began looking at the full-sequence gene data for the Stanford Severely Ill Patients Study (SIPS). He searched for any gene where the genomic data indicated a damaged protein in every single one of the 20 patients in the study. He searched manually, and 86th gene was for IDO2, which metabolises the amino acid tryptophan to N-formylkynurenine.

There is one other IDO enzyme, IDO1, that does the same job as IDO2, but it has a significant weakness. High concentrations of tryptophan actually stop the enzyme from working (something known as substrate inhibition). So if cellular levels of tryptophan ever become very high, then the system becomes stuck at those levels, because tryptophan isn't being removed by the normal route to by conversion to N-formylkynurenine.

Here is a diagram showing the problem: IDO2 handles high tryptophan concentrations normally, whereas IDO1 has a small sweet spot of maximum activity, but then rapidly becomes ineffective as tryptophan concentrations rise.


This substrate inhibition weakness only becomes an issue if IDO2 is no longer in play, (because it is not blocked by high levels of tryptophan and will carry on converting it to N-formylkynurenine, and so bringing bring the levels of tryptophan back to normal). But those with damaged IDO2 (Phair said SIPS mecfs patients had an average of 1.7 predicted-damaged copies and we only have 2 copies in total) are at risk of being trapped in high tryptophan levels.

Rest of the idea
[So basically, if IDO2 is out of action then should tryptophan levels rise too high in the cell they will shut down the activity of IDO1, helping to lock the cell into permanent high levels of tryptophan. This is the metabolic trap.]

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I was talking about bistability and ME from about 1993, but often more in connection to chaos theory (in which there are strange attractors that are basically the troughs in the above graphs) but there did not seem to be any way to advance the idea. What I was trying to use in 1993 was a hill climbing heuristic, to try to find the nearby peak, using symptom progression and therapies. It kind of worked, but was limited. If we are in a stable alternate state then hill climbing is not likely to work.

 

Another effect mentioned in the talks was that kynurenine could end up too low and that could also lead to all sorts of downstream symptoms, for example kynurenine is a precursor of NAD+.

 

I am finding lately a lot of interesting connections between IDO1, Kynurenine, Ahr Receptor and CYP1A2, i wont get into that to avoid derailing the thread.

Regarding your question @Ravn some interesting parts from the following paper :

and regarding Ahr Receptor :

Here is another interesting paper linking B6 Status with IDO / Kynurenine (sorry if this is a repost) , see page 14 :

https://folk.uib.no/mfapu/Pages/BV/BVSite/pdf_files/literature/ueland_2017_mam_53_10.pdf