A Metabolic Trap for ME/CFS?

M Paine

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From the article:
Because the treatment strategy would involve tweaking one of the major systems in the body, though, it has the potential to do either good or harm. Worried that in the wrong hands, it could backfire – making ME/CFS patients worse – Davis and the Open Medicine Foundation are keeping the details of the possible metabolic trap under wraps until they know more about it.
I wonder if this is directed at practitioners, patients, or both. On one hand, it's really tempting as a patient to want to know more about the detail. On the other hand, it does get a bit worrisome to see people experimenting on themselves. I want someone to find something that works, but how many people here have tried and failed, possibly to some detriment to their own health. Maybe with a more rigorous and objective approach to finding proven results, some of that can be avoided. So hats off to the team for that choice, I'm sure it's not a choice that was made without hesitation. The community is very supportive to Ron and OMF, so to withhold information is not something that would happen lightly I'm sure.
 
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As Phair dug deeper into the possible causes of the weird data, a “metabolic trap” – a kind of biological sinkhole – opened up before his eyes. Once the process – which involved amino acid oxidation – started, he saw no way for an ME/CFS patient to get out of it without outside help (e.g. a treatment). Looking further, he and Davis realized it could conceivably explain some fundamental symptoms in ME/CFS.

Since then, he’s been creating model simulations to test his hypothesis. Thus far, he’s created kinetic models of the central metabolic systems in the body (mitochondrial electron transport chain, TCA cycle, fatty acid beta oxidation, amino acid oxidation, glycolysis and pentose phosphate pathway, purine synthesis and degradation, and NAD synthesis).


...Because the treatment strategy would involve tweaking one of the major systems in the body, though, it has the potential to do either good or harm. Worried that in the wrong hands, it could backfire – making ME/CFS patients worse – Davis and the Open Medicine Foundation are keeping the details of the possible metabolic trap under wraps until they know more about it.

I don't know what's up with me in a psychological sense but when someone says they've discovered a possible treatment but it's so dangerous they want to keep it under wraps i suddenly want to devote my life to figuring out what it is!

I wonder if this article will have a similar effect on others and whether we will spend the next few months in a state of high animation (High for us, that is. I doubt the animation will go beyond the couch.)
 
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mattie

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[Moderator note: according to this post, Dr. Phair now now has enough 23andMe data but could still use whole exome or whole genome data.]

Help Dr. Phair with his research and send in your genome!

rphair@integrativebioinformatics.com


Your data would be most comprehensive and powerful in the form of .VCF (Variant Call Format) file but we will work to find a way to analyze your data in any format you are able to provide.

Please also tell us your age and gender and write a paragraph or a page with a description of how you came down with ME/CFS. A list of current symptoms is optional, but desirable.

E-mail from Dr. Phair regarding 23andme data:

Yes, the .txt format will work. 23andMe only covers three of the five genetic variants that are important for the metabolic trap theory, but I can say that even this limited information is useful.

The 23and Me file that I need has a filename like this: genome_firstName_lastName_Full_date_time_in_digits.txt
so if it was mine it would be something like
genome_Robert_Phair_Full_20180315085441.txt
.zip instead of .txt is also fine
If you can open the file in a text editor it should begin with a header that looks like this:
# This data file generated by 23andMe at: Wed Jun 14 12:04:30 2017
#
# This file contains raw genotype data, including data that is not used in 23andMe reports.
Regards,

Robert D Phair PhD | Chief Science Officer | Integrative Bioinformatics Inc
Mountain View, CA
www.integrativebioinformatics.com



Edit: Dr. Phair now now has enough 23andMe data but could still use whole exome or whole genome data
 
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alex3619

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Is there someone out there who can describe a metabolic trap?
Without the details of the biochemistry any explanation will be vague. I started thinking about metabolic traps 25 years ago. I presented a paper to an ME/CFS conference in '99 on one type of trap, which was later shown to be wrong.

Lactic acidosis is perhaps a case example. In lactic acidosis, excessive lactic acid overwhelms the acid buffer in the blood and the then alters the blood pH toward acid. As this happens a chemical in red blood cells has an altered rate of production, that leads to less oxygen being supplied. Less oxygen leads to worse oxygen metabolism, and hence more lactic acid.

Now in this case that means that lactic acid leads to even more lactic acid, until after a few days its fatal if untreated. ME would have to be different. My guess is something gets depleted, possibly even NAD or some other energy metabolite, and then the body is incapable of making enough NAD to reverse the situation, since NAD is needed for energy production and you need that energy to do things like regulating metabolites or making enzymes etc. It might not be NAD though, that is only an example.

So a trap would be a metabolic state where things are so bad that the capacity to reverse that state to normal is gone. In chaos theory this would be a pathological strange attractor.

Similar theories have surfaced on patient forums regarding methylation, and methylation traps, which I have not looked at in detail.

For a more everyday analogy, its like falling into a deep well. You know freedom is just a few feet away, but you cannot climb the walls of the well, or at least not easily. Some might succeed, hence the rare recoveries or temporary remissions. In a temporary remission its like you almost climbed out of the well but then fell back in, perhaps injuring yourself further in the fall.

Now a healthy person might have a ladder, or stepping stones, or the well is very shallow, and so they easily get out of it when an infection or other physical insult resolves.
 

alex3619

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The first biochemical (not exactly metabolic) trap theory of ME I encountered was the eicosanoid theory. In this eicosanoids, very short range fat based hormones, drive inflammation and other processes to create more eicosanoids, perhaps involving a wider range of chemicals than just these hormones alone. It was only a theory, and not proven, but you can look up Grey and Martinovic on PubMed. Dr Martinovic was my treating doctor from 1993. I knew I had to do something or drop out of my PhD.
 

alex3619

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This theory seems to assume there isn't any ongoing immune activation or trigger. Am I right about this?
A qualified yes. It does not presume any ongoing immune trigger, and does not rule it out either. A point of concern is that ME and such infections or toxins or trauma might reinforce each other, each preventing recovery ... which means this would really be a subset of ME under this hypothesis, or perhaps a complication or comorbid problem.
 

Wishful

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A more concise term is: positive feedback loop. Trigger it once, and the changes reinforce the changes, locking the system into that abnormal state. The question for ME/CFS is just what is changing and being reinforced. Hopefully, we'll just need a one-shot treatment to break the feedback loop and get back to normal function. If we're predisposed to triggering that feedback loop, we might need repeat treatments for new triggerings. If we know what is involved, we might even be able to find something to counter the predisposition.

That this is a positive feedback loop isn't news to me. That someone is actually studying ME/CFS from that perspective is very good news to me.
 

ljimbo423

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No. This metabolic trap hypothesis would predict major changes in metabolism. It may be those metabolic changes are activating the immune system.
Hi Janet- That makes a lot of sense too. I might even have some personal experience that validates that view.

Last summer I was taking 400 mg a day of coq10 and didn't experience any flu-like flares that I would get from going out walking. The flares felt just like the flu and would last 4-5 days.

I dropped down to 100 mg of coq10 a day but also made several other changes in the same time frame and started to get the flu-like flares again. Because I made the other changes too, I didn't realize it was lowering the coq10 that caused the flares to come back.

A few weeks ago, after several months, I went back up to 400 mg a day of coq10 and have been out walking again several times with no flu-like flares.

It seems very clear to me now that the high dose coq10 is preventing these flares, which seem to be very connected to the immune system somehow.

I want to be clear that these are not colds or flu's but something that feels just like a flu.

It seems like the biggest changes coq10 is making would be in the mitochondria because it plays such a big role in oxphos phos and creating ATP. The thing that makes this experience even more intriguing to me is that these flu-like flares are not PEM.

The PEM I experience has a specific pattern, just like clockwork. It's hits me at 48 hours after I over do it physically and never lasts more than 24 hours. So the flares are something very different and are alleviated by the coq10.

It just seems like the coq10 is doing something in the mitochondria that affects my immune system somehow and has stopped these devastating flu like flares, that would usually put me in bed for 4-5 days.

Sorry about the small novel.:)

Jim
 

Cort

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Darn! Nice analogy. I wish I had thought of it! I had a well image I would have put in there - In fact I just put it in there



So a trap would be a metabolic state where things are so bad that the capacity to reverse that state to normal is gone. In chaos theory this would be a pathological strange attractor.

For a more everyday analogy, its like falling into a deep well. You know freedom is just a few feet away, but you cannot climb the walls of the well, or at least not easily. Some might succeed, hence the rare recoveries or temporary remissions. In a temporary remission its like you almost climbed out of the well but then fell back in, perhaps injuring yourself further in the fall.

Now a healthy person might have a ladder, or stepping stones, or the well is very shallow, and so they easily get out of it when an infection or other physical insult resolves.
 
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Cort

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From the article:

I wonder if this is directed at practitioners, patients, or both. On one hand, it's really tempting as a patient to want to know more about the detail. On the other hand, it does get a bit worrisome to see people experimenting on themselves. I want someone to find something that works, but how many people here have tried and failed, possibly to some detriment to their own health. Maybe with a more rigorous and objective approach to finding proven results, some of that can be avoided. So hats off to the team for that choice, I'm sure it's not a choice that was made without hesitation. The community is very supportive to Ron and OMF, so to withhold information is not something that would happen lightly I'm sure.
I assure it's not. He is quite worried that someone would hurt themselves. Phair looked over the draft but then Ron wanted some of it removed because of his concern.

I just learned that Phair stumbled on this metabolic trap last December. We're so lucky that the Pineapple fund stepped in with that funding - now we will know if the hypothesis has legs or not by the end of summer. That's certainly not par for the course for ME/CFS. Van Elzakker came up with his vagus nerve hypothesis over five years ago and we're still waiting to hear about that.

The Davis team seems pretty excited about this hypothesis
 

FMMM1

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A qualified yes. It does not presume any ongoing immune trigger, and does not rule it out either. A point of concern is that ME and such infections or toxins or trauma might reinforce each other, each preventing recovery ... which means this would really be a subset of ME under this hypothesis, or perhaps a complication or comorbid problem.
I'm slightly reluctant to speculate but possibly your comments may also apply to people who have problems with their blood-brain barrier [see Baraniuk's 2017 paper & Cort Johnson's article on same]. Great to see OMF testing the metabolic trap theory and we should have results later this year.