List of causation hypothesis for follow up after DecodeME

[Kiristar]

Coming back up out of the detail we could really do with leveraging the Decode ME and other recent findings and working out a research roadmap which we could perhaps refine at the showcase event to develop the what next plan?

Someone on the initial findings thread suggested developing a list of hypotheses, which feels to me like the next step towards that.

So I thought I would create a new thread so any hypothesis ideas don't get lost in that very detailed thread.

Hope that is a workable approach and makes sense to people ....?

 

[V.R.T.]

I think it would be worthwhile to talk about the hypotheses or areas of investigation we find the most compelling. An offical S4ME list could perhaps be contentious and require a vote to make it fair, but at least in an informal fashion i think it would be a good idea.

 

[V.R.T.]

My original post in the main DecodeME thread that was referenced in Kiristar's post above, for reference.

Another thought: Would it be worthwhile to create a list of the hypotheses we think are worth pursuing, both by members here and by others? In a members only post or even a private group. We could then speculate on what experiments could be done to validate/falsify these hypotheses.

 

[V.R.T.]

The comment i was replying to

My feeling is we urgently need to be thinking of ideas and hypotheses, however half formed, so we can bounce them around the forum and elsewhere and come up with reasonable ideas of what experiments to do next, besides more genetics.

 

[Jonathan Edwards]

My view on this is that there are some broad hypothesis options worth highlighting in the wake of DecodeME and some maybe to put aside.

1. The potential significance of a gamma delta T cell related gene strengthens the case for more functional T cell studies along the lines that Jackie Cliff has been exploring. Forgetting the FcRI idea from our Qeios paper I think there is a case for 'a little more T cells'. The hypothesis would be broadly that by analogy with psoriasis or Reiter's syndrome ME/CFS is at least in part a persistent T cell activation problem, maybe most likely involving rather 'innate' populations like MAIT or gamma delta. They would need to some sort of 'covert' population in terms of their trafficking and effector role. (The paper posted here on MAIT cells going to meninges is intriguing.) The practical idea would be to replicate the sort of work Jackie has been doing with a focus on looking for priming of circulating T cells. Looking for T cells in the head might be justified but I doubt it would be easy.

2. The CA10 locus, apparently shared with chronic pain suggests that there may be a susceptibility to an amplification loop involving synapses that is relevant both to pain and other ME/CFS symptoms. How you investigate that beyond more refined genetics I am not sure. I just wonder whether it would be worth looking for links with migraine on the basis that that seems to be another situation where a brain loop generates signals that should not be there.

3. Where 1. focuses on T cell overactivity and maybe interferon gamma production I think the idea that interferon alpha acting locally might be more important long term, perhaps from dendritic cells or from 'trained' tissue macropahges or microglia is worthy of attention. As jnmaciuch has pointed out, this might make sense of several DecodeME hits. Microglial activation studies make sense, even if I am pessimistic that they will show much with current methods.

Areas DecodeME would encourage me further to move away from include autoantibodies, mitochondrial energy supply and persistent viruses. (Jackie's focus does involve persistent herpes viruses but I think the significance of her studies may go beyond any specific relation to herpes.) But there's no surprises there.

 

[V.R.T.]

The research and hypotheses I am most interested in currently:

The Edwards/Cambridge/Cliff Hypothesis, if it still stands post DecodeME, and whatever emerges like a phoenix from its ashes if it doesn't.

@jnmaciuch's interest in type 1 interferons, and interferon as a possible lead generally.

Fluge and Mella's ongoing work on Daratumumab and llpc depletion.

Paul Hwang's work on wasf3.

The recent 3d skeletal muscle paper by Mughal et al.

 

[wigglethemouse]

If there is persistent T cell activation would we expect to see more gramzyme B and perforin in the blood? I think from studies certain T cell types don't make as much of the two when tested in the lab.

According to the Selin lab only a subset show gamma-delta T cell differences. I suspect identifying subsets and testing longitudinally will be important in researching T cells. There is also the debate of fresh vs frozen cells and sorting methods and how they affect results. It's not as easy as it sounds to do a deep dive with large sample numbers. I'm sure what Dr. Cliff learns about longitudinal sampling will be helpful for others moving forward.

Anyone know if Dr Selin and Dr Cliff meet up to brainstorm T cells? Might be worthwhile given the DecodeME pointers.

From my experience of being a research subject it takes a lot of tubes of blood to have enough of some of the rarer type T cells......

 

[jnmaciuch]

The paper posted here on MAIT cells going to meninges is intriguing.

It has nothing to do with trafficking, unfortunately. MAIT were found in the meninges in healthy conditions, as were other T cell subsets. It was the lack of MAIT that lead to increased meningeal barrier permeability, which they said was due to a lack of MAIT-secreted free radical scavengers (where ROS seemed to interfere with cell-cell junctions in the barrier). And they showed nothing about T cells crossing the barrier themselves.

 

[Kiristar]

But why only hypotheses? For a Roadmap couldn't there be also be a host of sensible genetic work or follow-up work that can also be entirely hypothesis free?

I was just thinking that projects test hypotheses so was thinking you'd start there then move to designing projects as an outcome of knowing what we need to answer next. But if a different method to get to the projects works I'm all for it.

 

[DMissa]

I am intending to look along the lines of how specific mechanisms that may lead to altered ER-mitochondria interactions (including by biogenesis or phagy of either, lipid content of or lipid shuttling by either, calcium storage or mobilisation, etc) may interact with activation of or signalling by particular immune cell subsets. But this depends on funding. I have samples, collaborators, techniques and facilities in place to do all of this but need $ to do it. Writing proposals.

PS i already have a funded study (halfway in) that’s looking at T cell activation in collaboration with T cell experts. stay tuned

 

[ChronicallyOverIt]

@DMissa not sure if this is the right place to post this, but if you’re doing any high throughput screeen automation I’m happy to donate my time. I’m an automation engineer with 7+ years of experience in biotech specializing in high throughput screening on liquid handlers: Hamilton, Beckman (Bravos & echo), Tecans, thermo-fisher work cells, and custom integration work cells.

I’ve ask OMF in the past but have learned it’s cheaper outside of biotech to just hire grad students to pipette instead of buying robotics. If anyone working on CFS needs automation consulting happy to donate my time.