Davis speech from Millions Missing. Some new info on metabolic trap hypothesis

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I didn't transcribe this. The entire thing has been pinched from Reddit. Credit for it is due to a user there called u/wackycrazybonkers
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Transcript of Ron Davis' speech.

Starts by thanking patients for donations and berating the NIH for withholding funding, mentions wanting to get a cheap diagnostic test rolled out to GPs

So the other thing to tell you just a little bit about, something that I'm pretty optimistic about, but I don't know for sure, this is the way research goes. And that is; we see a lot of effects on all your small molecules that are in your body, that your food gets converted to and that's what runs your whole body. We also have a lot of genetics that we've done, sequenced people's genomes, we have a tremendous amount of that data. And so we've been using that and comparing that data to all these metabolites and how they're generated. And then we have people who do systems biology, putting all this together and making networks of it.

When we've done that, we run into a possibility that what we call a "metabolic trap" is possibly there. Now that's just an idea, at the moment. But it's an intriguing idea because it kind of seems to be what happens to people when they come down with this disease. So many people go to bed at night feeling fine and waking up in the morning and there's something wrong. It's like a switch got thrown. That's exactly how a metabolic trap would function. And it also is a possibility when you look at the data that you can see why, in fact it's also one which could get worse and then better and then worse again and then better, and you never can get out of it, and that's why it's called a trap.

So it fits the behaviour, but the question is; is it right? So we're not talking about it in any detail, because I'm not sure if it's right, but we have found now several traps that are possible and we're going to test each one of them. And so now if it's true that it's a trap, and that's why I wanted to share this with you, is that it will probably be very easy to cure. That's what I'm excited about, because I want to cure my son. I'm desperate to do that. And it won't be very expensive either. And the treatment would be done in an outpatient kind of setting, basically under supervision of a doctor to make sure nothing goes wrong, but it's not going to require surgery, it's not even going to require a new medication.

And again, that's why we focus on what we focus on, and that is, I don't focus on trying a new drug, it's going to be twenty years before we can use it. And so, re-purposing drugs is one way to do it, but even trying to figure this out, what's causing it, so that we can come up with a very effective cure for this that doesn't involve drugs.

Now the complexity of this trap idea is such that I can't imagine anyone accidentally discovering it. And so we've also first looked at what people have tried, what made them better and so forth, but they would probably have never stumbled across this because to get out of it requires a very special treatment that probably nobody would have done.

Also when we monitor this computationally it's very likely that patients, if this trap is true, they will actually get worse with the treatment before they get cured, and that would prevent somebody from doing it, because they'll try it, get worse and stop. So that's why it needs to be very carefully supervised and analysed, we need to figure out the tools for doing this. But anyway, that's the next stage. If we're wrong, it will lead to the next venue. And that's how the research goes. But we clearly don't have enough of it.

Ends by thanking anonymous donor pineapplefund for their donation and calling for help with research and more funding.
You can see the whole event here: https://www.facebook.com/OpenMedicineFoundation/videos/1463510460420037/?t=2449. Ron starts speaking at the 42 minute mark.

I think the wholly new parts here are:
1. There are several possible metabolic traps to test;
2. Patients may not have stumbled on this because you'd get worse before you got better.
3. What your food gets converted to is important (linking here with @ChrisArmstrong research presented ta last year's omf symposium?)
 
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He's chasing four candidate biomarkers that distinguish patients from healthy controls. Point being that the doctor won't be able to say 'Go home, there's nothing wrong with you'.

He isn't sure we need (or can obtain) a diagnostic test that isolates me/cfs in a single test. He wants to prove *something* is wrong, and later test for MS etc to see if its those things. "Almost all those other diseases have their own diagnostic tests, " he says.
 
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ljimbo423

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Now the complexity of this trap idea is such that I can't imagine anyone accidentally discovering it. And so we've also first looked at what people have tried, what made them better and so forth, but they would probably have never stumbled across this because to get out of it requires a very special treatment that probably nobody would have done.
Thanks for the post Murph. It sure has gotten my attention!

This makes me think he is talking about people trying supplement protocols and that might be what he is talking about when he says "treatment".

Jim
 
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This bit of the speech sounds like a bluff but hey, if it cranks up the pressure to get more funding, I'm all for it:

Davis: "I think it's possible that's what's wrong in ME/CFS actually triggers autoimmunity, and could be the basis of all autoimmunity. And I've told that to Francis Collins [head of the NIH] and said you'll be really embarrassed if we discover that this is the basis of all autoimmunity and you guys have totally missed the boat by not funding this disease. Because this may be the pathway."
 

pibee

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This bit of the speech sounds like a bluff but hey, if it cranks up the pressure to get more funding, I'm all for it:

Davis: "I think it's possible that's what's wrong in ME/CFS actually triggers autoimmunity, and could be the basis of all autoimmunity. And I've told that to Francis Collins [head of the NIH] and said you'll be really embarrassed if we discover that this is the basis of all autoimmunity and you guys have totally missed the boat by not funding this disease. Because this may be the pathway."
Can this story get more strange..... :nervous:

Thus ME CFS isn't really a true Autoimmune disease like the others, it's the creator of one, like Ground Zero.
ME the Creator?
This could definitely get us some religious votes/donations.
:cautious::D

Creator's disease.

The OA. (Original Autoimmunity)

The OI = Original Illness.

Many potential names that I like :D
 
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Research 1st

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My interpretation of what Ron isn't saying here but has said in the past is they are finding that ME CFS patients perpetually activate the defective Metabolic Mechanism (for ME CFS to occur in the first place) over and over again, probably with every new infection or stressor that flips that switch into the danger zone (e.g. the common cold, lack of sleep, allergies, stress, exercise, inflammation, ATP depletion via activity - sound familiar?!).

If so, then the defective Metabolic Mechanism of ME CFS, is the core reason we remain ill and don't recover (hence we serially 'relapse' with exertion as we activate the 'defect' - hence CBT/GET destroys us) Vs other more classical autoimmune diseases where you also experience the consequence of the defective Metabolic Mechanism at onset, but then advance past this so it becomes historical, not current. With all other Autoimmune diseases, you aren't then stuck in the defective Metabolic Mechanism itself that's broken and held in stasis in ME CFS patients - yet both involve contact with it - hence Ron's suggestion one disease might explain all the others occurring is sensible and not an exaggeration at all, it's common sense theory.

So to me, I feel Ron's team will eventually find the cause of the defective Metabolic Mechanism, E,g. why this occurs in ME CFS following a 'virus that never left me' (common complaint of 'Chronic Lyme' patients BTW) and thus potentially it really would apply to all autoimmune illnesses if correct because...

If we know there is a major event, lets called it Event X (The activator of the defective Metabolic Mechanism - E.g. a common community acquired Pathogen) then all Autoimmune diseases can also potentially be shown to require contact with Event X, meaning by default, all ME CFS patients are held back by Event X perpetually because now we know this feeds the defective Metabolic Mechanism defect - hence the Mitochodrial energy in ME CFS shuts down to protect the patient and keep them alive (as Paul Cheney has claimed for decades - hence the abnormal 2 day VO2 max exercise test now makes sense), Vs other Autoimmune diseases where Event X took place as well (E.g. EBV triggering MS), but went onto state 1a, 2b, 3c which we have as established autoimmune disease states.

Thus ME CFS isn't really a true Autoimmune disease like the others, it's the creator of one, like Ground Zero.
 

mariovitali

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I went through the speech by Ron and the most important points are IMO the following :


"What your food gets converted to is important" : This i do not understand are there any pointers as to what Ron refers to ? It does sound interesting but i would like to know more regarding the context (e,g Glycolysis? Bile Acids? Fat Absorption?)

Then we have :

1) Multiple pathways involved
2) ME/CFS may hold the secrets of all autoimmune disease.

I agree in both of the above. However, I also have to point out that a number of questions that are very easy to test (ie what is the prevalence of Hemochromatosis / Wilson's Disease / Cholecystectomies and many more "Liver stressors" to ME/CFS Patients) have not been answered yet.

If a high prevalence of these "Liver Stressors" + ME/CFS does hold and also their relevance to ME/CFS Symptoms , then the "Metabolic Trap" Hypothesis sounds overly simplistic at least for a subset of ME/CFS Patients.
 

Gingergrrl

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This bit of the speech sounds like a bluff but hey, if it cranks up the pressure to get more funding, I'm all for it:

Davis: "I think it's possible that's what's wrong in ME/CFS actually triggers autoimmunity, and could be the basis of all autoimmunity. And I've told that to Francis Collins [head of the NIH] and said you'll be really embarrassed if we discover that this is the basis of all autoimmunity and you guys have totally missed the boat by not funding this disease. Because this may be the pathway."
I find this fascinating @Murph and I have no idea if he is "bluffing" like you said or if he is on the verge of solving the whole of autoimmunity (or somewhere in between)! Either way, it is intriguing to follow (and hopefully gets more funding).

If we know there is a major event, lets called it Event X...

... Vs other Autoimmune diseases where Event X took place as well (E.g. EBV triggering MS), but went onto state 1a, 2b, 3c which we have as established autoimmune disease states.

Thus ME CFS isn't really a true Autoimmune disease like the others, it's the creator of one, like Ground Zero.
This is really interesting to me, too, b/c I fit this definition of having a major event (actually a series of three of them) which started off as a post-viral illness but morphed into massive autoimmunity.
 

alex3619

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I'm inclined to believe them when they say the hypothesis is detailed and they are keeping those details secret to prevent people like me from jumping the gun and attempting something risky before they've tested it!
So many of us are so used to testing things on ourselves that its almost automatic that many will. So if the treatment has serious risks its very prudent to keep it quiet until more details are figured out.

I am much less prone to testing on myself these days, but a decade and more ago I would test everything that looked even slightly promising.
 

alex3619

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"What your food gets converted to is important" : This i do not understand are there any pointers as to what Ron refers to ? It does sound interesting but i would like to know more regarding the context (e,g Glycolysis? Bile Acids? Fat Absorption?)
I think this was just general background into metabolism. I think they are finding like 200 metabolic issues. Its not going to be summed up and simple at the same time as accurate and complete. So its a background statement, to set the stage.
 
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I went through the speech by Ron and the most important points are IMO the following :


"What your food gets converted to is important" : This i do not understand are there any pointers as to what Ron refers to ? It does sound interesting but i would like to know more regarding the context (e,g Glycolysis? Bile Acids? Fat Absorption?)
It reminds me of the Australian research that suggests something goes wrong that affects the way nutrients are processed, leaving us in a state of depressed energy.

You can see it depicted in slides 7 to 11 of this talk by Chris Armstrong

https://www.melbournebioanalytics.org/me-metabolism-and-i-by-chris-armstrong-august-2017/

And you can see the relevant part of the speech here

 

mariovitali

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It reminds me of the Australian research that suggests something goes wrong that affects the way nutrients are processed, leaving us in a state of depressed energy.

You can see it depicted in slides 7 to 11 of this talk by Chris Armstrong

https://www.melbournebioanalytics.org/me-metabolism-and-i-by-chris-armstrong-august-2017/

And you can see the relevant part of the speech here

Thank you @Murph

I believe that the interesting bit starts at the 46:00 minutes mark. I've never looked at the work of Chris Armstrong which sounds very interesting.

If i understand well, AMPK may be the switch that Ron talks about (?). However it is more interesting to focus on why as Chris Armstrong puts it "less and less nutrients are being absorbed". This is where a key piece of the puzzle probably exists, it is this trap that needs to be found.
 

unicorn7

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Thus ME CFS isn't really a true Autoimmune disease like the others, it's the creator of one, like Ground Zero.
There actually already is a pathway known for this.
There is a lot of evidence that ME/CFS patients have leaky guts. The bowel is permeable for certain bacterial parts (LPS). Patients have high LPS in blood and high CD14 (receptor for LPS).

I also know that leaky gut is a condition that precedes auto-immune diseases. I've read some research where they had mouse models for diabetes type 1, where all the mouses developed a leaky gut a few months before they developed diabetes type 1.
 

ljimbo423

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My interpretation of what Ron isn't saying here but has said in the past is they are finding that ME CFS patients perpetually activate the defective Metabolic Mechanism (for ME CFS to occur in the first place) over and over again, probably with every new infection or stressor that flips that switch into the danger zone (e.g. the common cold, lack of sleep, allergies, stress, exercise, inflammation, ATP depletion via activity - sound familiar?!).
Morris and Maes found a very similar "metabolic trap" in ME/CFS-

EDIT- "O&NS" means "oxidative and nitrosative stress".

The proposal made herein is that once generated chronically activated O&NS and immune-inflammatory pathways conspire to generate a multitude of self-sustaining and self-amplifying pathological processes which are associated with the onset of ME/CFS.

Sources of continuous activation of O&NS and immune-inflammatory pathways in ME/CFS are chronic, intermittent and opportunistic infections, bacterial translocation, autoimmune responses, mitochondrial dysfunctions, activation of the Toll-Like Receptor Radical Cycle, and decreased antioxidant levels.

Consequences of chronically activated O&NS and immune-inflammatory pathways in ME/CFS are brain disorders, including neuroinflammation and brain hypometabolism / hypoperfusion, toxic effects of nitric oxide and peroxynitrite,

lipid peroxidation and oxidative damage to DNA, secondary autoimmune responses directed against disrupted lipid membrane components and proteins, mitochondrial dysfunctions with a disruption of energy metabolism (e.g. compromised ATP production) and dysfunctional intracellular signaling pathways.

The interplay between all of these factors leads to self-amplifying feed forward loops causing a chronic state of activated O&NS, immune-inflammatory and autoimmune pathways which may sustain the disease.
LINK

Jim
 
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Aroa

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Last Year I was very excited when I heard Dr. Davis during the Q&A update in March saying :

"" It’s possible that we can find something that will work, at high concentration – but not be the target that the drug was originally developed for. Now, at these high concentrations there will be side effects – but as Dr Naviaux explains, it’s possible that all we need to do is to trigger the body to go back to normal – and so these side effects may not be so bad. This is not a drug that you’ll probably have to take year after year; it may be that a single dose will cure you. ""


Over the last months I listened to Dr Ian Lipkin, Dr. Jarred Younger, Dr. Alain Moreau, Dr Zaher Nahle and Dr. Walter Koroshetz, saying that ME/CFS could have different subtypes (or even diseases) and that most likely would need different treatments for each one.


Now I prefer to take things easy, be cautious about any statement and wait till we have some scientific evidence.
 

ljimbo423

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@ljimbo423

CC : @JaimeS


Thanks for this link, very very interesting! Here is my version of the Hypothesis sent to Stanford Researchers in 2015 (Ron Davis was not a recipient). Notice the mentions that several pathways are involved and that a vicious cycle takes place.

View attachment 27206
I think there are several or many biochemical feed-forward loops or vicious cycles that help sustain ME/CFS. I think that is probably why it's so hard to treat.

For instance, I found that high dose coq10 stopped 95% of the flu like flares I use to get. It seems that somehow, coq10, by improving mitochondrial function, stopped the immune system reaction I was getting, that was causing the flares!

So I think that mitochondrial dysfunction, causing immune system up-regulation, which causes more mitochondrial dysfunction, from the oxidative stress immune system up-regulation causes, is one of many feed-forward loops.

So mitochondrial dysfunction= immune system up-regulation=mitochodrial dysfunction=immune system up-regulation, etc. One of many feed forward loops I think.

Research says that mitochondrial dysfunction can cause immune system up-regulation and an inflammation "circle".

Inflammation and mitochondrial dysfunction: A vicious circle in neurodegenerative disorders?

Here we provide a comprehensive overview on how inflammatory mediators impair mitochondrial metabolism and discuss how defective mitochondria can elicit and potentiate an inflammatory response.
LINK

Jim