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

Ravn said:
This potential ME-trigger-to-tryptophan route is mighty confusing.
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That's why I don't really see the point of people like me trying to discuss or pick apart Phair's hypothesis. My knowledge of physiology and biochemistry is too limited to grasp the complexities of the metabolic pathways, genetics, epigenetics etc. involved.

All I can do is enjoy the lecture that gives me a glimmering of what they are talking about, and wait to see if it pans out into a solid theory, or is, as Ron Davis hinted, just one of many ideas awaiting testing, most of which will be disproved. That's how science of this exploratory sort works. You do your best to come up with hypotheses based on current high quality data, then test them in every way you can think of to try to disprove them.

About half way through this short video Ron Davis explains what I'm talking about - that real scientists test their ideas to destruction, they don't just cherry pick the bits that support their theory. (I tend to ignore his optimism and assurances that they will 'solve this disease' soon - I hope he's right, but biology is incredibly complicated).

Kalliope said:
The Norwegian ME Association, Buskerud County, participated at the Stanford ME symposium and made this greeting to patients from Ron Davis.
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So as I understand it (possibly incorrectly) this theory is suggesting that people with this mutation will remain healthy if their Tryptophan concentration remains well within 10µM or so. Up to around this level the transfer function between Tryptophan concentration and IDO-2 remains positive - increasing Trp concentration results in increased IDO-2, which in turn holds Trp concentration in check. For healthy people this positive transfer function (Trp concentration to IDO-2) persists for all Trp concentrations levels, no matter how much higher; though the slope reduces at the top end it is still positive. Not sure if this is an actively regulating feedback loop, or if it is simply that increasing IDO-2 effectively depletes ('consumes'?) Trp and so works to reduce its concentration, thereby offsetting its tendency to rise. Either way it doesn't matter in this context; the Trp concentration to IDO-2 transfer function between the two is always positive (increasing the former increases the latter).

So the suggestion seems to be that for susceptible people, the crunch point comes if their Trp concentration gets to around the 10µM region, where the transfer function drops to very low positive values, goes through zero and then turns negative. Once this transfer function goes negative then it works against itself; increasing Trp -> reducing IDO-2 -> further increasing Trp.

The comparison that I think of for this, is a dislocated joint. The joint effectively has two stable regions, located and dislocated. Within each region there is an operational range of activity, but within the unhealthy (dislocated) region, that range is very unpleasant and debilitating. I knew someone once who had a congenital jaw defect, where their jaw joints were improperly formed. If he yawned too widely, or vomited, his jaw tended to dislocate; once it got past a certain point, then the muscles/sinews would pull his jaw out of its sockets, instead of into them. I witnessed this once and went to hospital with him. For healthy people of course it takes a lot of physical trauma to do this. For him his only escape from this unhealthy condition was with medical assistance, relatively easy in his case because the medics knew what needed doing.

Phair showed his S-shaped curve, with the unhealthy region more or less the same shape (albeit differently oriented) to the healthy region. I imagine in practice the unhealthy region could well have its own peculiar characteristics. Phair was of course just illustrating the notion of bistable behaviour.

I found it especially interesting Phair spoke of two different operating regions; there being a continuum of operating points within each one. This would therefore accommodate the notion of ME symptoms fluctuating whilst still locked within the unhealthy region. PEM coming and going?

Also, if (big if I appreciate) Phair's theory were right, then presumably there could be knock on consequences on how various other body subsystems behave, each triggering their own set of symptoms. A potential cascade effect.

Phair also spoke of the tipping point into the unhealthy region becoming locked in only once the provocation condition had persisted for a long time, albeit that at this time being from his mathematical modelling. Would like to know more of that.
 
Ravn said:
I've only read the abstract which I interpret - in/correctly? - as not referring to tryptophan synthesis but only to tryptophan metabolism, i.e. the conversion of – presumably dietary - tryptophan into other metabolites such as kynurenic acid.

Does the article itself say anything more? It's too long for my current energy level to read.
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Doesn't it say that humans can only acquire tryptophan from diet?
 
Milo said:
Hi @mariovitali, since the mid 1980’s we know that about half of the patients with ME have needed to have their gallbladder removed (from Osler’s Web by Hilary Johnson, p 28???)

in my case i had lab-confirmed EBV onset with liver involvement (elevated liver enzymes and lots of pain, ultrasound showed sludge in gallbladder but no stone. 5 months after onset i had the mother of all gallbladder attacks, and it was removed, the surgeon found no stone, still sludge, and it was necrotic. I also developped GERD very early into my illness.

The problem we are facing and i will speak of Canadian patients is that the doctors learn early on to not offer testing, and specialized scans would only be ordered by a specialist authorized to perform these scans, under specific criterias. This is to reduce costs to our socialized health care system. They also become very suspicious when the patients start asking for further tests. And really we are suffering from the ‘no testing, no problem’ kind of attitude. Same goes on with brain scans and other specialized testing which would inform a specialist seeing the same population of patients, which would help in looking for similarities and generating research questions. The system is truly broken for us.

Edit to add: @mariovitali the other peculiar symptoms that patients with ME have is sensitivity to epinephrine. (Like when going to the dentist and getting anesthesia which contains epinephrine causes a prolonged crash to many of us) this has not been investigated much. It would be interesting to understand this mechanism, as it is not understood well and patients have trouble convincing dentists not to use epinephrine.
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Thank you Milo for pointing out what happens in our medical system in Canada. The main focus when one is at the doctor’s office or in hospital is to reduce costs. Thus, tests are not ordered, investigations rarely initiated, particularly anything out of the norm. Milo is correct: No test, and no problem.

Going to our hospitals or clinics at least in Montreal is a fearful experience, something one tries to avoid.

Thank you Milo for pointing out the truth about socialized medicine in Canada.
 
Milo said:
Edit to add: @mariovitali the other peculiar symptoms that patients with ME have is sensitivity to epinephrine. (Like when going to the dentist and getting anesthesia which contains epinephrine causes a prolonged crash to many of us) this has not been investigated much. It would be interesting to understand this mechanism, as it is not understood well and patients have trouble convincing dentists not to use epinephrine.
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It´s probably explained by the fact that COMT- mutations are more common in PWME than in a healthy population. I didn´t dig into this but I trust the late Rich Van Konynenburg who listed SNP´s that are more prevalent in PWME, in his video-recorded talk on the Internet.

As the enzyme, which is related to COMT, is needed to break down adrenaline/epinephrine properly , mutations can cause the kind of symtom at the dentist that you mention. Also sensitivity to coffein and situations that produce adrenaline will affect the person with COMT mutations. I´m homozygote myself and finally found that explanation to my symptoms after having had gene tests. COMT
SNP´s, if you have any of importance, can be found in the results from e.g. a 23andme test. Some tell that they can´t cause symptoms, but they clearly can.
 
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Trish said:
That's why I don't really see the point of people like me trying to discuss or pick apart Phair's hypothesis. My knowledge of physiology and biochemistry is too limited to grasp the complexities of the metabolic pathways, genetics, epigenetics etc. involved.
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You are perfectly right of course @Trish. None of us laypeople is going to work out the solution for a problem in such a complex biological system, no illusions there.
I suspect one of the reasons we entertain ourselves with much happy speculating regardless is that we suffer from a couple of co-morbidities: Curiosity Syndrome (CurS) and a Need to Understand Things Syndrome (NUTS) :D. Phair's hypothesis lends itself particularly well to such nerding because it can be approached almost entirely with logical thinking and doesn't require the ability to interpret high-tech scans or similar.

I also think our amateur speculation is more than just some entertaining brain gymnastics for nerds. One of my university lecturers always insisted we write our papers with a 7-year old reader in mind. Because if the 7-year old couldn't understand our concept then that was very likely the result of sloppy thinking – on our part, not on the 7-year old's. While writing for a 7-year old is a bit extreme I think if scientists were required to always communicate at a level an intelligent layperson can understand that would help expose faulty logic, unexamined assumptions and unanswered questions*. Which is, I think, what we're doing here. And I like to believe that just only very occasionally just maybe, just possibly, one of our questions or observations filters through to a scientist and sparks a new idea or just a different angle to approach their problem from.

PS: I'm not accusing Phair of sloppy thinking by the way, I'm only noting that what he has communicated to date doesn't answer all our question.

PPS: *Did I just come up with a way to overhaul the peer review system? Have a layperson on every peer review panel with the specific task of asking “dumb” questions in order to make the final paper clearer and more relevant. If we make the job paid it could even become an income stream for some of us here, even the brain-fogged could ask “dumb” questions... I'm beginning to like the idea more and more ;)
 
Ravn said:
You are perfectly right of course @Trish. None of us laypeople is going to work out the solution for a problem in such a complex biological system, no illusions there.
I suspect one of the reasons we entertain ourselves with much happy speculating regardless is that we suffer from a couple of co-morbidities: Curiosity Syndrome (CurS) and a Need to Understand Things Syndrome (NUTS) :D.
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You are right of course, and I'm as guilty of the next person of speculating and trying to understand the complexities of biology and hypotheses like the metabolic trap. I think I was having a grumpy moment. Please don't let my comment put anyone off discussing science from whatever level of understanding you start from. :)
 
nonstopflu said:
which is the "bad" column... "ref" or "alt"?
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As a general rule of thumb, ref is the original allele and usually the good one, and alt is the more recent mutation and usually the bad one.
But, as I said: rule of thumb only, plus applies only to bad (pathogenic or risk) mutations.
Many mutations don't do anything much (benign) so there it doesn't matter whether you have the ref or alt version.
And some mutations are actually protective and the alt version is the more desirable one.
And to really confound matters, some mutations are protective for one disease but a risk factor for another.

For the IDO2 mutations in question here I understand that the alt version is the bad one.
 
Ravn said:
And to really confound matters, some mutations are protective for one disease but a risk factor for another.
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yes, I have an "alt" mutation for the FUT2 gene, and I read somewhere that FUT2 genes are one of the ones that are darned if you do, darned if you don't - depending on which other genes you have, of course...... I think it's the combo of genes that does you in.... I can't find the article, and I wish I could... I'm very interesting in this gene..

thanks for the explanation! it took a long time for me to figure this out, and most ppl don't understand this...
 
How does the metabolic trap theory explain the improvement seen in patients receiving ampligen/cyclophosphamide? How does immuno suppression or modulation affect the trytophan pathway...since it's locked into an unhealthy state?
 
Speculation:

Just out of curiosity, I wondered if sleep deprivation might increase tryptophan. I guess I was thinking that the body might try to force sleep by producing more (if it can produce more). Or perhaps tryptophan is "consumed" during sleep - so its level would rise if you didn't sleep.

Effect of sleep deprivation on the human metabolome (2014)
During sleep deprivation, 27 metabolites (tryptophan, serotonin, taurine, 8 acylcarnitines, 13 glycerophospholipids, and 3 sphingolipids) exhibited significantly increased levels compared with during sleep. The increased levels of serotonin, tryptophan, and taurine may explain the antidepressive effect of acute sleep deprivation and deserve further study. [Bolding mine.]
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115565/
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I was chronically sleep-deprived just prior to onset - then I got the flu, and, at the very tail end of recovery (when I was probably still making up for a lot of lost sleep), I got ME.

Off the top of my head, I can think of two potentially sleep-deprived groups who have figured in reports of ME cases - nurses in hospitals and flight crews/flight attendants. I remember in the 1980's that one of the curious targets of ME seemed to be flight attendants. (Perhaps due to sleep issues from constantly changing time zones?)
 
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I was under the impression that vaccinations were causing the higher incidences of ME in the 80's and early 90's.

I've never been sleep deprived and got ME, my sister's been a flight attendant for almost 40 years and is as fit as a race horse.:D
 
Cort has a blog about Phair's hypothesis today. He explains Phair's search strategy for a mutation (I don't think I've seen it explained this way previously):

With his beginner’s mind, though, those 70 or so outbreaks caught Phair’s eye [...] The fact that so many people became so ill so quickly stood out. A pathogen sweeping through a community was obviously one component, but the wide swath of people suddenly becoming ill suggested that the pathogen had taken advantage of a widespread vulnerability.

Phair’s Factors
Most researchers have looked for rare genetic tweaks but nothing rare could account for the masses of people that typically became ill. Phair reasoned that the susceptibility to the disease had to be common [...and...] he was looking for genes tied to systems that featured “bi-stability” – the system could be stable in two different states- a healthy state and an illness state. [...]

Plus, once one got into the illness state the system had to feature a kind of stuckness which made it difficult to return to health.

Plus, the system had to be vulnerable to a sudden stressor and it had to feature the ability to suddenly “flip”.

Plus, the gene mutation had to have the ability to affect multiple systems – to generate the kind of widespread illness that ME/CFS is.​

https://www.healthrising.org/blog/2...on-the-molecular-basis-of-me-cfs-at-stanford/

Interesting strategy, and the fact that he found a match to these criteria is perhaps encouraging.

Also interesting that different people are using different criteria to search for relevant mutations. At the CMRC conference, Mark Jones said he was looking at the genes of not only an individual with a particular disease but also their parents (who don't have the disease, presumably) and seeing what new mutation the individual has (i.e. which bit of their genome didn't come from either parent) to get disease-causing candidates.

Another good reason to get everyone in the same room. :whistle:
 
I've just read Cort's overview of the hypothesis (I'm still to watch the OMF videos - are they broken down on YouTube yet?) and other than giving me a shudder of horror, recalling systems engineering lectures from almost two decades back, my main question is this: wouldn't an inhibition in IDO-mediated tryptophan catabolism, causing increased serotonin, lead to symptoms of serotonin syndrome?
 
Mij said:
I was under the impression that vaccinations were causing the higher incidences of ME in the 80's and early 90's.
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The outbreaks were associated with infections in just the same way as the earlier ones. The only vaccine I remember being associated was the hepatitis B one. I think some individuals had vaccines at the start of their illness but most people, then as now, believe it started with an infection.
 
Londinium said:
I've just read Cort's overview of the hypothesis (I'm still to watch the OMF videos - are they broken down on YouTube yet?) and other than giving me a shudder of horror, recalling systems engineering lectures from almost two decades back, my main question is this: wouldn't an inhibition in IDO-mediated tryptophan catabolism, causing increased serotonin, lead to symptoms of serotonin syndrome?
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I think they did say that the brain has become accustomed to the higher serotonin levels.
 
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