Open Medicine Foundation (OMF)

Around February last year Ron announced they were going to use yeast to test for drugs to remove the metabolic trap. He spent most of the video explaining how yeast can be used for this purpose. It all sounded very promising until the very end when he said the machine they have to carry out these tests is very old and is broken and they were having trouble finding someone who could fix it. More recently Janet stated they were still trying to get it fixed. It's all starting to sound like "the dog ate my homework" excuse.

 

I'm assuming this job ad is for OMF (Stanford)

https://careers.insidehighered.com/job/2504268/basic-life-research-scientist-1-year-fixed-term-/

 

I think getting a science communicator wouldn't achieve much of anything. The problem is that Ron Davis simply cannot get anything done. Every single project he is involved in has been on halt for the last 4 years and every time he comes out with a different excuse. They clearly have the funding, they raised tens of millions of dollars in the last few years. Either there are some serious management issues or the executives have simply decided that Ron's work is not worth funding.

 

Over $1M from OMF to Ron's lab in 2020, about $300,000 last year — so it does look like maybe the work has slowed significantly. They are sending more money to Alain Moreau and Chris Armstrong these days, but what is surprising to me is how much they have on hand — nearly $10M at the end of last year. Seems like there is maybe a problem getting money out the door and put to good use at OMF. Not a bad thing for a non-profit to have some funds to smooth out fluctuations in fundraising, but that's as much as they spend on research in two years.

 

The NIH pulled funding to the nano-needle during initial development. Private funding finished the project.

There is no large validation of the nano-needle. Only a tiny cohort was tested at a single lab.

The nano-needle has not been tested to see if it detects many diseases or only one.

The project manager did not find solutions to the problems they were facing. While testing would be slow the last three years have been wasted because of excuses.

There is no plan to start slowly testing the nano-needle against different diseases or a larger cohort of ME/CFS. Private funding is available for this testing.

Testing was ready to precede with MS but Covid prevented it from starting. No plan to restart in the future.

Would the results of those tests make the nano-needle more appealing to NIH?

There is private funding available to reduce the cost of nano-needle testing, moving it from research laboratories to clinics. Private funding is inconvenient for one researcher's tenure.

The NIH who pulled funding for this project, must reverse that decision, replace private funding with public tax dollars.

It's the NIH's fault that developer isn't going to get tenure. Tenure is so wonderful it is worth millions of patients suffering with no bio-marker for the last three years with no end in sight.

To persuade the NIH to reverse course they are being insulted and condemned for their past decisions. Patients need to help persuade the NIH to coddle one developer's tenure so we can receive a bio-marker.

Please, tell me if I'm understanding the situation correctly.

 

For me the problem is that the nano needle never really made sense. Measuring impedance in a suspension of cells might measure something but it is very hard to see how it would be a useful way to measure it rather than something much more routine. I forget the details but it looked rather as if it was measuring cells dying. There are much better understood ways of doing that.

I am afraid that I think people with understanding of basic chemistry tried to apply it to a complex biological problem without having any idea of how that sort of problem is best addressed.

It is a bit like Francis Crick trying to discover the mechanism of consciousness. He didn't understand the problem or the relevant physics.

 

This is Mark Davis's presentation at the NIH Fatigue Conference last year starting at 4h 49mins. He shows ME data for these KIR+ CD8 cells at the end of his timeslot.
https://videocast.nih.gov/watch=42563

You can look at NIH Reporter to see publications under Ron Davis's NIH grant
https://reporter.nih.gov/search/FlLWGi39aEWiMahXbwpSBA/project-details/10159206#publications

It shows Mark Davis published the work explained in the video. I don't think they included ME data in the paper. I think they were in the process of gathering more samples to follow up on initial leads
KIR+CD8+ T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8995031/

I really like the concept that these KIR+CD8 T cells may not be properly policing other immune cells in a subset of ME/CFS and perhaps that would tie in with Lipkin's paper on non-specific B-Cell clonal expansion in ME/CFS that was replicated by Sato et al in Japan in a different cohort using different methods. Nath at NIH was incredibly excited by these two papers so I wouldn't be surprised if he will report on his findings in this area.

For reference
Skewing of the B cell receptor repertoire in myalgic encephalomyelitis/chronic fatigue syndrome, 2021, Sato et al
https://www.s4me.info/threads/skewi...ronic-fatigue-syndrome-2021-sato-et-al.19883/

Plasma proteomic profiling suggests an association between antigen driven clonal B cell expansion and ME/CFS, 2020, Lipkin et al
https://www.s4me.info/threads/plasm...expansion-and-me-cfs-2020-lipkin-et-al.16005/

EDIT : Here is some additional information on KIR+ CD8 cell work in a Stanford news article. It explains in easier to understand language.
‘Military police’ cells arise to arrest infection-induced autoimmunity, study finds
https://med.stanford.edu/news/all-news/2022/03/immune-cells-autoimmunity.html

 

@Art Vandelay Here is some additional background info on T Cell receptor sequencing work at Stanford.

Mark Davis gave a short talk entitled “Decoding The Human Immune System” where he states “There are no metrics of immunological health”



About halfway through he explains what they have learned about T cell receptor sequencing. If I remember right, in a nutshell, two people can respond to the exact same antigen but their T cell receptor sequence code can be different. In order to resolve the data so that they can perform matching they need to create libraries of sequences that will respond to an antigen and then use computer matching techniques to match those to actual human T cell receptor sequences. Only then can they see if there are common sequences.

@Chris Ponting

 

You've got me thinking. The latest message that I got was that it was the plasma (below copied from: https://www.virology.ws/2019/12/16/...grath-on-ron-davis-on-something-in-the-blood/)

"As in the previous graph, impedance shoots up for ME/CFS in their own plasma, while nothing much happens for healthy cells in their own plasma (patchy yellow line – sorry, a poor quality screenshot of video). But when ME/CFS cells are tested in plasma from healthy patients (green line, indicated by the arrow), the ME/CFS cells now behave much like healthy cells

So, something in (or missing from) the plasma seems to be affecting cells, making ME/CFS cells act abnormally. And finding the something responsible for that could provide a big clue to understanding ME/CFS."


I'd be interested to see how robust the findings continue to be, because if it is good at differentiating that's a big clue. I understand the need to have theories as to why you do something before you do it, and to try and explain what you see, but on the basis of this difference being secure there is another stage as to what 'difference' it is actually showing (other than 'ME' from 'non-ME' - and we don't know the sample details there).

It measures current, introduces salt and when you think about the ions, PH, concentration that come into it I'm assuming they've looked at the plasma without the cells in it having salt added so they know what they are 'attributing to cells in the plasma +salt' rather than 'plasma + salt'? Confirming that detail is quite pertinent for various reasons.

 

It might possibly but as far as I can see no real link ha been down here.
We know KIR+CD8 T cell police other immune cells. That I what KIR and CD8 are for a ha been known for decade. But that doe not mean that a lack of the function is the cause o any common autoimmune disease. It might be something quite different. And the findings in ME are about B cell clonality, not T cells - which are what Davis was talking about.

The discussion I have seen from these groups is to me very old tired stuff about autoimmunity that didn't turn out to be confirmed by experiments in the 1990s. It is a pity that it is still so often quoted - and it is, very often.

 

Yes, that is what they have been saying, but what they are measuring is a change in behaviour of cells that seems to be due to what is in the plasma. Impedance seems to me a crazy thing to look at if you want to look at changes in cell behaviour. There are much more routine things to look at that ought to tell us more directly what the problem is.

It is a bit like putting electrodes across your omelette to see if it cooked when it is much easier to tell by looking.

 

Do you thoughts on what should be looked at? Are there more direct investigations that should be happening that might give more insight into why this electrical effect appears?

The impedance finding does seem like it indicates something is going on. Obviously, they need to figure out if this happens in some group of illnesses or just in ME, but it also seems important to try to figure out what is actually happening. Their 2019 paper suggested the next step was to separate out the various plasma components to see which ones were involved in the effect and to separate out different cell types as well. But it doesn't seem like that work is happening.

 

There is this old blog post in which it was shown that a change in the dielectric properties of the cells in the sample might explain the increase in the real component of impedance we see in samples from patients (see paragraph 6)

https://paolomaccallini.com/2019/05/05/impedance-the-biomarker-you-wouldnt-expect/

 

Unless the initial findings were an artefact of the way the experiment was set up, which so often happens in preliminary studies.

 

Isn't that pretty much by definition the case?
The question is why we should be interested in dielectric properties of cells or cell membranes perhaps. What change in useful behaviour might that be indirectly measuring. The original paper I found opaque on the simple geometry of the situation so I could never figure that out.

 

Chris Ponting's genetic (Google "GWAS") study might provide evidence of the underlying cause(s) of ME/CFS; e.g. this* very small study indicate the TPPP gene might be implicated. If the underlying cause can be identified then that should help in the identification of biomarker(s).

I have very limited knowledge but I gather that the nanoneedle "test" is based on stressing cells (placing cells in dilute salt - requiring the cell to pump it out) and then measuring the impedance. Problem seems to be that no one knows what the signal actually means. Again, post Chris Ponting's study it might be possible to identify groups of people and to see if the signal is useful.


*[https://www.s4me.info/threads/genet...ential-risk-loci-2022-hajdarevic-et-al.25070/]

 

Actually came to mind that there are comments on this thread* (from Jonathan) that e.g. if TPPP gene is relevant then you may not be able to develop a biomarker based on that (primary/disease causing) change. Genetic (GWAS) studies in Alzheimer's have demonstrated that it is an inflammatory disease/process; however, there's no biomarker for Alzheimer's (to my knowledge). That, of course, has been problematic in Alzheimers since you can't act early to prevent deterioration.
Too early to say though e.g. if TPPP is relevant then it might be possible to find something that can be measured and is a biomarker - even potentially diagnostic.


*[https://www.s4me.info/threads/genet...ential-risk-loci-2022-hajdarevic-et-al.25070/]

 

I think the OMF does excellent work.
I think Ron has done excellent work.

You see what I am saying?

We owe Ron, like the OMF does, that doesn't automatically imply giving him more money is the best way forward.

 

Am I right in assuming that to measure impendence they are using the nanoneedle to penetrate the cell itself?

and how do they get salt into the cell without it going into the plasma, and would it matter if they did?