Ron Davis speech at 14th Invest in ME Research International ME Conference.

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(This video may not work here in the forums but if you click "watch on youtube" it should work)

It included some data on sleep in severely ill patients I had not seen before, and a slide showing how ctokine levels track with severity. (of course I wonder if the correlation would be even stronger in a provocation study)

Screen Shot 2019-07-24 at 10.01.37 am.png Screen Shot 2019-07-24 at 10.04.18 am.png

THis next one is interesting. He says the gene that makes indoleproprionate is not a human gene, it's a microbiome gene. The problem is a missing gut bug.
Screen Shot 2019-07-24 at 10.07.49 am.png

He says taking this as a drug might help, once it is available (still under testing).

At the 17 minutes mark he talks about Copaxone, which he says makes MECFS patient blood "look healthy" (presumably in terms of impedance)

He also talks about the IDO hypothesis. They now think it must be present in just 1% of cells and they can't get a good signal, they hypothesise that is because of the media they are testing the cells in, which they think might be polluting the signal. In summary the theory is very attractive but there is not good evidence for it yet.
 
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perrier

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I seem to recall, once before, Dr. Davis mentioned that the medium is an issue; and he also once mentioned that access to powerful spectrometer is another hurdle. Would someone please indicate the date of this presentation?

Dr Davis did look very good in the video and seemed very positive. Brilliant man.
 
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I think I should correct Dr Davis’ explanation of flipping coins 66 times which showed heads all 66, as an anaology for the IDO2 mutation.

The proper analogy should be 46 times. This is because the first 20 do not count due to being cherry picked. For example, if you take any random population of 20 people, there will be genes that all 20 have, even if 75% of the population has them. This is due to pure chance. You could also get 20 people to flip coins 1 million times, you will get plenty of meaningless patterns and correlations in there to due the enormous number of flips (or genes).

The next 46 were (hopefully) not cherry picked. Since we specifically chose to look at that gene for the 46 next people tested. This is just to help people understand stats a bit better. I’m sure Dr Davis would agree with my correction.
 
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I think I should correct Dr Davis’ explanation of flipping coins 66 times which showed heads all 66, as an anaology for the IDO2 mutation.

The proper analogy should be 46 times. This is because the first 20 do not count due to being cherry picked. For example, if you take any random population of 20 people, there will be genes that all 20 have, even if 75% of the population has them. This is due to pure chance. You could also get 20 people to flip coins 1 million times, you will get plenty of meaningless patterns and correlations in there to due the enormous number of flips (or genes).

The next 46 were (hopefully) not cherry picked. Since we specifically chose to look at that gene for the 46 next people tested. This is just to help people understand stats a bit better. I’m sure Dr Davis would agree with my correction.
Even if 46 consecutive randomly chosen people present with a mutation that is present in only 75% of the population, that's screamingly unlikely.

Or, as Ron Davis says at 36:37, the other possibility is the data are wrong. (Could be the new data or the comparator data that give the 75% rate.) Given everything I think I know about this hypothesis I put some weight on that possibility. I am pleased to hear that he's alert to that.
 
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Even if 46 consecutive randomly chosen people present with a mutation that is present in only 75% of the population, that's screamingly unlikely.

Or, as Ron Davis says at 36:37, the other possibility is the data are wrong. (Could be the new data or the comparator data that give the 75% rate.) Given everything I think I know about this hypothesis I put some weight on that possibility. I am pleased to hear that he's alert to that.
Yes, 46 would be very, very, unlikely. The only other possibility could be if there is some connection between the IDO2 mutations and other genes that are implicated in the disease. For example, if genes X, Y and Z are implicated in the disease but incidentally always come along with IDO2 mutations for some reason. In this case, we would see all patients with the IDO2 mutation, but in reality genes X, Y, and Z are the real culprit.

That being said, Dr Davis knows infinitely more genetics than I ever will. I am just trying to explain that there COULD be some reason why the (0.75)^46 probability is incorrect - for example if the IDO2 mutation is not independent from the real genetic causes of ME/CFS that we are not aware of.

I should also note that from Janet’s twitter responses it seems that the metabolic trap is still a very viable hypothesis. At least from the end of June, when she said it hasn’t been disproven yet!
 

maple

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@Janet Dafoe (Rose49) Thanks to you all for your excellent work. I just watched this video. I expect it has already been considered by your team, but in case not.... is it possible that the absence of indolepropionate is due to a bacteriophage that is eliminating the bacterium/a that should be generating this compound: in other words, the microbiome is infected with bacteriophage?
 

bctjr1993

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(This video may not work here in the forums but if you click "watch on youtube" it should work)

It included some data on sleep in severely ill patients I had not seen before, and a slide showing how ctokine levels track with severity. (of course I wonder if the correlation would be even stronger in a provocation study)

View attachment 33848 View attachment 33849

THis next one is interesting. He says the gene that makes indoleproprionate is not a human gene, it's a microbiome gene. The problem is a missing gut bug.
View attachment 33850

He says taking this as a drug might help, once it is available (still under testing).

At the 17 minutes mark he talks about Copaxone, which he says makes MECFS patient blood "look healthy" (presumably in terms of impedance)

He also talks about the IDO hypothesis. They now think it must be present in just 1% of cells and they can't get a good signal, they hypothesise that is because of the media they are testing the cells in, which they think might be polluting the signal. In summary the theory is very attractive but there is not good evidence for it yet.
Thank you for your summary, but I disagree with your summary of the IDO hypothesis. I don't know how you could watch that and think he doesn't have good evidence for it. 66 out of 66 people have the mutation. He has been trying to prove this theory wrong, and has been unable to. Three days before he gave this presentation, he released an update in which he even went as far as to say that the IDO hypothesis is "probably correct".
 

JES

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Thank you for your summary, but I disagree with your summary of the IDO hypothesis. I don't know how you could watch that and think he doesn't have good evidence for it. 66 out of 66 people have the mutation. He has been trying to prove this theory wrong, and has been unable to. Three days before he gave this presentation, he released an update in which he even went as far as to say that the IDO hypothesis is "probably correct".
The IDO2 genetic observation is not necessarily tied to the IDO metabolic trap hypothesis, although it does agree with it. The data tells us that a faulty IDO2 is very likely required to develop ME/CFS, along with perhaps some other genes like @Cam Newton mentioned. But that only brings us one step closer to the IDO1 trap theory. It could also be that IDO2 serves some other role that keeps people with a functioning IDO2 from developing ME/CFS, it may not necessarily tie to the trap model of Robert Phair.

One thing that concerns me a bit is how common this IDO2 mutation is. Robert Phair was originally looking for mutations that were not rare (by rare is probably implied something like less than 1% of population), but now we have found a mutation that affects the majority of the population. If 0.5% of the entire population gets ME/CFS, then with 75% having a faulty IDO2, if you belong to the faulty IDO2 group, you still only have a 0.66% likelihood of getting ME/CFS. In other words, a lot that has to go wrong for someone to develop ME/CFS even with a faulty IDO2.

To contrast it with some other disease causing mutations, for example there is a well known BRCA mutation that is tied to breast cancer. It is estimated that a massive 70% of women with BRCA mutation develop breast cancer during their lifetime, as opposed to around 12% in the general population.
 
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Ron told here that SS-31 and Capoxone would help patients. And he said this might be b/c both medicals contain each a different four amino-acid chain which both have one lysine and one tyrosine each.
Maybe it can relate to this finding?:

Diasamidze GA, 1970 (in: Voor Med Khim), article in Russian:

[The effect of tyrosine, methione and lysine loading on the regional distribution of the free amino acid pool in the brain of white rats]



Of course, with only the titel it is difficult to estimate how much the article says,
but maybe it can even relate to the considerations on PBMC´s?

Oestein Fluge et al, 2016 - serum amino acids are altered, like pyruvatedehydrogenase would not work
Then pyruvatedehydrogenase is located in the mitochondrial matrix ... so maybe:

Cara Tomas et al, 2019 - mitochondria itself work fine
from the conclusions
The results showing no difference in mitochondrial activity in permeabilised PBMCs were unexpected given that mitochondrial function in PBMCs has previously been shown to be significantly lower in CFS (Tomas et al., 2017). However, the lack of difference in complex activity in CFS PBMCs is in agreement with results reported by other groups who showed normal mitochondrial respiratory chain complex activity (Lawson et al., 2016; Vermeulen et al., 2010), and postulated that changes in mitochondrial ATP synthesis should be attributed to other causes such as the transport capacity of oxygen (Vermeulen et al., 2010). Given the results here, the future of bioenergetic studies in CFS should concentrate on mechanisms upstream of the mitochondrial respiratory chain.
 
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ljimbo423

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If one was interested in taking indoleproprionate, could it be taken orally or would it need to be taken subcutaneously or intravenously? Any ideas?

Thanks.
I don't know about taking indoleproprionate directly. Wikipedia says that fiber increases levels of it-

In 2017, elevated concentrations of IPA in human blood plasma were found to be correlated with a lower risk of type 2 diabetes and higher consumption of fiber-rich foods.
https://en.wikipedia.org/wiki/3-Indolepropionic_acid
 
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I don't know about taking indoleproprionate directly. Wikipedia says that fiber increases levels of it-
Yes, but as I have understood this is because the clostridium sporogenes, the bacterium that produces indoleproprionate, needs it and it then poduces the stuff.

But if there isn´t any bacteria, than it will be helpless. I have read (don´t recall where) that a lack of this bacterium is quite common (don´t know how common). So it would be along with IDO2 a second common predisposition, however.
 
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