Ron Davis: Preliminary data shows problems with energy metabolism

[snowathlete]

Nice article @Simon, very clear for my foggy brain.

I have commented before about my sugar cravings, my body demands I eat more sugar. Things is, it doesn't seem to make my energy any better. I have wondered if I am just burning it all inefficiently and getting far less ATP than I should be getting, so maybe these findings would add some weight to that?

This work the OMF are doing is exactly what we need. I can't stress enough how impressive the team there is, not just the scientists but the others involved also. We need to get them more funds so they can look at a greater number of patient samples and further their work because I really think they are looking in the right areas, in the right ways.

 

[dannybex]

Indeed. I'm hoping based on Davis 'close to biomarker' etc that there must be identical findings. Otherwise you couldn't have a biomarker. It would be scary indeed if the TCA was disturbed differently for every patient as it could make a cure very difficult. I guess we need to wait and see, but I'm hopeful.

I'm no scientist, but have a feeling that that will indeed be the case -- different 'cures' for different patients.

It's shown already just with the three patients in this preliminary report.

And as @adreno and others of us have found out on 'the other' parts of this board. Our krebs / citric acid cycle tests show different abnormalities, probably based on different things (types of infections, environmental exposures, heavy metals, etc.) interfering with different parts of the cycle.

And figuring that out, has been really, really difficult. Most of us haven't, even after years of trying...

Huge thanks out to Dr. Davis and his team for their hard work and preliminary findings!

 

[JaimeS]

I have commented before about my sugar cravings, my body demands I eat more sugar. Things is, it doesn't seem to make my energy any better. I have wondered if I am just burning it all inefficiently and getting far less ATP than I should be getting, so maybe these findings would add some weight to that?

I commented the other day that the weird thing about carbs and sugars is that, while I like the taste of it and enjoy eating it, I feel like I never feel satisfied from eating them, and am just as hungry after consuming them as before. It's like I've eaten nothing at all.

Then there's the article from Armstrong et al. that did far simpler testing on PWME and found that the metabolites pointed to slowed or dysfunctional glycolysis.

I agree, @dannybex , that treatment will be an individual matter. I think that it's safe to say we tend to have energy-molecule-producing problems, but metabolism is so complex that this could translate to a dizzying array of potential defects.

The worst part is, some of them may be simple to address with available medical techniques, and some may turn out to be untouchable.

-J

 

[A.B.]

My experience with sugars is that first there is a boost of energy, which turns into distinct feeling of discomfort (for the lack of a better word), only fixable with more sugar. There can be an episode of hypoglycemia.

This discomfort can last for up to 1-2 days.

This is a vicious cycle which eventually leads to a sort of crash.

Smaller doses every now and then seem to be okay.

Sound familiar to anyone?

 

[Ben H]

I'm no scientist, but have a feeling that that will indeed be the case -- different 'cures' for different patients.

It's shown already just with the three patients in this preliminary report.

And as @adreno and others of us have found out on 'the other' parts of this board. Our krebs / citric acid cycle tests show different abnormalities, probably based on different things (types of infections, environmental exposures, heavy metals, etc.) interfering with different parts of the cycle.

And figuring that out, has been really, really difficult. Most of us haven't, even after years of trying...

Huge thanks out to Dr. Davis and his team for their hard work and preliminary findings!

Hi @dannybex

I'm no scientist either. Just a pissed off, determined patient relearning biochemistry.

Sorry, 'cure' was meant to say 'biomarker' in that sentence. Brain fog. Apologies.

Everyone's TCA will most likely be slightly different, a different blockage, higher and lower metabolites in certain areas etc. That's probably to be expected with the heterogeneity. But the underlying issue so far is that every patients TCA is abnormal, somehow. That is the case with the 3 patients.

I don't believe every single patient will be totally different as we could not get a biomarker that way, based off of TCA if that happens to be the case.

Many people here have tried correcting and supplementing the TCA based on OAT tests with mixed results, certainly no one I know has got fully well from it which suggests to me, and has already been hinted at, that it's a downstream effect of something else, potentially a stuck CDR. CDR mechanism stuck causes all kinds of issues, initiated by viruses, bacteria, 'stress' and the effect of that is vast (redox status suffers, metal homeostasis, vitamin availability etc). These could explain the issues in TCA many of us have.

Thus, hopefully a cure, and it is certainly hinted at, would be aimed at sorting the mechanism(s) that are causing these TCA abnormalities.


Bottom line is treatment I think will be aimed at this mechanism, whatever it turns out to be, rather than just the individual cofactors in the cycle. Probably a mixture of both. The mechanism is more important though. The heavy metals, lack of cofactors etc look to be downstream effects of a mechanism gone wrong. If it were that easy to fix TCA by providing the missing factors from an OAT test, many of us would be better by now. Something is keeping us ill.

Linky to CDR here: http://www.sciencedirect.com/science/article/pii/S1567724913002390


P.s. It's all just educated (I hope) guesses until we have the data.


B

 

[Comet]

The worst part is, some of them may be simple to address with available medical techniques, and some may turn out to be untouchable.

Even if some turn out to be untouchable, imagine what it would be like to get support, respect and empathy from friends, family and the medical community, and to be recognized as actually being sick.

It would mean one less fight to fight and perhaps more medical support!

Even if untreatable maybe an understanding of what is going on could lead to better symptom management too.

But I keep reminding myself not to get excited and to wait and see...

 

[Ben H]

Even if some turn out to be untouchable, imagine what it would be like to get support, respect and empathy from friends, family and the medical community, and to be recognized as actually being sick.

It would mean one less fight to fight and perhaps more medical support!

Even if untreatable maybe an understanding of what is going on could lead to better symptom management too.

But I keep reminding myself not to get excited and to wait and see...

You may be right Comet, but I can assure you, OMF and Davis are going for a complete cure. He doesn't believe it to be untouchable, and references M.E/CFS as 'solvable' often. I don't think anything less than a cure would cut it for him, he is an extraordinary being, with extraordinary cutting edge medical equipment and an extraordinary team at his disposal.

So, keep the hope


B

 

[dannybex]

Hey @Ben Howell, absolutely no need to apologize for anything -- my brain is a wasteland of rotting mush, and no doubt I didn't make myself clear at all.

An example of that is that I agree completely with you that 'every single patient' will probably not be different -- just that there will probably be a lot of differences, or at least different approaches to 'fixing' the problem(s).

And you're probably right that some of this could be downstream problems. There's also the possibility/probability that these various nutrients/co-factors need to be balanced (some will need more of this, less of that) and figuring that out is a problem.

That CDR paper is really interesting. Quoting the intro:

"The cell danger response (CDR) is an evolutionarily conserved cellular metabolic response that is activated when a cell encounters a chemical, physical, or microbial threat that could injure or kill the cell. Common microbial threats are viruses, bacteria, fungi, and parasites. Physical threats include heat, salt, or pH shock, or UV or ionizing radiation. Chemical forms of danger include heavy and trace metals like lead, mercury, cadmium, arsenic, and nickel, certain electrophilic aromatic chemicals like the plasticizer bisphenol A, the chemical flame retardants like the brominated diphenyl ethers (BDEs), and certain halogenated pesticides like chlorpyrifos and DDT."

Unfortunately, some of this could also play into the hands of those who believe ME/CFS is primarily a psych disorder stemming from childhood trauma, as noted in the following quote:

"Psychological trauma, particularly during childhood, can also activate the cell danger response, produce chronic inflammation, and increase the risk of many disorders."

Still, a very, very interesting paper. Thanks for the link.

 

[Never Give Up]

Great graph showing the significance of 16 standard deviations, @JaimeS!

 

[cmt12]

It's important not to miss the forest for the trees. This is the forest:

Ron Davis, who has previously studied patients with physical trauma also noted that mitochondria “shut down” in these patients and said that a key question is why they don’t start up again in ME/CFS patients.

Trust me.

 

[Forbin]

At least one data point from Whitney Dafoe’s energy metabolism molecules was 16 standard deviations away from the average of the control group.

A hugely important point. What makes these findings interesting is how extreme they are (almost off the scale), but it's still only three patients.

"Extreme" is almost an understatement. In a normal distribution, 3 standard deviations below the mean equates to 1 finding in a population of 741 samples (with another sample three SD above the mean). The percentage of a population 4 SD below average would be 1 in 31,457.

Most look-up tables don't go any lower or higher than 4 SD, but I did find one online calculator that went as far as 8 standard deviations.

8 SD equates to about 1 in a population of 250 trillion, and that's obviously nowhere near as small as 16 SD would be.

 

[Bob]

8 SD equates to about 1 in population of 250 trillion, and that's obviously nowhere near as small as 16 SD would be.

I had been wondering about how 16SD translates to a percentage of the population - it suggests that the particular test result might be unique, or almost unique, to Whitney. Which is probably partly why Ron is talking about personalised medicine.

 

[Ben H]

Hey @Ben Howell, absolutely no need to apologize for anything -- my brain is a wasteland of rotting mush, and no doubt I didn't make myself clear at all.

An example of that is that I agree completely with you that 'every single patient' will probably not be different -- just that there will probably be a lot of differences, or at least different approaches to 'fixing' the problem(s).

And you're probably right that some of this could be downstream problems. There's also the possibility/probability that these various nutrients/co-factors need to be balanced (some will need more of this, less of that) and figuring that out is a problem.

That CDR paper is really interesting. Quoting the intro:

"The cell danger response (CDR) is an evolutionarily conserved cellular metabolic response that is activated when a cell encounters a chemical, physical, or microbial threat that could injure or kill the cell. Common microbial threats are viruses, bacteria, fungi, and parasites. Physical threats include heat, salt, or pH shock, or UV or ionizing radiation. Chemical forms of danger include heavy and trace metals like lead, mercury, cadmium, arsenic, and nickel, certain electrophilic aromatic chemicals like the plasticizer bisphenol A, the chemical flame retardants like the brominated diphenyl ethers (BDEs), and certain halogenated pesticides like chlorpyrifos and DDT."

Unfortunately, some of this could also play into the hands of those who believe ME/CFS is primarily a psych disorder stemming from childhood trauma, as noted in the following quote:

"Psychological trauma, particularly during childhood, can also activate the cell danger response, produce chronic inflammation, and increase the risk of many disorders."

Still, a very, very interesting paper. Thanks for the link.

No worries, you know what it's like

I agree completely. I think there will be slightly different approaches, but not as much as we may think. A central mechanism, and then some specifics. The idea, I believe, is that once the mechanism behind this is fixed, TCA should fall back into place. The balance may occur on its own, or it may need supplementing. We need Davis to let us know, when he finds out

Yea it's an unfortunate coincidence. But the other factors involved in inciting CDR (viruses, bacteria, chemicals) negate that somewhat. Stress has always been implicated in M.E, but this mechanism is far beyond what the psychs know about, and doesn't fit with their biopsychosocial model at all, in the way that they present it.

We are firmly in the realms of biochemistry here. Psychology please walk on by....
(They are not mutually exclusive, I know, but this paper could be the meteor for the dinosaurs).


B

 

[Sasha]

I had been wondering about how 16SD translates to a percentage of the population - it suggests that the particular test result might be unique, or almost unique, to Whitney.

Not necessarily - it's just a measure of how far it is from the healthy-population average. We might all have the same one (or we might not) - the fact that it's 16 SD out doesn't mean that the odds of anyone having it are 1 in trillions: just that the odds of such a difference happening by chance alone are 1 in trillions.

 

[Sasha]

You may be right Comet, but I can assure you, OMF and Davis are going for a complete cure. He doesn't believe it to be untouchable, and references M.E/CFS as 'solvable' often. I don't think anything less than a cure would cut it for him, he is an extraordinary being, with extraordinary cutting edge medical equipment and an extraordinary team at his disposal.

So, keep the hope


B

I feel very hopeful, partly because I went from years of being bedbound to years of "recovered" (which turned out to be a remission) before having now had years in relapse.

I hope that means that most of us have the potential for full remission: and if Ron Davis can find what triggers that...

 

[alex3619]

I had been wondering about how 16SD translates to a percentage of the population - it suggests that the particular test result might be unique, or almost unique, to Whitney. Which is probably partly why Ron is talking about personalised medicine.

I think this is deceptive. Yes, it might be right. However 16SD might indicate a very strong signal and it might actually be very common. This is an issue of the unexpected, and statistics fails badly at predicting the unexpected. This is why "rare events" occur far more often than statistics would suggest. I think its a result of a variation of the closed world hypothesis.

Any occurrence of an event that rare is something that should have us shouting Eureka!!! unless it really does prove to be unique to a few select cases.

PS What @Sasha said.

 

[Bob]

Not necessarily - it's just a measure of how far it is from the healthy-population average.

Ah, yes, good point. If Ron is comparing the test result to healthy controls then my comment is redundant.

 

[Comet]

You may be right Comet, but I can assure you, OMF and Davis are going for a complete cure. He doesn't believe it to be untouchable, and references M.E/CFS as 'solvable' often. I don't think anything less than a cure would cut it for him, he is an extraordinary being, with extraordinary cutting edge medical equipment and an extraordinary team at his disposal.

So, keep the hope


B

Yes, I have hope! Was trying to point out that even if something remains untreatable, there is an upside.

As far as Ron Davis goes, I'm a big cheerleader and have made several donations to the OMF! Here's a link in case anyone has a little extra to spare.

But still, I believe in cautious optimism. Although recently I feel more optimism than caution!

Was just thinking about what I would enjoy if I started to feel better! It wasn't difficult to come up with a long list!

 

[JaimeS]

Great graph showing the significance of 16 standard deviations, @JaimeS!

Thank you!

So hard to even conceptualize, even with the pic! I think ppl don't realize how completely insane that is. It's like, 99.99% of ALL DATA should be somewhere around that little sine curve, and... *mind blown*

Even 5 SD away is nuts.

As others have said, though, that standard curve represents healthies.

 

[JaimeS]

My experience with sugars is that first there is a boost of energy, which turns into distinct feeling of discomfort (for the lack of a better word), only fixable with more sugar. There can be an episode of hypoglycemia.

This discomfort can last for up to 1-2 days.

This is a vicious cycle which eventually leads to a sort of crash.

Smaller doses every now and then seem to be okay.

Sound familiar to anyone?

Yes, for sure. I can't really do sugar anymore except in very small quantities. It's to the point I'm monitoring my daily intake, not just for added sugars, but for sugars overall.

I've heard from so many PWME that they subsist on protein and, in the words of one PWME I spoke to today, "certain vegetables." Fourth person I know who lives on that diet with ME. It's interesting, even if it directly proves squat.

-J