MEAction 2021 MECFS researchers video with R Davis,Prusty

Just on the IDO2 mutations: I remember reading that at least some of the mutations show up in 23andME and WGS results, and that Dr Phair has published the rs codes of the SNPs he identified. They should be easy enough for patients to pick up themselves, as long as the orientation is made clear. Quite a number seem to have done these tests, so it ought to be easy to pursue more data.

 

That's correct. Three out of five IDO2 mutations that Dr Phair identified in his metabolic trap presentation(s) are on the 23andMe v4 chipset.

Here's some n=1: I have all three. I am severe.

 

My understanding is this:

C > T describes a substituation at the DNA level (cytosine replaced by thymine).

R248W describes a substitution of the amino acid at position 248, normally R (arginine) with W (tryptophan).

Y359STOP means there is a premature stop signal at position 359 so the protein can't be made correctly.

The rs identification number (rsid), like rs10109853 identifies a mutation. I understand they actually group very similar mutations together under the same identification number.

What you're interested in is any mutations in the relevant genes that are predicted to be potentially damaging or the relevant rsids. If you have a mutation in the IDO2 gene, it's more likely to be a common one. You could have an uncommon one whose rsid isn't listed by Phair.

 

I gave an answer on the IDO2 variant thread. I thought perhaps discussion on variants is better there.
https://www.s4me.info/threads/ido2-gene-mutations-snps.12912/#post-344783

 

Aptamers work much the same way as the antibodies used in assays. The difference is that researchers can make their own custom aptamers more easily than engineering the antibodies.

 

Could it be this which was published in Nature in 2020. It's too complex for me to even try to understand the method of determining the pathways.

Herpes simplex virus blocks host transcription termination via the bimodal activities of ICP27
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962326/

 

The data from a GWAS like DecodeME is perfect for testing this as well as many other hypotheses. Ultimately, it is lab and other experimental work that will prove things in or out, but any hypothesis that is rightht for a substantial number of people with mecfs is very likely to have a genetic signal in a GWAS.

Equally - and the main reason for the study - if there are genetic signals in DecodeME, they are very likely to point to biological causes. As above, further research will be needed to find definite answers, but if DecodeME does find signals they should be strong leads.

I must have seen close to a hundred hypotheses come and go in the 26 years I have been ill. Maybe we will get lucky with the metabolic trap etc. If not, DecodeME provides a more systematic way to make progress - as well as a tool that researchers can use to investigate their own hypotheses.

Re defective IDO - I'm not sure they published robust comparison figures for controls. DecodeME will do that.

 

A couple of extra thoughts on OMF's data.

First, is it only data or do they include methods used to generate that data? Obviously the data and methods would be better.

Secondly, is there any reason why a researcher/researcher group couldn't write a paper (or papers) reviewing the data, published and otherwise, available from the OMF?

 

No, should be OK—I believe that’s what they want...hence the “open” in Open Medicine Foundation. I think you do need to provide a justification to acquire data sets.

https://docs.google.com/document/u/0/d/174XaalBtCgVC135bN5N2Z_HhYt2VHC-DHSNlnD8Xn30/mobilebasic

https://endmecfs.stanford.edu/about

 

Watching the video I think this can do with a clarification. The issue is that the immune cells are hypothesised to be kynurunine deficient due to the tryptophan trap. The liver supplies lots in the blood, but the immune cells do not absorb it well and need to make it from tryptophan, which is easily absorbed. Hence a block in tryptophan metabolism leads to an insufficient supply of kynurunine. This in turn leads to immune cell issues especially in viral infections.

 

No. That is the whole point of open medicine and considered desirable.

 

I want to comment on the cell model of the tryptophan trap. Yes, they have a yeast model, but its genetically modified so all NAD has to be derived via IDO1 activity, and the IDO1 gene is the human gene. So when they test drugs, after inducing the tryptopn trap, which is easy in yeast cultures, its a human gene they are testing.

It does not end there though. They have a human immune cell model, and any drug found working in the yeast model can then be tested on the immune cells.

 

He actually explains why this is the case. There is so little research funding that funding on trivial or unimportant studies takes money away from the studies that might actually advance key science in this area.

 

For those complaining about the lack of communication from OMF they did release a 3 hour open house video with their researchers that was posted on a different thread, which may not have been seen by forum members. I post it again here

https://www.youtube.com/watch?v=8xRLEhCog0s

Maybe if @Lisa108 has interest/energy she could publish a transcript for this.....Thanks.

Video also posted here:
Open Medicine Foundation

 

It looks like I'm a lot more positive to the Metabolic Trap Hypothesis being a possible explanation to ME, than a lot of others here. But I'm curious, those of you who are very sceptical and have almost discarded it already, have you actually taken the time to try to understand the model on a deeper level? Because to me it sounded much more plausible and logical after I actually took the time to try to understand what the kynurenine pathway does, what NAD does, Niacin etc.

I think we should be just as cautious when it comes to dismissing theories that could prove to be relevant, as we are about not blindly accepting false ones.

 

Unlike the PACE authors etc. who take a hypothesis and base their trial on the presumption it is already proven.

 

Quite a few of us shared our files with the results from 23andme with @Valentijn. She put together in tabels, the SNPs that were discussed at that time. I´ll see if I can get in contact with her, or if anyone know how to do that, it would be great.

 

Another difficulty of not publishing is that no one is able to ask the hard questions that are necessary to make sure that research is solid. Rather than being a waste of time, publications can lead to eliminating flawed theories or strengthening good hypotheses because of input from the larger community. Ron Davis certainly doesn’t have to worry about establishing a reputation - he did that long before he began working on ME/CFS. But he does need to put the details of his work through a peer reviewed system and have it published for the greater research community to weigh in, with support and criticisms.

I sympathize with his sense of urgency. He’s an elderly man with a sick son. But skipping the necessary steps just won’t lead to better science.