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Remarkable researchers hunting for ‘something in the blood’ of people with ME
- Thread starter Simon M
- Start date
chillier
Senior Member (Voting Rights)
It was a lot of fun talking with you @Simon M and quite an honour to be featured in your blog! Audrey and I have both been a big fan of your science, science communication, and patient advocacy for years, so this is wonderful to see.
We're trying our best to make sure it's a success - which to us means to generate a solid piece of evidence that can really point to whether the 'factor in the blood' is real or not. Then to go on from there.
Yes I hope that a positive result might increase our chances but I'm still unsure it would be enough to move mainstream funders sufficiently to be willing to support work in this field. I also hope DecodeME might help shift the ME/CFS research public funding situation more generally should they see a positive hit.
Thank you I'm glad to hear that
. This is exactly right. If we get a positive result but can't secure mainstream funding we hope we can persuade charities/others to support this work until the time mainstream funding is achievable.
We're trying our best to make sure it's a success - which to us means to generate a solid piece of evidence that can really point to whether the 'factor in the blood' is real or not. Then to go on from there.
Yes I hope that a positive result might increase our chances but I'm still unsure it would be enough to move mainstream funders sufficiently to be willing to support work in this field. I also hope DecodeME might help shift the ME/CFS research public funding situation more generally should they see a positive hit.
This is fascinating and promising-looking stuff and even I understood it!
What worries me about the funding is if a researcher is on a fixed-term contract and has to put in a new application to follow up a result - the time-gap might be enough to force them to take a different job. I hope the charities will speedily support this work if it comes up with a positive result.
Thank you I'm glad to hear that
. This is exactly right. If we get a positive result but can't secure mainstream funding we hope we can persuade charities/others to support this work until the time mainstream funding is achievable.
chillier
Senior Member (Voting Rights)
Yes good management of expectations, and as we see it a negative result is also an informative outcome. We deserve to know one way or another.
Yes, lots of studies looking for differences in the blood in the form of proteomics/metabolomics, ELISAs and so on, but not to specifically look for blood factors that are causing an experimental result such as this one.
It's conceivable to me that this hasn't been done due to a lack of resources. Separating the blood into various fractions based on size etc is not difficult in itself, but it requires you to rerun the assay every time with each fraction which could get costly and time consuming depending on the assay. The seahorse that we're using for example requires something like 9-15 replicates per sample so is possibly not the ideal assay for actually searching for the factor.
As for the factor itself, there's various possibilities for what the nature of it might be.
- It could be a single protein/protein complex or some other molecule (which you might expect (prote)omics to have picked up in the past).
- It could be a modified protein eg phosphorylated/cleaved (which proteomics is likely to miss)
- It could be the absence of something that is present in the healthy blood
- It could be multiple proteins/molecules that either work in concert or redundantly, which may also vary between patients but still leading to the same endpoint.
Audrey spoke with Karl Tronstadt at some point last year about this and other things. It's not my place to relay what he said but I think it's probably fine to say it's simply something that they haven't done, there's no concerning reason.
We're using the methodology they use in their 2016 paper of course, it's a replication after all. We're designing our specific plans and carrying out this work ourselves, on a different cohort, in a different lab with different equipment. As it's come up, we might run these plans by Karl if he wants to/ has time. It can only be improved by doing this.
Sasha
Senior Member (Voting Rights)
Great stuff, @chillier - I didn't realise you were a forum member. This is very exciting work and you explain the intricacies very well (I hadn't considered that something might be missing from PwME's blood, for instance, as opposed to us having something dodgy in it).
It's great that the timeframe on this is so fast, relatively speaking. Looking forward to getting results!
It's great that the timeframe on this is so fast, relatively speaking. Looking forward to getting results!
Thank you, @Simon M for the article and @chillier and Audrey for your work. It is such important work. We need to know whether the hopes that have been raised by several tiny studies about 'something in the blood' can be replicated.
In terms of funding, I would hope that UK government funding agencies should look positiively at any application for ongoing funding. If not, then surely the ME Association could fund the next stage. They seem to have large financial reserves and I can't think of a better project and researchers to continue to fund.
In terms of funding, I would hope that UK government funding agencies should look positiively at any application for ongoing funding. If not, then surely the ME Association could fund the next stage. They seem to have large financial reserves and I can't think of a better project and researchers to continue to fund.
Simon M
Senior Member (Voting Rights)
Sorry the blog went down for a while yesterday (not because it was overwhelemed, as far as I know).
It's great to see this response to Charlie and Audrey's work, and thanks for the kind words about the blog.
(I did my degree project in a lab where replication was the norm and the field advanced by finding stuff out, confirming it and building on it - like making bricks and building a house. I thought that was how sicence worked.)
Thanks again, Charlie (and Audrey) for all you are doing. I hope there will be a way for you to carry on doing it.
It's great to see this response to Charlie and Audrey's work, and thanks for the kind words about the blog.
And that is why it was such a pleasure talking to you and Audrey. You are going about this in a rigorous way aiming to find ut if something is real or not. Sadly, that is not the norm.
(I did my degree project in a lab where replication was the norm and the field advanced by finding stuff out, confirming it and building on it - like making bricks and building a house. I thought that was how sicence worked.)
Another reason to be impressed. One problem with repelication is that the repeat study may have changed the method is small but significant ways, and this minimises the risk.
Ah, I hadn't clocked that.
Thanks again, Charlie (and Audrey) for all you are doing. I hope there will be a way for you to carry on doing it.
Thank you for your insights, @chillier !
Have you considered using PEM samples for your projects and to compare them?
I can not really say a lot about it, but I have funded some proteomics work (with a very small sample size; results remain unpublished so far) in the past, and the conclusion was that without 'good day vs. bad day samples' they would have been unable to find any (potential) signal.
If you have the option, it might be advisable to use PEM samples, at least in a subset of your cohort. You could either use Moreaus's PEM inducing technique or just ask patients to get blood drawn when they have PEM, if a more standardized approach is out of reach.
I don't know whether or not Tronstadt controlled for PEM, but either way, not controlling for it could make readouts less reliable?
Thank you for your work.
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Agreed. Comparing the same patients before and after inducing PEM would not only ensure that every single participant actually has ME, but it would show if the ME biomarker is really a PEM marker.
And I'd control with non-ME deconditioned people, like fatigued cancer patients, before and after the same exercise.
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Grigor
Senior Member (Voting Rights)
There's also a couple of collaboration with the Netherlands that are working on it as well but I agree that I wonder why they didn't do it themselves before. I'm not sure how costly it is.
https://www.linkedin.com/safety/go?...llen-bij-mecvs&trk=flagship-messaging-android
Jonathan Edwards
Senior Member (Voting Rights)
Maybe it's TGFbeta after all.
It was the one cytokine to actually show up in some studies.
It is a mediator of repair and tissue strengthening.
It is a potent modulator of T cell function.
It gets invisibly painted on to tissue matrix so that tissues can 'remember' how to respond over long periods.
Or of course it might be TGFbeta's best mate.
It was the one cytokine to actually show up in some studies.
It is a mediator of repair and tissue strengthening.
It is a potent modulator of T cell function.
It gets invisibly painted on to tissue matrix so that tissues can 'remember' how to respond over long periods.
Or of course it might be TGFbeta's best mate.
chillier
Senior Member (Voting Rights)
Echoing this thank you everybody for your kind words
Not for this project. We recruited/collected from Sheffield with our collaborator Caroline Dalton and prioritized getting as large a sample size as we could over selecting for whether they were currently in PEM or not. We anticipate that there might be more variance in the ME cohort than the healthy controls and PEM could be a part of that heterogeneity - amongst other things. We collected more ME patients than controls (roughly 60:40 ratio) for that reason. Tronstadt did not control for current PEM status at the time of sampling in their 2016 paper.
I agree it would be really interesting to see work done that looks at PEM and related things such as longitudinal sampling, response to exertion/exercise, or good day/bad day sampling.
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U
Understood, thank you.
If you see a realistic chance to include a small PEM pilot cohort, and if it’s just 5-10 samples, and if you think it’s a good idea, I might be able to help you with funding for it.
In such a scenario, please reach out via DM and let me know what you think (a good guess would be enough for now) what kind of funding volume would be required.
If for whatever reason it’s not realistic, just ignore this message, and all the best for the project as it is!
Thank you!
Echoing this thank you everybody for your kind words
Not for this project. We recruited/collected from Sheffield with our collaborator Caroline Dalton and prioritized getting as large a sample size as we could over selecting for whether they were currently in PEM or not. We anticipate that there might be more variance in the ME cohort than the healthy controls and PEM could be a part of that heterogeneity - amongst other things. We collected more ME patients than controls (roughly 60:40 ratio) for that reason. Tronstadt did not control for current PEM status a the time of sampling in their 2016 paper.
I agree it would be really interesting to see work done that looks at PEM and related things such as longitudinal sampling, response to exertion/exercise, or good day/bad day sampling.
Understood, thank you.
If you see a realistic chance to include a small PEM pilot cohort, and if it’s just 5-10 samples, and if you think it’s a good idea, I might be able to help you with funding for it.
In such a scenario, please reach out via DM and let me know what you think (a good guess would be enough for now) what kind of funding volume would be required.
If for whatever reason it’s not realistic, just ignore this message, and all the best for the project as it is!
Thank you!
Ravn
Senior Member (Voting Rights)
Those last two are possibilities have been haunting my thoughts for a while. Partly because if it was a single something you'd think somebody would have at least narrowed the field down by now, though I take your point that some somethings are harder to find than others
One thing is finding something, another is finding an absence of something, especially when there are a lot of potential somethings in the blood that could be AWOL. How would you do that, technically speaking?
But a single something wrongly present or wrongly missing would, once identified, have a huge target on its back. If pharma doesn't get interested then I don't know what would make them take notice
On the other hand, the very real possibility that it could be multiple combinations of multiple factors that ultimately all converge on same endpoint just ties my brain cells into knots
Anyway, very happy to read about your efforts - and thanks for writing about them @Simon M - and your rigorous approach to trying to finally give us a yea or nay on the question if the something in the blood finding replicates. I'm almost getting speed wobbles reading about your project, not used to ME research moving so fast
Another question just popped into my head: have similar experiments - expose some cells to patient vs healthy blood/serum - been done in other conditions?
I would assume it fundamentally doesn't change much. They whittle down both healthy and sick blood to smaller and smaller subsets of weight or type. Subsets which still have different effects on cells.
Maybe they eventually see that the effect is still evident when both samples only have small sized proteins. They have a much smaller pool of options to do specific tests for, so they check if the healthy blood has some specific small sized proteins that the sick blood doesn't and vice versa.
wigglethemouse
Senior Member (Voting Rights)
On Twitter I asked Karl Morten why his initial muscle cell + patient blood experiments looked so promising but the follow-up was negative. This was the response.
"We used plasma initially. There is a huge complement affect on primary cell models. 5% plasma kills HUVEC cells. The serum affects are very large on a range of parameters. I feel the complement plasma affect was masking the ME/CFS factor affect and also causing the variation."
"The model is challenging to set up. Sheeza set it up in Oxford and we saw similar affects on oxygen consumption. The work will need a large grant with the Barcelona group very involved. Our new PEM study will provide serum for testing. This still needs ethics."
@chillier
"We used plasma initially. There is a huge complement affect on primary cell models. 5% plasma kills HUVEC cells. The serum affects are very large on a range of parameters. I feel the complement plasma affect was masking the ME/CFS factor affect and also causing the variation."
"The model is challenging to set up. Sheeza set it up in Oxford and we saw similar affects on oxygen consumption. The work will need a large grant with the Barcelona group very involved. Our new PEM study will provide serum for testing. This still needs ethics."
@chillier