Ron Davis: Preliminary data shows problems with energy metabolism

[wastwater]

I think I read that the citric acid cycle has an effect on GABA if its not working well it leads to low GABA im not sure if that's because of excessive glutamate is driving it down.
I always thought of GABA being linked to anxiety,if its low then high anxiety is seen.
Carbohydrate metabolism is thought impaired in autism/ASD
A piece on FM ME/cfs https://www.verywell.com/gaba-glutamate-fibromyalgia-chronic-fatigue-716010

 

[alex3619]

Marty Pall's model, RIch's, and my later hypotheses, all looked heavily at aconitase, but this is not the only enzyme involved. Glutathione is needed for functional aconitase, nitric oxide inhibits it, and peroxynitrate destroys it.

One test, as I remarked before, that I would really like to see is an assay to determine what percentage of aconitase is functional, including from misfolding. Normal aconitase quantity is not the same as normal aconitase function.

I never investigated the other candidate enzymes to see if they had the same level of vulnerability. How many are native to the mitochondria, for example. Aconitase is imported from the cell, and its encoded in the cell nucleus.

One possibility that intrigued me, and far from proven, is that aconitase might be a point where energy production can be suppressed. Viral replication would be massively slowed if cell metabolism were slowed. Rising citric acid levels would flush the cell of unbound divalent metals, as this is a divalent cation chelator, though I am unclear that effective clearance mechanisms exist to remove the chelated metals.

 

[Janet Dafoe]

IMHO Ron Davis was using a few examples of initial results on the first few patients tested to illustrate the types of results they can get, such as huge deficiencies of one intermediate in the TCA cycle.
My notes are incomplete, but another example was from branched chain amino acid metabolism where there was a significant increase in B hydroxy isovaleryl carnitine. The enzyme, 3 methyl crotonyl CoA carboxylase is the next ? step in this pathway and is biotin dependent. He said that one patient's health had been completely turned round on biotin. Not sure if this related to one of the 3 or so, very serious patients whose blood has been analysed yet or not.

The third pathway he mentioned was tryptophan metabolism. I think someone already posted this, but I'll add my info. Indolamine 2,3 dioxygenase was upregulated. This patient had an infection which upregulates the enzyme. From my notes, this took the tryptophan on a different pathway from the manufacture of melatonin or 5HT.

The last pathway was conversion of GTP to biopterin. I think he said GTP and BH4 ,both look low in PwME. (or it could be that GTP cyclohydrolase is low). BH4 is used in the production of serotonin and dopamine.

To reiterate, Professor Davis was not 'presenting data' in the 'these are the results of our study...'

Rather he was demonstrating the range of metabolic pathways the data will cover and a few of the major differences picked up so far.

Hopefully someone with more recent biochemical training can work out whether the above makes any sense @Simon,@ Jaimie etc.

Ron says this makes sense. Good job.

 

[Janet Dafoe]

IMHO Ron Davis was using a few examples of initial results on the first few patients tested to illustrate the types of results they can get, such as huge deficiencies of one intermediate in the TCA cycle.
My notes are incomplete, but another example was from branched chain amino acid metabolism where there was a significant increase in B hydroxy isovaleryl carnitine. The enzyme, 3 methyl crotonyl CoA carboxylase is the next ? step in this pathway and is biotin dependent. He said that one patient's health had been completely turned round on biotin. Not sure if this related to one of the 3 or so, very serious patients whose blood has been analysed yet or not.

The third pathway he mentioned was tryptophan metabolism. I think someone already posted this, but I'll add my info. Indolamine 2,3 dioxygenase was upregulated. This patient had an infection which upregulates the enzyme. From my notes, this took the tryptophan on a different pathway from the manufacture of melatonin or 5HT.

The last pathway was conversion of GTP to biopterin. I think he said GTP and BH4 ,both look low in PwME. (or it could be that GTP cyclohydrolase is low). BH4 is used in the production of serotonin and dopamine.

To reiterate, Professor Davis was not 'presenting data' in the 'these are the results of our study...'

Rather he was demonstrating the range of metabolic pathways the data will cover and a few of the major differences picked up so far.

Hopefully someone with more recent biochemical training can work out whether the above makes any sense @Simon,@ Jaimie etc.

Ron says: I wanted to illustrate that different patients can have different things wrong, and they may appear different, but it's still the same disease. And that one problem can lead to a multiple array of symptoms.

 

[Justin30]

Ron says: I wanted to illustrate that different patients can have different things wrong, and they may appear different, but it's still the same disease. And that one problem can lead to a multiple array of symptoms.

I understand that one disease can lead to an array of symptoms I agree with this.

I am just so curious as to why as Dr Bell noted in one of his talks that people with neurological manifestations are worse off and is this the same problem? As well as the decrease in blood volume and POTS in this patient group....

I guess what I am getting to is that is ME and POTS one and the same or is POTS a completely different animal.....the symptom cluster for a group is patients you could based on symptoms have ME or POTS...

Thanks Rose for your feeback.

 

[MEMum]

More from Rich Van Konynenburg re: the Krebs cycle:

Wow!

 

[MEMum]

Ron says this makes sense. Good job.

Phew!

 

[Janet Dafoe]

Janet Dafoe may know if access to testing is possible somewhere @JaimeS

Laurel Crosby and Ron are working on a way for people to get tested at Metabolon, hopefully at lower than their normal cost. I can't say details yet, but very soon you will hear about it. Laurel is working really hard on this. Very exciting....Stay tuned....

 

[A.B.]

Laurel Crosby and Ron are working on a way for people to get tested at Metabolon, hopefully at lower than their normal cost. I can't say details yet, but very soon you will hear about it. Laurel is working really hard on this. Very exciting....Stay tuned....

I'm glad to hear this. Please don't forget the ethical aspects. There will undoubtedly be a lot of interest from desperate patients, and it's in both the patient's and the company's interest that expectations are kept within reasonable limits and interpretation of test results is available (a test without the ability to interpret the results isn't worth much). It will also be necessary to clarify how reliable the results are.

Back when XMRV was a hot topic, tests were sold, people reported positives even, but it all turned out to be nonsense.

 

[aimossy]

It could also be a possible way to increase a study size though. If people who did pay for testing were later well characterised, even retrospectively. Crowdfunded research, the same way Dr Klimas asked for genetic information to be sent in for her study. I mean sure, there are ethics to think of, I agree. But considering funding limitations it could be an added motivator for donating to research for many people. Pay for a test and contribute to science, what is cool is that you get to see your own data. There could be a way to do it maybe.

 

[slysaint]

if I'm wrong excuse my ignorance but hasn't a lot of this been covered before?
http://drmyhill.co.uk/wiki/CFS_-_The_Central_Cause:_Mitochondrial_Failure

 

[Ben H]

if I'm wrong excuse my ignorance but hasn't a lot of this been covered before?
http://drmyhill.co.uk/wiki/CFS_-_The_Central_Cause:_Mitochondrial_Failure

Dr Myhill has a very basic understanding of the mitochondria, like most of us do.

She has measured very basic markers of things that the TCA cycle is involved with (coq10 etc) and was one of the first to implicate mitochondria in the disease, to be fair.

What Ron Davis is doing is looking at the mitochondria, but via cutting edge metabolomics and other methods, and the associated metabolic pathways, which is infinitely more complex. Kind of the difference between looking at an engine, and physically taking the whole damn thing apart!

Dr Myhill also hasn't discovered why the mitochondria seem to be faulty, which Davis is looking to find I.e. The underlying mechanism.

So yes, the subject of mitochondria has been implicated before, but the degree to which Ron Davis and the OMF are looking at it is mind blowing. Literally every metabolic pathway they can to find out why and how M.E is happening. Dr Myhill has just said 'the mitochondria are faulty' (in so many words).


P.s I'm a patient of Dr Myhill, so I'm not out to slate her, but the difference between the two is so gigantic, it's really not comparable, apart from the subject matter.



B

 

[slysaint]

Due to MCAS I cant take most probiotics

you might like to look at this cheese
https://www.researchgate.net/public...with_Antioxidative_and_Antimicrobial_Activity

 

[slysaint]

also found this article on
Mitochondrial Dysfunction, Post-Exertional Malaise and CFS/ME
http://www.prohealth.com/library/showarticle.cfm?libid=18840

again, apologies if you've already covered it

also interesting but not new
https://floxiehope.com/2015/02/24/study-finds-that-ciprofloxacin-depletes-mitochondrial-dna/

 

[Janet Dafoe]

Dr Myhill has a very basic understanding of the mitochondria, like most of us do.

She has measured very basic markers of things that the TCA cycle is involved with (coq10 etc) and was one of the first to implicate mitochondria in the disease, to be fair.

What Ron Davis is doing is looking at the mitochondria, but via cutting edge metabolomics and other methods, and the associated metabolic pathways, which is infinitely more complex. Kind of the difference between looking at an engine, and physically taking the whole damn thing apart!

Dr Myhill also hasn't discovered why the mitochondria seem to be faulty, which Davis is looking to find I.e. The underlying mechanism.

So yes, the subject of mitochondria has been implicated before, but the degree to which Ron Davis and the OMF are looking at it is mind blowing. Literally every metabolic pathway they can to find out why and how M.E is happening. Dr Myhill has just said 'the mitochondria are faulty' (in so many words).


P.s I'm a patient of Dr Myhill, so I'm not out to slate her, but the difference between the two is so gigantic, it's really not comparable, apart from the subject matter.



B

This is true. Ron says he couldn't have written that better! Before metabolomlic results Whitney had his mitochondria tested with the most up to date methods available and the results all came out normal. It was disturbing, since Ron has really thought that the mito were involved for years but couldn't get any data to show it. That's all changed now. It's not that the mitochondria are necessarily faulty, the problem is with their regulation. The problem may not even be in the mito, but in the pathways associated with and outside of the mito that affect their functioning.

 

[Ben H]

This is true. Ron says he couldn't have written that better! Before metabolomlic results Whitney had his mitochondria tested with the most up to date methods available and the results all came out normal. It was disturbing, since Ron has really thought that the mito were involved for years but couldn't get any data to show it. That's all changed now. It's not that the mitochondria are necessarily faulty, the problem is with their regulation. The problem may not even be in the mito, but in the pathways associated with and outside of the mito that affect their functioning.

Exactly! That's made my day!


B

 

[Janet Dafoe]

It could also be a possible way to increase a study size though. If people who did pay for testing were later well characterised, even retrospectively. Crowdfunded research, the same way Dr Klimas asked for genetic information to be sent in for her study. I mean sure, there are ethics to think of, I agree. But considering funding limitations it could be an added motivator for donating to research for many people. Pay for a test and contribute to science, what is cool is that you get to see your own data. There could be a way to do it maybe.

Ron says: Yes. In order to help patients, we need a large amount of data. Crowd funding where patients contribute their own data is a much faster way than relying on NIH funding. Helping patients immediately with the data may be difficult, but this may help them faster than waiting for NIH. Once the data is analyzed it will hopefully reveal things that we can use to help them by putting out information that their doctors can use to help them, and to make recommendations for over-the-counter supplements that are likely to help.

 

[justy]

you might like to look at this cheese
https://www.researchgate.net/public...with_Antioxidative_and_Antimicrobial_Activity

Its the fermentation that's the issue so I don't think this would be any better, histamine wise - but thanks for thinking of me!

 

[Tuha]

This is true. Ron says he couldn't have written that better! Before metabolomlic results Whitney had his mitochondria tested with the most up to date methods available and the results all came out normal. It was disturbing, since Ron has really thought that the mito were involved for years but couldn't get any data to show it. That's all changed now. It's not that the mitochondria are necessarily faulty, the problem is with their regulation. The problem may not even be in the mito, but in the pathways associated with and outside of the mito that affect their functioning.

Sorry for the question - I have no scientific background. But are for example Ron´s methods acceptable in the scientific community? I mean that noone can say later that he doesnt use good methods, technologies, techniques....
I think for example dr. Myhill was accused that her techniques to mesure mitochondria disfunction are not validated

 

[Janet Dafoe]

Sorry for the question - I have no scientific background. But are for example Ron´s methods acceptable in the scientific community? I mean that noone can say later that he doesnt use good methods, technologies, techniques....
I think for example dr. Myhill was accused that her techniques to mesure mitochondria disfunction are not validated

Ron is a very well-respected scientist with an impeccable track record of being careful and meticulous. He has developed a number of the technologies that he and others are using for molecular analysis of diseases. He has even worked with the FDA and the National Bureau of Standards in establishing accuracy of methods for sequencing and gene expression.