A Dozen Different Diseases? Stephen Holgate Calls for Radical Change in ME/CFS Research

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Professor Stephen Holgate says ME/CFS is a spectrum of disorders that need to be understood through new approaches, and patients must be partners in research. Simon McGrath reports.


Houses of Parliament, site of Prof Holgate's talk

ME/CFS probably isn't one disease, or even a few different ones - but could be as many as fifteen. So said Professor Stephen Holgate, Chair of the UK Research Collaborative (CMRC), when he addressed the Forward ME Group in the House of Lords on 2nd July. He also argued that a radical New Science was needed to tackle ME/CFS and said patients must be partners in research. Not bad going for one talk.


More than a dozen different diseases?

Most researchers believe ME/CFS is more than one disease, and quite a few believe even ME is more than one, but I was surprised when Stephen Holgate said that ME/CFS could have twelve to fifteen different 'causal pathways'. That's an awful lot of different illnesses mistakenly lumped together in one pot. I asked Stephen about the number and he said that at this stage nobody knows for sure, but it's highly likely to be fifteen or even more disease process, given it's such a heterogeneous condition. There are, he mentioned, fourteen different causal pathways in Breast Cancer, seemingly a far more uniform illness. However, he added that some of the ME/CFS causal pathways will probably be interlinked, so it could come down to five or six underlying disease mechanisms. That would still be half-a-dozen different diseases - and it could yet be more. Stephen refers to ME/CFS as 'a spectrum of disorders' and has said that looking for the cause is a lost cause (Nature Reviews: Neuroscience 2011).


New Science needed



With such complexity, it's perhaps not surprising that little progress has been made to date. Professor Holgate said some researchers new to the field had been shocked by the poor quality of much ME/CFS research, and even commented that some had 'made a career' out of ME/CFS theories that could be shaky.

Also, while medicine has made great progress in many areas, it has been struggling to tackle the remaining problems, particularly chronic illnesses. A fundamental issue, he said, is "the breakdown of the linear relationship between cause and effect". That was a bit over my head, so I asked him to elaborate: he's always been amazed by the ability of our bodies to restore themselves in response to adversity, such as an infection - either compensating in part or restoring normal function. He believes that the complex networks responsible for this ability of the body to restore itself have gone awry in ME/CFS, and perhaps other chronic illnesses too.

He says the only way to tackle such a complex problem is, ultimately, to track down and understand the individual causal molecular pathways: if you know the pathway you know the way to deal with the disease, and that was the way to get the drugs industry involved. Identifying the pathways is a big challenge, but Stephen Holgate believes that now is a fantastic time to study ME/CFS as new techniques emerge that are up to the job.


Mega-study planned: 5,000 patients

To have any hope of identifying many different diseases (or causative pathways) within the umbrella definition, a lot of patients are needed; and there are early plans for a study involving a 5,000-strong cohort of patients. The idea is to explore everything: phenotypes, genotypes, gene expression, cells, cytokines, metabolites and more. Some of these individual features have been researched before, but not all together: and never on such a scale. High quality scientists would then have to be involved to look at applying the new technologies to the data generated from patients. But there has to be a multi-disciplinary approach, and nurses, for example, would be just as important as mathematicians in this operation.

New computer technology would be used to probe the mass of data, with the aim of finding distinct groups of patients who 'cluster' together with similar features, which should make it easier to home in on different causal molecular pathways in different types of patients. It is identifiying causal pathways that will lead to a much deeper understanding of ME/CFS and, hopefully, provide targets for drug therapy too.

Stephen Holgate’s vision for ME/CFS research requires a radical change. The majority of research funded in the UK to date assumes that whatever triggers ME/CFS, it is perpetuated by patients’ flawed beliefs and behaviours. The new approach focuses instead on differences between patients, to see what this might reveal about different underlying causal mechanisms. Though of course, as yet, nothing is proven. Also, if he is right, and there are up to fifteen different causal processes involved, it might explain why biological findings have been inconsistent across the small-scale studies we have seen to date.


Patients as Partners in Research

• breakdown in trust patients to help shape research agenda

Stephen Holgate acknowledged that over the years there had been a breakdown of trust between patients, healthcare providers and researchers. He wants to change that, pointing out that in most areas of medicine the patient voice was now valued and recognised. (Read about the growing Patient Revolution here.) The ME Association's Dr Charles Shepherd said the new CMRC Executive wants patients to attend meetings so that they could meet researchers. Holgate added it was also so patients can help set the research agenda - wow!

Patients, charities and the public must come to the CMRC's Annual CFS/ME Scientific Conference, which starts next year (details yet to be announced). He would like to set a half-day aside for patient involvement, but is discussing with charities how best to do this.

With plans to engage with patients in setting the research agenda, and a new approach to research, we could well be at the start of a new era in the UK for the understanding of ME/CFS.


A man who likes a challenge
Not many scientists choose to work with ME/CFS. Even fewer when, like Stephen Holgate, they already have impressive careers (he's made several key discoveries about asthma for example). But Holgate positively sought out ME/CFS research and its politics.
He told the former Chief Executive of the Medical Research Council (MRC) that ME/CFS was a problem that needed sorting out - and was promptly asked to attempt just that. He began in late 2009 with a workshop and the MRC Expert group on ME/CFS, which ultimately led to MRC grants of £1.6 million ($2.3 million) for biomedical research in 2012. It was followed by the launch of the UK CFS/ME Research Collaborative (CMRC) earlier this year, endorsed by the MRC and two other major research institutions.
So Stephen Holgate gets things done, but why did he choose to get involved? In an interview he revealed that what he most loved about being a scientist was new challenges, particularly helping others who deal with "complex issues around complicated diseases" - a nice summary of ME/CFS, which he gave as an example.
Asked what he would like to be remembered for as a scientist he replied:
"That I was prepared to listen and take on difficult challenges and continue even if prevailing opinion was against me!"

This could be just what the field needs.
Stephen Holgate is the MRC Clinical Professor of Immunopharmacology and has been a visiting professor at both Harvard and Yale universities in the US.


Note: unfortunately I wasn't at Forward ME Group meeting, and wrote this from the extensive meeting minutes, with some additional information from Stephen Holgate himself. Any errors are my own.

Simon McGrath tweets on ME/CFS research




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Comments

Great article, Simon. This is a very positive development. I bet we'd all like to be one of the 5,000 volunteers!

Has there not recently been a CAA-funded study that attempted to define groups of patients by clusters of symptoms? I can't remember the data source or the number of patients involved.

I like Prof. Holgate's strong push towards biomedical research and his wish (and the CMRC Executive's) to involve patients in setting the research agenda. These are all very positive signals.

If anyone is reading the article on the home page, you may overlook (as I did) the sidebar giving an interesting bio of Prof. Holgate - if you missed it, have a look. It makes it very clear we're extremely lucky to have him.

Thanks again, Simon.
 
Thank you Simon for the hard work writing this article. I am impressed with Dr. Holgate's willingness to tackle this complex disease. I like the large scope and scale of the suggested study. It seems true that the latest findings and thoughts about ME/CFS point to the fact that it might not all be one disease. I am just a bit confused. You mention the example that he mentioned about breast cancer showing many causative agents, yet breast cancer is just one disease. Could it be that ME/CFS likewise is just one disease state resulting for different causes and/or pathogens?
 
Simon

To have any hope of identifying many different diseases (or causative pathways) within the umbrella definition, a lot of patients are needed; and there are early plans for a study involving a 5,000-strong cohort of patients. The idea is to explore everything: phenotypes, genotypes, gene expression, cells, cytokines, metabolites and more.
Very interesting! I guess at this point how those 5000 would be chosen and participate would be just speculation. Though it would seem that they would have to be located in the UK, for logistical reasons.

Thanks so much for writing this up.

Sushi
 
Great article, Simon. This is a very positive development. I bet we'd all like to be one of the 5,000 volunteers!

If anyone is reading the article on the home page, you may overlook (as I did) the sidebar giving an interesting bio of Prof. Holgate - if you missed it, have a look. It makes it very clear we're extremely lucky to have him.

Has there not recently been a CAA-funded study that attempted to define groups of patients by clusters of symptoms? I can't remember the data source or the number of patients involved.
Thanks, Sasha!

And yes, I agree that we are very lucky to have Stephen Holgate. Like Ian Lipkin, he has an abundance of other good opportunities and to have such able people taken a leading role in ME/CFS bodes very well for the future.

And there is a CDC study underway that has a similar aim, the multi-clinic study with around 500 patients. To date, this has a greater emphasis on clinical data but is a similar idea (also, it is already funded, unlike the current plan which is at an earlier stage - though I would never bet against Stephen Holgate getting what he wants).

Thank you Simon for the hard work writing this article. I am impressed with Dr. Holgate's willingness to tackle this complex disease. I like the large scope and scale of the suggested study. It seems true that the latest findings and thoughts about ME/CFS point to the fact that it might not all be one disease. I am just a bit confused. You mention the example that he mentioned about breast cancer showing many causative agents, yet breast cancer is just one disease. Could it be that ME/CFS likewise is just one disease state resulting for different causes and/or pathogens?
This is where it gets complicated! Breast cancer refers to tumours in the breast, and what Stephen was saying is that there are 14 known, separate causal pathways that lead to breast cancer. So whether it would be breast cancer or breast cancers, I'm not quite sure. I think the choice of treatment depends on the precise type of breast cancer (eg particular mutations/causal pathways) so this is more than splitting hairs. The more we know, the more complicated things get.

With ME/CFS, what Stephen is saying is that there are probably many different causal molecular pathways, but some of these will be related. He said several of the molecular pathways could be part of the same disease mechanism, or 'causal network'. You could see each of these causal networks, or disease mechanisms, as one Disease, with ME/CFS then being made up of multiple diseases.

You might picture it like this:
cluster1.png


But he is saying ME/CFS is more than one disease.

Another way to look at it is to roll back a couple of decades to when thyroid and adrenal problems leading to fatigue were often misdiagnosed as ME/CFS (still are, occasionally). These problems were not the same disease as ME/CFS, even though they can 'look' very similar. There could be several other such diseases that lurk under the current ME/CFS banner, completely unrelated to one another in causal or mechanistic terms, but appearing to be similar on the surface.

Hope I haven't gone on too much there.

And glad you liked the article.
 
And there is a CDC study underway that has a similar aim, the multi-clinic study with around 500 patients. To date, this has a greater emphasis on clinical data but is a similar idea (also, it is already funded, unlike the current plan which is at an earlier stage - though I would never bet against Stephen Holgate getting what he wants).

The results of the study I'm thinking of were presented at the FDA workshop earlier this year, I think - just can't remember much more about it. o_O
 
The results of the study I'm thinking of were presented at the FDA workshop earlier this year, I think - just can't remember much more about it. o_O

Sasha - are you thinking of Susan Vernon's presentation at the FDA regarding the study being conducted with Biovista?
 
The results of the study I'm thinking of were presented at the FDA workshop earlier this year, I think - just can't remember much more about it. o_O
That's the same one - I wrote that blog from the FDA video of Elizabeth Unger's presentation.
 
Sasha - are you thinking of Susan Vernon's presentation at the FDA regarding the study being conducted with Biovista?

I think that was about treatments but the study I vaguely remember was about clustering patients according to symptoms (which I suppose could have been a prelude analysis to identifying treatments)... :confused:
 
I have been saying for years that ME may be two or more different diseases, and CFS may be many different diseases. That is the way the evidence stacks up. It still requires more evidence to be sure though. Holgate is right about a lot of it in my opinion, including the need to focus on molecular mechanisms, but that could just be my bias as a biochemist coming out. There is a problem with that assumption though. Even with, for example, fifteen mechanisms identified, we still have to interpret those within the complex seething molecular cauldron that is the human body. A molecular mechanisms reductionist claim, and its not wrong, may be useful but to really interpret it you have to look at the big picture too. Fortunately for us the rise of systems biology may give us the tools to do that.

I also think that if there are fifteen underlying causal mechanisms, again to use that example, there will be common pathophysiological consequences. Indeed one big issue in our research that I have written about before is much of what we know may be pathophysiology and not tell us much about causation. It does tell us a lot about symptoms however.

Treatment for symptoms only requires an understanding of pathophysiology. A cure is best developed by understanding ultimate causation. Advances in both directions are beneficial, but to have a good cure (as opposed to a very problematic one) requires that we understand a broad diversity of molecular interaction in ME. However even a bad cure is better than no cure. I suspect Rituximab will turn out to be a bad cure, and an OK treatment. If we understood the mechanisms better then we could optimize such treatments better.
 
Hopefully they will eliminate all the "pwcs" with known causes first. I'm just talking
about the ones who completely heal via treating their known cause.

So far we know
about celiacs, lymies, moldies, potsies, and those with thyroid and adrenal
problems. I feel like I've forgotten a known misdiagnosis.

Of course they'll be some pwcs with all the above who still qualify as pwcs.

Great news ! I hope this entices others who like a challenge.

tc ... x
 
Can't eliminate the Moldies.

Biotoxin exposure is part of what started the CFS syndrome.

Doctors just didn't know it.. because they never acted in accordance with the basic purpose of creating a syndrome:

To look for the unknown factors.
 
In response to Erik Johnsons post.. I dont see how it could take anything away from ME clusters outbreak group as it would help to define that group as being its own depending on what they find separates all the groups.

Maybe some of the ME outbreaks too have been different things and not even exactly the same? Who knows (some of the outbreaks have been described quite differently but of cause that may also be due to the speciality fields or interests of whoever was studying it and reported at the time, different things will stand out to different people).

Nielk.. There are different kinds of breast cancer. My grandma was very unfortunate she got breast cancer which they thought was successfully treated but then developed a completely different kind of breast cancer (an extremely aggressive rapid growing kind) which killed her

............................

Thanks for this article, it helps give me hope that this illness may be figured out my lifetime. We so need good scientists like this one in the field, helping move things forward for us.

This scientists thoughts are on par to what Ive always believed, that there are many different illnesses involved (the ME outbreak group being one or maybe even that group may be two or three different things). I believe quite a few new illnesses will be found.

I think within our group, they are quite likely to discover also new atypical presentations of well known illnesses too, which will form new views around those illnesses as well. Maybe some of the diagnostic criteria for some other illnesses are needing some tweeking as may be missing some with those illnesses due to how illnesses are defined, not always being great. I believe new subgroups of other well known things will be found.
 
That would be redefining ME as whatever five thousand putative ME diagnoses have, instead of what the Royal Free survivors had.
And taking CFS away from the evidence and illness that started it. Substituting a new dataset.

Then combining two mistakes in one, calling it ME/CFS and compounding the error.

Whatever you came up with, you'd have to inform Dr Peterson's original CFS cohort that they don't have their own syndrome, but are some kind of peripheral subset, and probably not even CFS at all.

Oh, we've seen that trick before, haven't we?
But it was the CDC that pulled it last time.
 
That would be redefining ME as whatever five thousand putative ME diagnoses have, instead of what the Royal Free survivors had.
And taking CFS away from the evidence and illness that started it. Substituting a new dataset.

Then combining two mistakes in one, calling it ME/CFS and compounding the error.

Whatever you came up with, you'd have to inform Dr Peterson's original CFS cohort that they don't have their own syndrome, but are some kind of peripheral subset, and probably not even CFS at all.

Oh, we've seen that trick before, haven't we?
But it was the CDC that pulled it last time.
How would you explain myself fitting the ME international consensus criteria (my illness started out as a virus just like ME does, my illness is just like what Cheney and David Bell talks about with their patients) and my sister who developed what fits as CFS from accidently drinking from my glass? She hasnt got none of the ME abnormalities I do showing on her her test results and she doesnt met the ME international criteria (she's now been sick for 2 years, she does get post exertional symptoms). How can I not think she hasnt got what I do esp seeing she seems to have caught her illness from me. (I have 2 others in my family sick too, one of the others does meet the ME criteria while the other also doesnt)

No matter what we do, due to not enough being know about ME, the whole thing is ONE HUGE MESS with us trying to draw a line between the illness but no one really knowing where the lines lay so it all comes down to some chance what defination you are going to fit under. Maybe there are others like my sis who may have ME but dont currently fit the current definition (note I do like the ME definition so my post isnt certainly one against it..but it is probably missing some with ME.. either that or I wrongly fit it myself).

I think anyway no matter which views we have, we all agree its a huge mess. Till they find the ME virus? or whatever, it will continue being a huge mess.
 
Only an academic mind would see fit to make a puzzle easier to solve by shaking fifteen of them together and trying to solve them all simultaneously.

ME is first and foremost, everything that was known about the Royal Free cohort.

CFS is the term for the illness and evidence under scrutiny by the Holmes committee, when they felt compelled by the weight of that evidence to contrive a syndrome in order to study it.
(Yes, even the stuff in Osler's Web that they... strangely saw fit to leave out of the definition.)

Deviation from those parameters must be carefully considered for inclusion.
Not because they might be less severe, but to avoid complicating the problem.

I'd stick with the basics. But that's just simple-minded me.
 
I see Erik's point...
It would be silly to ignore geographical outbreaks when investigating ME/CFS.
But Peterson has provided his samples to Lipkin (and to Beth Unger, and I assume his own Simmaron research projects), so his patient cohort is being investigated.
I don't know how many outbreaks we've had in the UK (memory fails me) but I think they are very unlikely to get investigated, because I don't think the patients have been closely followed by any current doctors or scientists. I might be wrong.
In any case, most people with CFS/ME are not from outbreak areas, so they also need to be investigated, and subgrouped.
I think the proposals are a promising and necessary step forwards for CFS/ME research.
Like Tania, it gives me reason to be optimistic.
Especially because I think Stephen Holgate is very capable, with the best motivations.
 
The point of creating a new paradigm called "Benign Myalgic Encephalomyelitis" in response to the Royal Free outbreak was that the authors felt they were on strong enough ground to delineate a discrete illness entity.

This was a step up from "Iceland Disease" and "Epidemic Neuromyasthenia"
But ONLY if you consider to ME to be the evidence that constituted the REASONS the authors were on strong ground.
To set these aside and think of ME as "everything in general", is moving ME below the standards which gave the entity a strong enough footing to qualify as a discrete entity.
-----------------------------------------


http://findacureclub.weebly.com/uploads/5/2/5/1/5251327/acheson_amjmed.pdf

The Clinical Syndrome Variously Called Benign Myalgic Encephalomyelitis,
Iceland Disease and Epidemic Neuromyasthenia
E.D. Acheson, D.M., M.R.C.P.

The Case for a Clinical Entity
It is significant that the first review of the
syndrome under discussion was entitled, “Not
poliomyelitis”45; the second, “A new clinical
entity?”22. In later articles entitled, “Epidemic
myalgic encephalomyelitis”46, “Benign
myalgic encephalomyelitis”46a and “Epidemic
neuromyasthenia”15,16, the authors considered
themselves on sufficiently strong ground to
describe and name the syndrome. This
sequence indicates that the first and minimum
requirement in the definition of an entity is the
essentially negative one of showing that the
syndrome is not an unusual manifestation of a
disease already recognized. Later, as evidence
accumulates, it may be possible to define the
disorder in positive terms.
 
This is exactly what happened with "CFS"

By finding new evidence, Cheney and Peterson moved the "CEBV Syndrome" entity up to a level that the CDC couldn't ignore. (The CDC just didn't TELL you about all that evidence. Nice trick, eh?)

It is easy to bypass the CDC contrived confusion by conceiving of CFS as.. "The illness AND EVIDENCE under scrutiny by the Holmes committee"

In this way, we have two discrete databases, for easy analysis.

One called ME, and one called CFS.

So we can see where they overlap.