Chris Ponting's project to replicate Mark Davis’s remarkable findings of immune activation in ME/CFS (S McGrath blog)

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A team led by Edinburgh University’s Professor Chris Ponting has won funding for a PhD student who would follow up and expand on remarkable recent findings made at Stanford University where Dr Mark Davis may have pinpointed a major issue in the immune system in ME/CFS.

Last year, Davis produced strong evidence of T cell clonal expansion, similar to that seen in illnesses including multiple sclerosis and acute Lyme disease. His discovery came from a new and sophisticated way of looking at the immune system in ME/CFS, that revealed the strongest evidence yet for immune activation in this disease. These results could indicate autoimmunity or a response to infection in ME/CFS, and could point to the core problem in the disease.


Human T cell (photo: NIAID)
So if the results of the PhD work are as hoped then they could narrow down the cause of ME/CFS for some patients. The ultimate aim is for this research to form part of a concerted effort that provides affordable diagnostic tests and targets for treatment.

The PhD will be based at Ponting’s Computational and Disease Genomics lab in Edinburgh. The £90,000 cost of the PhD will be jointly funded by Action for ME and the Scottish Government’s Chief Scientist’s Office. Samples from patients will be provided by the UK ME/CFS Biobank, subject to a successful full application to the Biobank.

Ponting has drawn in impressive collaborators for this project: senior immunologist Professor Georg Höllander from Oxford University and molecular biologist Dr Lia Chappell from the prestigious Wellcome Sanger Institute. I am pleased to say that I have also been involved with this study from the outset and the successful PhD candidate will engage with more patients as the project gets underway.

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Very interesting indeed - this sounds very promising and it's exciting to see a UK researcher jumping to try to replicate something good coming out of the US. I'd like to see more UK research joining in the international effort and trying to speed the whole enterprise up.

Thanks very much for explaining all this, @Simon M.

 

Very interesting, hopeful and clearly explained, thanks Simon.

How long is it likely to take to get the improved technology online?

So three years for a PhD, but will we have to wait until then or might something be published before that?

 

Nice that @Action for M.E. are funding some proper research for once too, btw.

Is this something that could lead to a cure though?

 

If the feature is already recognised in cancer and MS has it lead to any treatments especially in MS?

 

Glad you liked it!

Because the technology is still being developed, there isnt an exact timetable for when it will be up and running in this project. But if Chris manages to recruit a suitable candidate to start this autumn, the new technology could be being used late 2019 running into 2020.

I know that’s not as soon as everyone (including me) would like that’s how things look at the moment. Don’t forget, that this is a massive expansion of the original work by Mark Davies. The aim is to analyse 10,000 cells per patient instead of a few hundred, and many more patients.

The PhD candidate will be blogging and engaging with the patient community and I hope that will involve sharing results when they are available, so long as it won’t jeopardise publication (which would be an essential part of the candidate gaining a PhD).

 

At the Invest in ME conference today, Ron Davis announced that OMF would be funding Mark Davis to investigate this idea further as well.

 

One thing for sure - something is definitely going on here ...

 

Mark Davies is trying to find the antigen that he believes has set of the clonal expansion. That could identify if this is autoimmunity or driven by a particular pathogen. So if that checks eggs then it could lead to targeting the pathogen/autoimmunity and say potentially lead to a cure. That’s his hope, he said.

0MF recently announced that they were funding Mark Davis to continue other aspects of his work on T cells. Do you know if they said they would fund replicating T cell expansion specifically?

I don’t know. I believe that MS was chosen because Davis knew there would be clonal expansion and so makes a good reference. I don’t think it’s a new discovery.

Added: I don't know if T cell clonal expansion had been demonstrated this way before: it may have been detected more generally by flow cytometry and noting there were more T cells overall. The cure thing would depend on whether or not they can detect the antigen that provokes T cell clonal expansion, and whether or not that's something they don't already know (I'm not up on ms research).

 

Specifically talked about the clonal expansion work and used the same slide that you've used in your blog, the pie charts one, to show why it's worth investigating.

 

Sorry, my comment wasn't very clear. I really shouldn't post before I'm awake.

The OMF review on 25 May said:

The "click here" details.

Looking again at that, they are taking 25 patients and

Many studies have highlighted issues with the immune system in ME/CFS, ranging from altered cytokines to impaired NK cell function. Recently, Dr. Mark Davis’ team discovered evidence of clonal T cell expansion in ME/CFS patients – meaning that the killer T cells responsible for eliminating infected cells are making copies of themselves. Expansion happens when there is an active infection that the immune system is fighting, but it can also happen in autoimmunity, when the immune system mistakenly attacks the body’s own cells. Dr. Steinmetz’s team has developed new technologies to sequence single T cells and measure their gene expression. Understanding the behavior of these expanded T cells and what they are targeting will help us to better understand – and hopefully treat – ME/CFS. For example, it’s possible that some patients’ T cells are reacting to a microbial infection, and that some may have a truly autoimmune disease – which could in turn point to treatment via antimicrobials or immunomodulation.

To explore these possibilities, this project includes the following objectives, in a group of 25 ME/CFS patients this year:

1. Capturing and sequencing single T cells using these new technologies for identifying clonally expanded T cells and measuring their expression of thousands of genes, to understand their function in ME/CFS. The technologies were pioneered in tuberculosis patients, and the team is now hard at work optimizing them for ME/CFS patient samples.
2. Sequencing key immune-related genes: HLA and KIR. These genes – whose variants are associated with risk for infectious and autoimmune disease – are very difficult to sequence using traditional methods, so Dr. Ron Davis and his collaborators have developed better methods! Applying them here may help to interpret the other immunological data from this project.
3. Identifying the targets of expanded T cells. These may be infectious or autoimmune targets, and as described above, identifying them will reveal important insights into ME/CFS and its effects on the immune system of these patients.

So looks like they will measure clonal expansion in 25 patients, though it's not clear that they will use more cells than before (c300 per patient vs 10k per patient in the new PhD).

 

Is it known what sort of patients are to be tested? Given the smallish numbers involved it would be interesting, whatever the results, if patients from opposite ends of the spectrum could be identified, say one group with acute onset from an identified virus, and one group of idiopathic slow onset.

Probably one would want to subdivide each into groups of less than say 5 years duration, and those of more than 12.

Clearly such matters will have been considered by those involved in this group. Have they made any public comment?

 

Now wouldn't that be something. Yes, it sounds sensible that a good step will be to establish if the clonal expansion is in response to a real threat, or an autoimmune issue. Really promising line of research it would seem.

 

This is from another thread but thought I'd add it here. Would be good to understand why there isn't more funding for this study.

Also, I would guess Mark Davis' work will have progessed a lot in the next few years if he continues to get funding from OMF. Is there a fear that a PhD study which doesn't have a lot of financial backing might end up being too far behind?

 

Thread on the Phd funding here, https://www.s4me.info/threads/new-biomedical-phd-funding-t-cell-receptors-chris-ponting.4305/

My guess as to why there isn't more funding being asked for is because Chris probably didn't ask for more. I know that is a tautology but I guess Chris believes that, to replicate the work, one PhD is all that is needed. And given that it is replication work, I wouldn't have thought falling behind Mark Davis is an issue - even if he makes a breakthrough, it will still need to be replicated.

 

How's the Q&A coming along, @Andy? Any indication of when we can expect to see it?

 

Fingers crossed, in the next week or so.

 

Thanks again for all your hard work in setting it up. Looking forward to it!

 

Yes.

For clarity, the PhD is funded to £90k (half from AfME, half from the Scottish Chief Scientist's Office). Chris will cover direct costs for kit etc from his lab budget. I don't have figures, but wouldn't be surprised if the final cost is closer to £150k.

In addition, the core technology for this work is being developed by Dr Lia Chappell, a postdoc at the Wellcome Sanger Institute, in conjunction with Georg Hollander, an immunology prof. Both are putting in time in advance of the PhD student starting. I imagine the cost of their work, funded by Wellcome Sanger, would be considerable as well.

 

Here is @Chris Ponting talk from CMRC 2020 conference on the T cell receptor expansion research described by this thread. First results are expected at the end of 2020.



They are testing the null hypothesis in blinded samples that there is no difference detected between the four groups of study participants. I'm not quite sure why blinding is needed for a discovery project that might think of additional needed data as the projects progress, but if the blinded samples produce something significant it gives the results more weight. Seems a pretty cost effective project for research that is so complex.

Of note was that the same samples will be processed by another researcher to look at B cell data. Great to see this collaboration!

He credits @Simon M with introducing him to the topic via the OMF symposium talk given by Mark Davis. Thank you @Simon M