IDO Metabolic Trap Hypothesis Published Today

Ben H

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Hi guys,

Some really good, exciting news:




Dear Friends,

We are proud to announce that Dr. Robert Phair has published the IDO Metabolic Trap Hypothesis in an open access publication. This publication validates and helps to spread awareness of the critical research OMF is funding. We are grateful for Dr. Phair's active participation in our research and his commitment to our OMF community.

OMF Science Liaison, Dr. Chris Armstrong, has provided you an overview of this new publication below.

Through your donations, OMF is leading research and delivering hope around the world. Thank you for supporting our shared mission.

With hope for all,


Linda Tannenbaum
Founder & CEO/President

The IDO Metabolic Trap Hypothesis Published

By Christopher Armstrong, PhD

Dr. Robert Phair has just published a paper detailing his “metabolic trap” hypothesis underlying ME/CFS, a theory that combines engineering and physiology put together by a man adept in both fields. Dr. Phair is co-founder and Chief Science Officer of Integrative Bioinformatics, Inc, a small company built around a unique software capable of modeling human biochemistry and theories of disease. Development of this theory was funded by Open Medicine Foundation (OMF). The paper, published in the open access journal, Diagnostics, is co-authored by Alex Kashi and Dr. Ron Davis, OMF Scientific Advisory Board Director and Director of the Stanford Genome Technology Center (SGTC).

Interestingly, understanding the theory of the “metabolic trap” opens the eyes to some unique elements of ME/CFS.

Like most chronic diseases, ME/CFS can be triggered by various factors and can run in families indicating a genetic element. Unlike other chronic diseases, ME/CFS can occur in outbreaks or epidemics. For outbreaks to exist, the genetic element of ME/CFS must be common enough for a large proportion of exposed people to get the disease. This thought process led Dr. Phair to look for damaging genetic mutations that were common in the broader population but present in 100% of ME/CFS patients. A search of public genome databases including the OMF-funded ME/CFS Severely ill Big Data Study led to IDO2. The IDO2 gene stood out because it has four common damaging mutations, and every ME/CFS patient in the Severely ill Big Data Study has at least one of them.

Read more.

Help advance ME/CFS research.



www.omf.ngo



B



 
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I wonder why they say this in the first sentence:

"Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating noncommunicable disease
brandishing an enormous worldwide disease burden with some evidence of inherited genetic risk."

I've heard comments that potentialluy 75% of people might be vulnerable to: "getting" ME from Dr. Davis; and that our main theory on what is this illness includes: viral or bacterial or other infectious agents initiating something from which: some not recover and ME can then set in.
 

Diwi9

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For those that did not read to the end, please note Dr. Phair's generous acknowledgement to patients and this forum...what a gentleman (thank you @HTester):
Acknowledgments
Genome sequencing data used for bioinformatic analyses described in this publication were contributed by Investigators of the OMF END ME/CFS Project, and are available at http://endmecfs.stanford.edu/. The authors thank ME/CFS patients around the world, notably Paolo Maccallini, Mateusz (Matt) Kaczmarek, Jenny TipsforME, Cort Johnson, and other members of Phoenix Rising and S4ME for their insightful blog posts, thoughtful critiques, and public discussion of the IDO metabolic trap. We also thank Whitney Dafoe, Nina Khosla, and Moritz Ernst for their courage, for the inspiration they offer to all of us, and for their parents whose extraordinary generosity has made this work possible. Portions of this work were presented at the March 2019 eMErge International Research Symposium on ME/CFS, in Geelong, VIC, Australia. That presentation won the Day 2 MDPI-sponsored best presentation award.
 
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So I wonder why our Tryptophan levels might be high enough to: shut down the Metabolic process....?

Whats causing that?

Wikipedia: under Tryptophan, has alot of info and says this: unclear if its in reference to bacteria or other...

"So high levels of tryptophan prevent tryptophan synthesis through a negative feedback loop, and when the cell's tryptophan levels go down again, transcription from the trp operon resumes. This permits tightly regulated and rapid responses to changes in the cell's internal and external tryptophan levels."


For this metabolic trap theory to deploy, whats causing our tryptophan levels to be so high?

And interesting this mentions low levels of tryptophan can cause depression. Yet we have high levels in theory? Maybe our version of depressed (because we feel ill and life-robbed) is not the same, as depressed from low tryptophan levels.
 
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I wonder why they say this in the first sentence:

"Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating noncommunicable disease
brandishing an enormous worldwide disease burden with some evidence of inherited genetic risk."

I've heard comments that potentialluy 75% of people might be vulnerable to: "getting" ME from Dr. Davis; and that our main theory on what is this illness includes: viral or bacterial or other infectious agents initiating something from which: some not recover and ME can then set in.
Viral infections are communicable, but they don’t last long (days to weeks). The disease itself is noncommunicable, and can often show symptoms months after the viral infection.

Just because 75% of people MIGHT be at risk of getting the illness doesn’t make it any more communicable. 100% of people are at risk of getting cancer.
 

sb4

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Does this mean we can induce ME/CFS in 75% of the population by elevating their tryptophan levels?
Interesting question.

I vaguely remember reading about lots of people a few decades ago getting quite similar symptoms to ME from taking supplemental TRP. The supplement was banned until it was decided the problem wasn't TRP but an impurity from some Japanese factory.

What if it wasn't impurity but just elevated TRP? Then again I would imagine we would have seen more cases if that where true.

Another thing is I have read that TRP depletion starves pathogens of food. "IDO/AhR acts as a double-edged sword by both depleting l-Trp to starve the invaders and by contributing to the state of immunosuppression with microorganisms that were not cleared during acute infection."

Do pathogens tend to use more TRP for their food? Why does the body lower TRP in response to pathogen but not other aminos, etc?
 
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I found this paper interesting. Not directly related to IDO2 but rather IDO1 on diabetes. If I follow the paper correctly, they found that a defect in IDO1 was related to a subset of diabetes. They then identified a way to in effect "fix it". By adding in a drug called Tocilizumab. All of which is to say, that (assuming I understand this correctly) there might be a way to kick start IDO2? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5926942/
 
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I also found this https://cordis.europa.eu/project/rcn/111574/reporting/en

We unexpectedly discovered IDO1 catalytic enhancers, i.e. VIS-119 and the more potent VIS-329, capable of increasing the affinity of IDO1 for its substrate, tryptophan, in both cell and biochemical (using a recombinant IDO1 protein) assays.

All of which is to say, that you might be able to alter how IDO1 and IDO2 are functioning (slightly broken or not) in order to return to a normal function. Super positive! (assuming the trap is the issue and also assuming that I understand all of this correctly)
 
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Ok... one more. Here is my humble attempt to explain this to my sister (who has CFS). Feel free to correct me.

Imagine you have a system that is designed to pump water. It uses two pumps. The first pump works like a hot damn until the water starts to get over 10 feet deep. It then starts to progressively get worse as the water gets deeper until it can barely function. The second pump never works all that well but it can continue to function at the same rate past 10 feet. In most cases the water never goes over 10 feet anyhow.

So people with CFS might have a broken/worse functioning second pump. Something then comes along that causes the water to rise over 10 feet. They are then locked in a state where the first pump struggles along but is never ever capable of getting the water under 10 feet.

The part that has made this so hard to figure out is that until a few years ago, scientists had no idea there was 2 pumps. It also is super confusing as the “something” that causes the water to rise could be a wide variety of external factors. Also, once "something" causes the water to rise, it is long gone.

This also hasn't been helped by the fact that doctors tend to fixate on what caused the water to rise when in this case it doesn’t really help the patient.
 

Navid

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What does it mean in terms of potential treatment possibilities to have this paper published. What are the next steps to getting to treatment?

Congrats to the team on this great accomplishment. Thanks for all your hardwork.
 

suevu

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What does it mean in terms of potential treatment possibilities to have this paper published. What are the next steps to getting to treatment?

Congrats to the team on this great accomplishment. Thanks for all your hardwork.
This is great research but its only a symptom of the many symptoms of the disease.

What's the underlying cause of this trap?
 

Gemini

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What are the next steps to getting to treatment?
@Navid, Ron Davis' update on the "IDO Metabolic Trap Hypothesis" last month at the Harvard Symposium indicated the next step was to test patient samples on a highly sensitive machine to see if the trap is present. He said there was a waiting line to get access to the machine.

The last sentence of the paper reassures the hypothesis can be easily tested:
"For any given cell type, this hypothesis is testable using labelled tryptophan combined with standard tracer kinetic analysis."

@Janet Dafoe (Rose49)
 
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HTester

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Does this mean we can induce ME/CFS in 75% of the population by elevating their tryptophan levels?
We always emphasize that we're talking about intracellular tryptophan (Trp), not plasma or extracellular Trp. Also the critical concentration of intracellular Trp, above which you fall into the trap, is ~100-fold above normal, so it's not easy to achieve.

Nevertheless, with these provisos, the answer to @Chelby 's question is, yes, that's what the theory predicts.
 

HTester

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The last sentence of the paper reassures the hypothesis can be easily tested
We've been working on this test for a year. When we started, we thought it would be easy, but it's not. We're measuring small concentrations in a small number of cells, so we're pushing the limits of the technology. Previous investigators have measured much higher concentrations by activating the cells with IFN-gamma. We're trying to measure what's actually happening in the patients' cells.

It's worth re-emphasizing that the immune cells (dendritic cells) we're testing were chosen because there is almost surely an immune component of ME/CFS, and because these cells can be isolated from a patient blood sample. We're imagining ways to measure kynurenine pathway flux in brain using imaging technology because it seems likely that serotonergic neurons and neighboring microglia are critical to the disease. It's easier (note humorous understatement) to convince people to donate plasma dendritic cells than to donate cells from their brainstem, but that doesn't mean we can ignore neurons. It just means measuring kynurenine flux is easier in immune cells than in brain, so we're doing the easier test first.
 

HTester

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"So high levels of tryptophan prevent tryptophan synthesis through a negative feedback loop, and when the cell's tryptophan levels go down again, transcription from the trp operon resumes. This permits tightly regulated and rapid responses to changes in the cell's internal and external tryptophan levels."
Definitely bacteria. Trp is an essential amino acid for humans so this transcriptional control system is not relevant.
 

HTester

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For this metabolic trap theory to deploy, whats causing our tryptophan levels to be so high?
We're only speculating here, but one of my favorite ideas is that the stressors we all talk about as initiating the first crash do so by inhibiting IDO1 for long enough to build up the substrate Trp beyond the critical point. For example, nitric oxide is a potent inhibitor of IDO1. This could be combined with excess Trp in the diet, which some of you know is my hypothesis for how so many athletes and body builders have contracted ME/CFS.

In the Australian Dubbo study of infections, I think it was 9% had ME/CFS symptoms 6 months post-infection. These tended to be those who had the most severe infections, so we're thinking that's the immediate cause of increasing cellular Trp.

Then, of course, after cellular Trp increases beyond the critical point (defined in the paper), you can be cured of the precipitating infection, but you are still in the IDO metabolic trap.
 

suevu

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We're only speculating here, but one of my favorite ideas is that the stressors we all talk about as initiating the first crash do so by inhibiting IDO1 for long enough to build up the substrate Trp beyond the critical point. For example, nitric oxide is a potent inhibitor of IDO1. T
I used to take no-explode for years before falling sick. Could this be related? jeeez all the pieces of the puzzle start to assemble.

And certainly I would love to take it again when I recover, it feels so good.