Dr Ron Davis - Updates on ME/CFS research - September 2019 onwards

LarsSG said:
Latest video from Ron Davis on the manganese hair study:
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Key information in video ( I thought this was another information-rich video that was a lot more confidence-inspiring than some earlier ones.)

Stanford has been successful in getting a grant of $1.6 million delivered over 3 years from the Department of Defence to investigate manganese in ME/CFS. Laurel Crosby wrote the application; Janet says that it got very good reviews. Vinod Khosla has supported the work at a low level over the years to allow to get it to the point of being able to attract this grant - his support was acknowledged.

The hair sample work started years ago - hair from ME/CFS patients was analysed with mass spectrometry. Advantages of hair is that it is a time series, it is easy to collect and it comes from cells. Levels of blood aren't always indicative of what is in cells. Hair can be contaminated e.g. Zinc in shampoos, so they couldn't do much with Zn levels.

Of all the metals, manganese (Mn) was lowest. Copper was next lowest, and frequently iron was low. Levels were low enough to suggest that patients likely had problems with activity of the enzymes that use these essential metals. Levels in the blood were not consistent; so the metals may be being digested and getting into the blood, but not into cells, and specifically not into mitochondria.

Mn is involved in a number of enzymes in the mitochondria. It's involved in:
1. the glycolysis pathway - and 'we know that people with ME/CFS have problems with this pathway', with burning glucose
2. the urea cycle - When you burn amino acids (and that seems to be an important source of energy in ME/CFS), nitrogen is produced. If the nitrogen is not eliminated via the urea cycle, then it can make ammonia, which is toxic.

Further on the urea cycle: it is involved in the making of spermine and spermidine. Abnormal levels of these two molecules were identified as risk factor in going on to develop ME/CFS after mononucleosis (in the Jason college student study - it's discussed here). Both spermine and spermidine can block ion channels and potentially affect how Mn gets in [to cells?].

The plan is to run experiments to see if the enzymes are functioning normally. If they aren't, Mn will be added to see if it improves function. They will look at metals other than Mn a bit, but Mn is the focus. With the grant being for three years, there is scope to follow leads and explore.

There are several metabolites that are involved in the regulation of spermine and spermidine. Mike Jensen who works in the Stanford/Ron Davis lab has worked out an assay for the metabolites using the electrophoresis instrument that was purchased with funds from Whitney's birthday fundraiser.

The grant funding allows for good sized experiments (100 rather than 5 or 10 patients). They (Laurel specifically) have been working with a company that has a device for collecting blood samples at home.

Supplements of Mn (and other metals and selenium) should not be taken without identifying a deficiency, as excess levels are toxic. Supplementation should be done under medical supervision.
 
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I find it interesting that parkinsonian-like syndrome is referred to as manganism. I would humbly advise not to take Mn, or at least not a high dosage. Mn toxicity seems to accelerate neurotoxicity from what I've read.

I had parkinsonian-like-syndrome back in 2000 and took mg/taurine injections for over 2 years.
 
Any use of metals as supplements will first be titrated in research and then, if shown useful, in individual patients. The safe range for most metals is very small. Its very easy to overdose. However if supplementation includes ongoing testing it should be possible to figure out the optimum dosage for an individual patient, and then keep monitoring it. Just taking these kinds of supplements from off the shelves at a static dose runs a much higher risk than with most other supplements.
 
I would like to know what is causing the underlying deficiencies. It can't all be caused from malabsorption?

My test panels indicated countless deficiencies.
 
Mij said:
I would like to know what is causing the underlying deficiencies. It can't all be caused from malabsorption?
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Without investigating much I can think of four broad issues, and it could even be a mixture of all four.

Malabsorption could be one. This is about how much is absorbed.

Malutilization could be another. We could need more and so run out. Or it could be used up inappropriately.

Malexcretion means we might be losing more of that substance.

The other one is trickier to look for: sequestration. We might have increased amounts somewhere, leading to deficiencies elsewhere. Blood levels might be low, for example, if certain tissues are absorbing or using too much.

These are not simple issues. Measuring simple deficiency is easy. Figuring out all the mechanisms is mondo difficult.

Clinical trials offer us an empirical way to find out a practical solution. If we correct the problem with a supplement, and don't have major side effects, and benefits are long term, then we have a solution even if we do not fully understand what is happening.

This investigation problem used to be the case with the common cold, though I am way out of date on the research so cannot speak to current understanding especially for corona viruses. We knew enough about causation and common pathology that we almost ceased looking. We lack knowledge of the fine details of the disease. Yet much of this is due to historical technological limitations, and I think that with current and future generation technology we will slowly fill in much of the missing picture.

I think this is currently a major issue with type 2 diabetes, with potential for major paradigm shift that seems to be happening right now. The notion that we need to optimize to blood glucose is under challenge as its better than nothing but quite suboptimal. People are being cured of type 2 diabetes, but a focus on blood glucose actually impedes a cure as many strategies to limit blood glucose spikes also drive diabetes progression in the long term.
 
Mij said:
I don't feel that taking a supplement is going to solve anything tbh.
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I think it might help but definitely wont solve everything. I have tried almost every supplement I thought promising, and countless thousands of patients have done the same. Some improve, some don't, and some attribute recovery to a supplement. Nothing is reliable in this kind of evidence. Heck, every now and again I found a supplement that some assured me would help but it made me worse.

What supplements are more likely to do, if we can advance the science enough, is tweak around the edges. It might set us up for a better response to treatments that we don't even know about yet. It might help prevent relapse. It might improve quality of life. All of this has yet to be demonstrated however. I really hope we can figure out what objective outcome measures to use, as I am very suspicious of quality of life questionnaires. Returning blood concentrations of something to the normal range might not be what we want at all. So much still needs to be figured out.

If they can figure out why something is deficient or in excess it might point to mechanisms, extra things that can be tested. This is where such data on nutrients outside the normal range might be best used, and will feed into the metabolic and systems models that are being developed.
 
Hi, around 14.00 - 14.15 minutes Ron mentions something which sounds like "bimer campations" --- OK I often misspell things (!) but anyone got a clue what he said/what he's referring to?

Thanks
 
Hutan said:
Key information in video ( I thought this was another information-rich video that was a lot more confidence-inspiring than some earlier ones.)

Stanford has been successful in getting a grant of $1.6 million delivered over 3 years from the Department of Defence to investigate manganese in ME/CFS. Laurel Crosby wrote the application; Janet says that it got very good reviews. Vinod Khosla has supported the work at a low level over the years to allow to get it to the point of being able to attract this grant - his support was acknowledged.

The hair sample work started years ago - hair from ME/CFS patients was analysed with mass spectrometry. Advantages of hair is that it is a time series, it is easy to collect and it comes from cells. Levels of blood aren't always indicative of what is in cells. Hair can be contaminated e.g. Zinc in shampoos, so they couldn't do much with Zn levels.

Of all the metals, manganese (Mn) was lowest. Copper was next lowest, and frequently iron was low. Levels were low enough to suggest that patients likely had problems with activity of the enzymes that use these essential metals. Levels in the blood were not consistent; so the metals may be being digested and getting into the blood, but not into cells, and specifically not into mitochondria.

Mn is involved in a number of enzymes in the mitochondria. It's involved in:
1. the glycolysis pathway - and 'we know that people with ME/CFS have problems with this pathway', with burning glucose
2. the urea cycle - When you burn amino acids (and that seems to be an important source of energy in ME/CFS), nitrogen is produced. If the nitrogen is not eliminated via the urea cycle, then it can make ammonia, which is toxic.

Further on the urea cycle: it is involved in the making of spermine and spermidine. Abnormal levels of these two molecules were identified as risk factor in going on to develop ME/CFS after mononucleosis (in the Jason college student study - it's discussed here). Both spermine and spermidine can block ion channels and potentially affect how Mn gets in [to cells?].

The plan is to run experiments to see if the enzymes are functioning normally. If they aren't, Mn will be added to see if it improves function. They will look at metals other than Mn a bit, but Mn is the focus. With the grant being for three years, there is scope to follow leads and explore.

There are several metabolites that are involved in the regulation of spermine and spermidine. Mike Jensen who works in the Stanford/Ron Davis lab has worked out an assay for the metabolites using the electrophoresis instrument that was purchased with funds from Whitney's birthday fundraiser.

The grant funding allows for good sized experiments (100 rather than 5 or 10 patients). They (Laurel specifically) have been working with a company that has a device for collecting blood samples at home.

Supplements of Mn (and other metals and selenium) should not be taken without identifying a deficiency, as excess levels are toxic. Supplementation should be done under medical supervision.
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Thank you so much for summarising the video. What incredibly interesting and exciting research. Very curious about what the enzyme results will be.
 
Has anyone confirmed the IDO2 genetic mutations in any other cohort or are they still basing this on the 20 severely ill patients alone?

It's confusing to me why we've heard so much about yeast experiments and little about confirming the genetic basis for the hypothesis, which seems like it would be cheaper and faster — though I assume DecodeME will answer this as well.
 
LarsSG said:
Has anyone confirmed the IDO2 genetic mutations in any other cohort or are they still basing this on the 20 severely ill patients alone?
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I have said before that this might only be a marker for severity risk. It might not apply to the general ME population. Any finding in the severe group has to be confirmed in a larger and more typical patient group. Its just easier to find things in severe patients.
 
Gist is, if the itaconate shunt idea is correct, it makes the idea of a persistent infection more likely. So Ron's lab is working on finding a persistent infection (or at least something that looks like an infection to the body) and on finding out if the itaconate pathway is dysregulated.

One of the researchers in Ron's lab, Peidong Shan, has been trying to look for infections. He's currently looking for viruses, looking for RNA and DNA. He has run a test for herpesviruses on about 50 patients. There are occasional activations, but it's not common and not much more common than in healthy people, so it doesn't seem as though that is the answer.

He's working on enteroviruses now and has done 20 samples and didn't find any. These are blood samples, and the infection may not be in the blood. They will test a sample from Whitney's J tube (stomach contents). (Mention was made later that Dr Chia had found enteroviruses in the stomach.)

Next up is parasites including trypanosomes. Some pilot studies are underway. One patient has a nematode in the blood, but that organism has not yet been sequenced - they are working on that (because when you know the genetic sequence, you can test for part of that in other patients.)

OMF got some funding allowing for work on the activation of the herpes viruses in Long Covid. Samples from Jonas Bergquist have been analysed (I assume in Ron's lab, and I assume the samples were blood samples). In a pilot, they found EBV was activated in 18 of the 20 samples. They will next look for other herpes virus activations. [edit to add: I didn't understand how this study differed from the one mentioned above by Shan on 50 patients, apart from being in Long Covid. I went back to listen again, but I still don't know. It seems odd that the results should be so different in ME/CFS and Long Covid. It wasn't explained.]

6.30 They are also looking at patient's genes and control regions. One they are looking at the BH4 pathway - so they are looking at genes that relate to that pathway. They are checking to see if there is a fault in an enzyme that makes BH4, among other things. They are also looking levels of BH4 (this is difficult as it is a short-lived molecule, easily oxidised) and downstream metabolites.

9.40 They are also looking at messenger RNAs that make the enzymes in the itaconate pathway. They are looking in cells from the blood; a collaborator in Harvard is sending muscle cells for this same analysis.

11.20 Ron notes that their assay for the herpesvirus requires that the virus is replicating. But the virus might be activated, but not actively replicating, it might just produce RNA molecules, but that might be enough to make the body respond as if there was an active infection. But that would mean that whole viruses can't be found.

They are very focused on finding if the itaconate pathway is 'on', and, if it is on, why. It sounds as though Vinod Khosla is the major funder of this work.
 
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Hutan said:
OMF got some funding allowing for work on the activation of the herpes viruses in Long Covid. Samples from Jonas Bergquist have been analysed (I assume in Ron's lab, and I assume the samples were blood samples). In a pilot, they found EBV was activated in 18 of the 20 samples. They will next look for other herpes virus activations. [edit to add: I didn't understand how this study differed from the one mentioned above by Shan on 50 patients, apart from being in Long Covid. I went back to listen again, but I still don't know. It seems odd that the results should be so different in ME/CFS and Long Covid. It wasn't explained.]
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This jumped out at me as well. Perhaps these results suggest EBV re-activation is common in the early months or years of Long Covid and ME, but not later. It would be interesting to know how long the patients had been sick for, especially the ME patients. This would suggest that maybe EBV re-activation is a consequence of some kind of immune dysregulation and not a cause of ME or LC (or it's a hit and run cause). That also tracks with the fact that some healthy people have EBV re-activations and it doesn't seem to be a problem.
 
I'm thankful for the people doing the write-ups here as it's hard for me to follow the video's. With regards to EBV, the doctor at the hospital that diagnosed me with M.E. said I had traces of inactive EBV or something along those lines. It was apparently still in the blood, but not active.
 
Solstice said:
I'm thankful for the people doing the write-ups here as it's hard for me to follow the video's. With regards to EBV, the doctor at the hospital that diagnosed me with M.E. said I had traces of inactive EBV or something along those lines. It was apparently still in the blood, but not active.
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I'm completely unqualified - but from what I understand - this is quite common for ME/CFS patients - IGMs found in the blood indicate a current infection, and IGGs found in the blood indicate a previous infection..
 




Unfortunately, it's not going to be recorded for us to be able to watch.

Edited to add:
Later in the video Janet said that an individual researcher may request that their presentation be recorded and that the recording will be given to that researcher to do what they want with.

Edited to add another tweet:

 
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