Ron Davis latest: more evidence of "something in the blood" (Simon M blog)

Latest from Ron Davis: more evidence of "something in the blood"

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© Mark Tuschman (with thanks for his permission to use here)

More clues are pointing to a role for blood plasma in ME/CFS. At a recent talk, Ron Davis presented data showing that ME/CFS cells behave normally in the nanoneedle test IF they are tested in healthy plasma. Also, red blood cells from ME/CFS patients are not as deformable as those from healthy people — but researchers only see the difference when cells are tested in their own plasma. Plus, a bigger and better pathogen hunt and another drug candidate emerges from nanoneedle testing.​

Dr Ron Davis recently revealed more evidence supporting the idea that there could be "something in the blood" that drives ME/CFS.

He's been on a tour of the US East Coast, winning over scientists and clinicians, one lecture hall at a time.

Open Medicine Foundation has made available his talk at the Albert Einstein Medical Centre is now available. Much of the talk's content will be familiar to ME/CFS patients. I am highlighting here the things that appeared to be new and particularly interesting.

Something in the (blood) plasma
Previous work from Ron Davis and others has suggested that an unknown factor in the blood is driving ME/CFS and can cause healthy cells to behave like ME/CFS cells.

Davis had already reported striking nanoneedle results. The nanoneedle measures electrical changes in a sample of simplified blood (effectively just white blood cells in plasma).

What proved to be revelatory in ME/CFS was the nanoneedle salt stress test. This simply involves adding some sodium chloride (table salt), which forces cells to use energy (sodium enters the cell and is a little toxic to them, so they must use energy to pump it out again).

When salt is added to a sample of healthy control cells not much happens electrically. But when salt is added to an ME/CFS sample, electrical impedance shoots up, as the graph below shows. It does this for every patient tested (an initial sample of 20, then 26 more), and doesn't do this for every control tested to date.


Previously, he’d said that white blood cells taken from ME/CFS patients behave like normal, healthy cells if they are tested in plasma from healthy patients. Here, he presented data from one patient showing exactly that.


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...
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Read the full blog​

 

Many thanks, @Simon M. Another excellent blog.

Just one question. You write: “When salt is added to a sample of healthy control cells not much happens electrically. But when salt is added to an ME/CFS sample, electrical impedance shoots up, as the graph below shows. It does this for every patient tested (an initial sample of 20, then 26 more), and doesn’t do this for every control tested to date.”

It doesn’t do it for every control, but has electrical impedance shot up for any controls in the way that it has with ME samples? My limited understanding was that it hasn’t but I’ve not followed developments closely.

[edit – typo]

 

That SS31 prevents the abnormal reaction to salt stress would be consistent with a mitochondrial problem. SS31 is described as "mitochondrial antioxidant" and "mitochondria-targeted" molecule in the literature.

 

That caught my attention as well.

I am currently interpreting it as meaning that for every control sample, tested to date, the impedance didn't shoot up in the manner displayed by the ME/CFS samples - which would appear to be what the squiggly lines show.

 

Still waiting for SS31/elamipretide to be market ready. The phase 3 trail for Primary Mitochondrial Myopathy (https://www.stealthbt.com/programs-pipeline/#pipeline - MMPOWER-3) ends this year. So with some luck it will be available 2020. If its in the price range of copaxone im definitely gonna try it out.

 

is it relevant that ME/ CFS cells have a nominally different response in healthy plasma too? ( less impedance)
would it be interesting to look at the cells ( ME/CFS in healthy plasma, normal controls in CFS plasma at the crossover point just short of an hour and see what is happening?

 

Is it too early for a SS31 for ME/CFS clinical trial?

 

Before we invest in it, I think we need to wait at the very least until the Phase 3 trial of the drug is complete, and the nanoneedle project has tested many more samples, including people with ME, people with other diseases, and healthy controls. If it still looks interesting, there may be a case.

Interesting work, though!

 

Thanks. No, it has not, take a look at this blog, with my labelling-tweaked verrssion of the PNAS paper graph

https://mecfsresearchreview.me/2019...d-lead-to-a-diagnostic-blood-test-for-me-cfs/

Yes. Neither Ron nor anyone else has suggested a trial. They are screening a whole load of candidate drugs, and my understanding is they will then do more work on the best ones.

Thanks. I think Bhupesh Prusty mentioned some work using non-nanoneedle measurement of electrical changes (results broadly consistent, tiny samples, IIRC, but not sur if they looked at plasma effect) but nothing published.

In the talk, Ron commented that the mecfs cells had spent most of their time in mecfs plasma, and that might explain the difference. Don't know how long they incubated mecfs cells in healthy plasma prior to testing. Also bear in mind this is data for just one patient (I think they tested 5 in total), so there will be variation.

 

What do nanoneedle findings actually mean? How do we know that what happens in this test in vitro will be relevant to what happens in vivo?

 

I think this image might be the most important experiment in the nanoneedle study. What it shows is that even healthy cells start behaving oddly if subject to ME/CFS plasma. It doesn't tell us for sure what is going on in vivo, but it seems to strongly indicate that something in the plasma of ME/CFS patients is causing cells to behave oddly.

What has taken frustratingly long is figuring out what this "something in plasma" actually is. According to Davis latest talk with Ben H., it seems that they were limited by the nanoneedle technology and a new device will help them in working further towards finding where the signal in the plasma is coming from.

 

Ron now wants to collaborate with a neurologist whose interest is things in the blood that affect the brain (I'm paraphrasing)

 

Awesome blog @Simon M , as usual. Thanks for all your hard work.

@Sean As far as other teams working on something in the blood, I believe Bhupesh Prusty is. The more the merrier. I want it to be a (controlled) race to find out what is causing this. That's presuming the nanoneedle is valid, and representative of in-vivo.

That's correct @JES , they have been limited by technology and a new prototype device has been made to aid in the endeavour. The new device is magnitudes (100x IIRC from Ron's New York talk) more efficient and capable. Thats one of the recurring and frustrating themes-a lot of this technology doesn't exist or exists at unattainable price-points-so it has to be made from scratch, which takes time.


B

 

Karl Morten remains interested in this area and does what he can with the resources available to him.

 

That is a very important question. It (or at least the biology underpinning the in vitro test) was discussed at length on deep into this thread but was over my head.

What I would say is that electrical changes are often used as proxies of changes in cells. It is used at the level of a solution of cells for testing antibiotics on bacteria — Ron says that the changes in impedance in this instance precede cell death/lysis (which would be expected to change impedance). He has also said in the past that they are fairly sure that the changes detected by the nanoneedle are not cell death.

As I said in my blog, what excites me most about the nanoneedle work is not the biomarker potential, but that it might have identified some critical pathology. Which is why I would love there was more work to identify exactly what's happening. In my ignorance, I imagine a team of cell biologists could make a lot of progress by looking at this. They wouldn't even need the nanoneedle apparatus but could look at what's happening to cells when treated with salt in the same way as in the nanoneedle test.

So I think there is reason to assume that the nanoneedle results mean something, and I hope that research will identify what that something is sooner rather than later.

Yes, this is very interesting. But what struck me about the latest talk was that Ron showed some actual data, rather than a diagram.

Also, the data shows that while healthy cells do look a lot more like ME/CFS cells when placed in ME/CFS plasma (see the image in the first post) — it still looks quite different from ME/CFS cells in their own plasma. though I am encouraged by the sight of hard data.

And am even more encouraged that the team seem to have found a way around is the nanoneedle logjam (or will have when they've moved from prototype to full version). Then, hopefully, we will start to see more data and bigger sample sizes.

 

Yep, that's true. I'm hoping he can have access to more resources and funding. I'd personally love to see a collaborative with funding with Prof. Davis. I think they're attuned to similar things.


B

 

This is a really good point Simon. I'm wondering if this is because of cellular damage that has occured to the ME/CFS cells, possibly over time even if it's short, whereas the healthy cells are more 'resilient' having not been in that environment but transplanted so to speak-maybe higher levels of antioxidants, glutathione or ATP etc as a random pondering. Or that could be total hogwash.


B

 

@Simon M Thank you.

SS31/elamipretide works for mitochondrial diseases. It is great that the technology of the nanoneedle advances but a critical step should be to identify that we have a change in impedance for ME patients vs other patient plasma with a mitochondrial disease. Not sure if this makes sense biologically speaking.If this impedance change is ME-specific under this setting then this is good news. If it is not, perhaps we should start looking at ME as a mitochondrial disease and there are plenty of things that we could try, today.

If anyone knows if a list exists on the agents that have been tried during the nanoneedle tests and where i can find it, please PM me.

 

I second Robert. This is an excellent summary, actually brilliant. Thanks Simon.