United Kingdom: ME Research Collaborative (MERC) [was CMRC] news

I don't think this is realistic Adam. What 'proper treatments' did they get? I don't know of any positive trials. I don't know about scans but the biopsies fizzled out because nobody could reproduce the findings. I am afraid I think it was all over-enthusiasm. We are now in a situation where genuine science is being applied. Most of the findings are negative, but at least the quality control is there.

 

I am not sure what you mean by a front for the MRC. The MRC does not do fronts as far as I know. Steven Holgate is, as I understand it, someone who has very successfully played the game of getting money from MRC in the past. He had an interest in ME and thought he would try his hand at helping ME researchers get MRC funds. The MRC is an old boys' club so that makes sense. As far as I can see he has not wanted to work on ME himself.

Faced with this task he lobbied for more biomedical research, as everybody wanted. He got some money ring fenced. The problem then was that although a few groups put in small indirectly related projects nobody actually had many ideas of what to do in the way of biological research, because there were no leads to follow. So relatively little was achieved. That was not Holgate's fault. It is a reflection of the fact that nobody knows where to start in ME, or at least where there is likely to be good pay off without doing a huge fishing exercise like MEGA.

Holgate was playing politics and I have no doubt that can be productive but it often means you have to compromise. The network was dominated by the psychiatric lobby and excluding them might well have meant that Holgate's project was stillborn. I do not know. I think he could have been much more singleminded, but at least he got something off the ground and got some funds for people like Ann McArdle and Julia Newton. I find it hard to believe that Holgate is himself a hard line BPS enthusiast. Why would he lobby for biomedical research if he was?

So things got very slow and I think Holgate made some mistakes in backing certain individuals. So that when the next logical step came along things did not fly. The next logical step was a big fishing exercise - called MEGA. It was exactly the right thing to try to do but was floated before it had been thought through.

In the meantime the LSHTM UK ME Biobank has had a second big grant from NIH and is getting samples out to people all over the world. The biggest error with MEGA was in duplicating the proposals form LSHTM instead of collaborating.

The situation now is very different. There is every prospect that first rate people with complementary skills will get together and attack ME directly with a well designed programme. Things may not be perfect but I would ask people what they think should happen that is not happening. There are very few clinicians in the UK with enough scientific training to head up useful ME research. Without that clinical base you will get pseudoscience. You cannot just buy in an amazing research programme with a £20M grant without people who know what they are doing.

I have disagreed a bit with Simon M about tactics over the last couple of years but I completely agree with him now. Hopefully we are on track.

 

That's not the full story @Jonathan Edwards and is an example of what I said above about the role of patients and families.

Stephen Holgate chaired the CFS/ME Expert Group, set up in 2008.

Early 2011 the MRC announced ringfencing of £1.5m (later increased to £1.6m) in response to a short Westminster Hall debate earned by EDM 778 (http://www.parliament.uk/edm/2010-12/778) tabled by Ian Swales achieving over 100 signatures, instigated by his contituents, sufferer of severe ME since her teens, Jan Laverick and her mother Margaret Laverick, and action by patients and families asking their MPs to sign.

The lion's share of that MRC funding was granted to Julia Newton.

The ringfenced amount would be nowhere near sufficient for the task and we patients knew the history of how grant applications for biomedical studies were unsuccessful and not because of poor quality as the same researchers got MRC grants for other projects, so we patients didn't stop there, we launched the Let's Do It for ME campaign a few months later (July 2011) and the money we helped raise includes funding of the B cell studies led by Jo Cambridge at UCL as well as the gut studies at Norwich Research Park.

Please watch this regional ITV News clip which features Jan Laverick, she is responsible for a great deal of positive activism, what I call one of our community's undercover agents for change as she is mostly bedbound.

https://www.youtube.com/watch?v=CalHKUZvYAA

(edited post to correct typos)

 

But one would not expect a pump priming injection of ring fenced money to be sufficient to solve an illness. Pump priming is designed to lower standards required for applications to at least get something started - no more. And I think we can be sure that applications were of low quality or at least low priority. I was at the meeting where the projects from the ring fenced money were show cases. I had lunch with Professor Maria Fitzgerald (UCL neuroscience) shortly after and we agreed that none of them was first rank. None would normally have got MRC funding. The great majority of research projects into ME are really not very good. And the MRC does not pretend to provide a comprehensive research programme for all illnesses. Most illnesses depend on charities to fund research.

 

Thanks, Jo. Where we have disagreed, it’s only been over tactics, not the overall goal of getting much more, high-quality, biomedical research.

 

That's pretty much what I meant by saying "The ringfenced amount would be nowhere near sufficient for the task" but this was the first time the MRC had awarded any substantial funds for biomedical research into ME (@Graham has the figures on this I believe) and many patients saw this as a breakthrough and the start of decent funding for biomedical studies to follow on from this (just as they were hopeful on CMRC in 2013).

That isn't at all surprising because I wasn't referring to those grant applications, I said "we patients knew the history of how grant applications for biomedical studies were unsuccessful and not because of poor quality as the same researchers got MRC grants for other projects".

I will try to find the source/s for this. ETA: Gibson Inquiry (thanks Graham)

I know this and it's consistent with what I said about patients and families getting on with funding the studies they want to see done (and having made the contacts with researchers to enable the studies to be proposed).

 

But there is one aspect of MRC funding that is relevant: their attitude towards biomedical research. It's fine to claim that the applications were of poor quality, but remember that the Gibson enquiry named three experienced researchers that had had applications rejected (it is impossible to get a proper list). One of them, Jonathan Kerr, said that his applications (note - plural) generally came back with scores of 9, 8 and 3. That smacks of very poor assessment techniques and suggests prejudice. If there are agreed criteria, and if the assessors understand what they are looking for, then gradings should be consistent. If not, the process is open to abuse. If my maths dept had ever come up with a contradiction in assessment grades like that on a project, I would have been very worried. You don't even get that much variation in Strictly!

If the perception from universities is then that such a prejudice exists, they will steer good researchers away into more likely areas.

Remember that the MRC set up a committee to look into this in 2010: they still haven't cracked it. A one-off grant in 2011 didn't do it either.

I suggest that the only way ahead is for the MRC to set aside a reasonable amount of money, guaranteed for a number of years, with a roll-over if insufficient good applications aren't there, for biomedical research.

Don't forget NIHR though: they spend about the same on research, and it's only recently that they have funded any research into ME - and that on Crawley.

Our other big research funder, the Wellcome Trust has, I think, only funded one psych study.

We do fund research ourselves, but considering so few of us work, and that, over time, our contact with well-off workers diminishes, it would take us a very long time even to match the £5 million spent on PACE. I'm afraid that only by putting their money where their mouth is, will the MRC and NIHR persuade good researchers that they have conquered the prejudice and that this is an area which will be funded.

 

We all have the goal of getting much more high quality bio research. It just hasn't happened.

Obviously in uk there's many obstacles which imo is why funders should have put in some continuous funding , I'm sure Newton, Bansal, even the biobank resesrchers could have done some good with it and who knows more good scientists like prof nut might have taken the bait, whatever happened to the xyrem research?!. And I agree with graham, good enough research was turned away, the Scottish Gow gene study nearly fell through as it struggled to get funds and PhD students trying to do studies couldn't sustain funding.
OR the CMRC could have done what the IOM did and focused on more ME than fatigue and so on to make the illness area seem more serious and appealing. I'm not surprised no one wants to study CFS with the current narrative and thinking people would just come across without easy picking funding incentives was naive.

I think Holgate possibly meant well but took the wrong approach with a big tent mainly focused on fatigue and I always felt like it was just dabbling around in hope rather than professional determined, powered effort of the type dementia or MS get /would get. However the me expert group did waste years, Holgate did seek wesselys advice, support wesselys in the press, suppprt Esther till the end, put white on the CMRC, go to mass media on CBT and fitnet and insist on broadest criteria when the General movement was refinement, there was fixation on mega and little else in the end years. I've not seen the CMRC really accept ME as systemic disease defined by exertion issues , the work they funded by Anne McIntyre was on Oxford criteria and the severe largely ignored. They got no funding extra, except the £200k for one study. So state funding for CFS biomedical research per person over 2012 -2018 is about 20p. It stinks.

I don't really get the whole relationship of CMRC with the MRC but certainly my letters to the MRC had replies which were always defended by the existence of the CMRC, the conferences etc as evidence that yes we are doing something, you got £1.5m in 2012 and content yourself with that. So the MRC see the CMRC as their CFS effort, if that's just because a representative attends the meetings idk.

I Fully get why people just want to be positive now, especially those not directly affected or newly involved. Let's hope round 3 finally starts something without more years blown deciding priorities, waiting for reports or setting up further structures.

It's fine saying the MRC usually leaves illnesses to charity but we could demonstrate from the 90s that that just wasn't working with ME and needed exceptional measures. Even today, The name , stigma and exercise cure hype make CFS extremely unappealing in public fundraising. The ms society currently fund 60 odd, big and small projects, some co funding, with figures to the tune of £19-20m currently funded projects , our charities combined about ten often small, with uk research total funds currently, mainly thanks to NIH American, perhaps currently totalling £2-2.5m, without NIH less than £1m. We needed help and got a small gesture, happy to make small starts and plod along. . The charities DID ask for continued ring fenced funds, sir Peter Spencer' AFME said it was vital and that what had been given was tiny compared to need, MRC just said no.

 

I believe that Adam said 'treatment' in the singular and that the treatment for ME known to be of best of effect in the 1980s was rest?
Simon Wessely understandably, albeit misguidedly in the case of ME, was concerned about this if memory serves me?

 

Thank you @Graham.

 

Actually, I forgot to add, the original MRC committee was set up in 2002 following a critical Chief Medical Officer's report. It was reorganized in 2006 after the Gibson report, and that was when Holgate took over the reins, so in that sense he has been running the show for 11 years. There's not a lot to show for 11 years.

Attempts have been made to find out who has made applications to the MRC to research ME over the years, but this is not available. One reason they give is that unsuccessful applicants would not like it to be known that they failed. This is why they set a 70 year embargo on it (they said), which means that an 21 year-old who fails to get a grant won't get embarrassed until he or she is 91. I think that shows a level of compassion that we didn't know they had. Well, either that or they don't want to air their dirty laundry.

I did put in a formal complaint to the MRC and one point they made was that generally the success rate for funding is rarely more than 25%. In the period 1996 to 2015 they received 84 proposals: off the top of my head (where there isn't a lot) I think they funded around 12 studies, around 14%.

 

Gosh @Graham, the Gibson report! i forgot all about that. I thought that would really make a difference. Ugh countless times i thought, 'oh we're really going to get somewhere now' the tide is turning, in fact all that's happened is a ruddy tsunami coming into shore instead.

I'm encouraged by @Jonathan Edwards' comments & perception of the state of play. But i cant take the disappointment any more, so i'll believe it when i see it.

 

I think people are unaware of just how good a research project has to be to warrant MRC funding. The system is far from perfect, and what gets funded is not always what ought to but if there were proposals in ME that have not been funded but were up to the sort of standard expected I have not heard of them. I never had MRC funding in RA,nor did anybody else much. The MRC is there to fund obvious winners. For the creative innovative stuff scientists have to scratch around wherever they can.

I have reservations about Holgate's tactics but at least he has tried to get the MRC to look at biomedical research for ME. And it may come to fruition now. It is not his fault if there are no proposals of adequate merit. It is nobody's fault. It is just that there are so few leads in ME that nobody can think of a cast iron project.

 

So, just like with the NIH, there is no funding available to establish basic facts? So we are still caught in the catch 22 situation of not enough is known about ME to be able to create research submissions of sufficient "standard", and because biomedical research doesn't get funded, we aren't able to find out about ME?

Edit: Remove an unwanted word.

 

Yes, I think that is a fair summary, or at least has been up until now.

The MRC and NIH have always put a lot of money into establishing basic facts about normal functioning of body systems. So the way the normal immune system responds to foreign material has had huge investment. The way the kidney control fluid balance has had huge investment. There has also been investment into disease processes where there is an obvious lead. Cancer is obviously about uncontrolled growth due to mutations - which could be seen as chromosome distortions a century ago. Diabetes is obviously about sugar and fat metabolism.

But it is only very recently that there have been deliberate attempts by government bodies to try to tackle problems where there is no obvious lead. Even in autoimmunity the MRC never really got involved. So individual scientists had to piece together the puzzle on their own.

Alzheimer's might be the new model - there has been a deliberate attempt to address it despite it being hard to see where to start. But even Alzheimer's has histopathology known for a century.

What has only recently change is that there are technologies for screening vast numbers of potential markers of causation - either whole genome studies or metabolomics or whatever. This is not an intellectually attractive approach - it is what used to be called blunderbuss science - but it may be the only way in for something like ME and it has had some (modest but highly advertised) successes in other diseases. The biggest pitfall with this sort of approach is that you can spend years measuring millions of data points that mean nothing because you are sampling something irrelevant.

So for the first time we are ready to tackle ME in what people call a 'hypothesis free approach'. And I think that is going to happen. The UK ME Biobank have been patiently working through immune system cells using properly sourced patient and control material. In the USA people like Hornig and Davis and Hanson and Unutmaz have been sifting through large amounts of data. I personally think there is too much attention to microbes. I doubt they will tell us much, but the negative data on viruses from pretty much all the groups now useful to have.

At the moment the systematic work in the UK is paradoxically funded by NIH. There is every reason to think the MRC and Wellcome could step in and help with establishing long term infrastructural support. The recent problem has been unnecessary overlap rather than collaboration. I have reason to think that may now change.

It became possible to understand RA in around 1990 for a very specific reason. The genes for the cell surface ligands that mediate the disease had mostly been cloned in the late 1980s. It was a bit like having access to the picture on the box to help put the jigsaw bits together. I strongly suspect that the tools needed to deal with ME have just not been available until now.

One thing I would hang on to though is that you are much more likely to be successful on a fishing trip if you have some idea which bit of water has fish in. And for diseases that comes from have a very clear idea of where you think in the tissues symptoms are arising. In ME people have suggested muscle or brain or immune system but I am not sure scientists are listening carefully enough to the patients to read the symptoms right.

The technique that i think ought to be useful in ME, and which has been around for forty years but apparently to much used is Magnetic Resonance Imaging. That gives you a profile of hundreds of molecules actually in the tissue while the symptoms are there. I would like to know simple things like the MR spectroscopy data on muscle lactate during rest, exercise and also during PEM. It should not be necessary to deliberately induce PEM. You just have a bank of patient volunteers who can ring the lab when they have PEM and a dedicated and thorough doctoral student who can come in at weekends to do the measurements. The sad thing is that quite often things like this get done but never published because of important but negative findings.

 

I have lost count of how many times I have heard this sort of argument, and I'm a relative newcomer.

There is nothing to suggest this time will be any different, other than blind hope.

Going on past performance, which is all we have to go on, I don't see how anyone can get enthusiastic about this.

I want millions for research as much as anyone but getting people's hopes up by throwing out words like dementia and platform, is wild speculation.

It reminds me of corporate statements where buzzwords are thrown around that dont actually mean anything, but sound impressive to those who don't know any better.

I don't want to appear negative, I am just not getting excited, I don't believe the hype. I think that's justified at this moment, but as soon as a high quality biomedical research study is funded I will certainly appreciate it. Just don't ask me to cheerlead for something before I know what's happening.

 

Very interesting! How could that be made to happen?

 

Thanks for the detailed answer.

To my, perhaps wonky, logical thinking, while this is welcome news, if they won't fund systematic work what is the point? It could be exactly like building the physical structure of a UK ME/CFS Collaborative Research Centre, but refusing to fund the research that is needed to find out about ME. Or is the idea "build it and they shall come", which seems all to speculative to me?

And talking of CRCs, how about taking up some of the reasonable research ideas that weren't funded by the NIH and/or looking to support the research being done at the existing CRCs? Though I suppose there are plenty of real world reasons why a seemingly logical approach like that wouldn't actually happen.

 

Another rejectee was a Principle Fellow of the MRC, another reason why people doubt that the applications were of such poor quality.

Quoting from the Gibson Report:

Biomedical applications in respect of CFS/ME known to have been rejected include those by Professor Jill Belch (herself a Principal Fellow of the MRC) and Dr Vance Spence of Dundee, as well as Dr Jonathan Kerr of St Georges, London.

The Minister indicated to the inquiry that few good biomedical research proposals had been submitted to the MRC in contrast to those for psychosocial research. We have however been told of proposals that have been rejected, with claims of bias against support for this type of research. The MRC should do more to encourage applications for funding into biomedical models of CFS/ME. The CMO’s Working Group report came out in January 2002. Despite paying lip service to the need to advance the understanding of CFS/ME, the MRC itself has confirmed that from April 2003 to date, it has turned down 10 biomedical applications relating to CFS/ME because they considered they were not of high enough scientific standards to compete against the many calls on its funds. These included applications under the headings of pathophysiology, genetics, biomarkers, immunology and neuroimaging.