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​

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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.​

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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.​

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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.​

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Asked what he would like to be remembered for as a scientist he replied:​

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"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.​

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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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Putting together the cohort of 5,000 will probably take a few years, (assuming it does secure funding); then probably at least another 2 years before the results of any research on the cohort is available. That will hopefully reveal cohorts and give clues at to molecular pathways.

It would be nice to do some joiny-uppy stuff and have any patients entering clinical trials (such as the Rituximab trial) also get included in this database.

 

It would be nice to do some joiny-uppy stuff and have any patients entering clinical trials (such as the Rituximab trial) also get included in this database.

I agree. And like the phrase 'joiny-uppy' too Am wondering if there has been anything with which we might compare. Some other disease that was looked at in this way, in the recent past on such a large scale? What say you Simon my man?

 

As I examined the history of antecedent epidemics, an interesting thing stood out.
Aside from the doctor or doctors who identified their own outbreak, the incident is never followed up.
Even if others use the name, researchers want to study "In their own backyard"

The name, the entity, the outbreak, and all the evidence gets lost as it shifts from one to the next.
Over and over. It's like throwing all the game pieces off the board, starting back at square one.

Oblivious to what they threw away, when they "moved on".

Some of what they threw away was worth knowing, but since they didn't know how much they had lost,
they called it "progress" anyway.

----------------------------------------------------------------------------------

"I'll tell you what I was most angry at. A group of scientists that came in this community. Did a study, and did not come back and tell us what had happened"
-Gussie Baker 1955 Punta Gorda Outbreak

 

It would be nice to do some joiny-uppy stuff and have any patients entering clinical trials (such as the Rituximab trial) also get included in this database.

It's an important point about how information gleaned from clinical trials integrate into big research cohorts like this. I don't know how practical it is to combine them directly: over on the Rituximab thread, Jonathan Edwards commented on the possibility of combining the proposed UCL study with the Norwegian one and said that while it makes good theoretical sense, the more complicated any study becomes, the harder it is to get high quality data. He said in practice it works better to do such things separately.

However, if the UCL study finishes before the cohort recruitment is complete, maybe there is a chance to enroll then UCL patients into the cohort. Could be worth suggesting to UCL, once the study is settled?

Alternatively, the 5k cohort study could be used to explore and build on any UCL findings. Let's say they discover that certain patients respond well to rituximab, and others don't, and they have identified the key factor, eg NK cytotoxicity levels. They could then test for that in the Cohort, to see what proportion of patients generally are likely to respond well to ritux.

I agree. And like the phrase 'joiny-uppy' too Am wondering if there has been anything with which we might compare. Some other disease that was looked at in this way, in the recent past on such a large scale? What say you Simon my man?

Er, good question. Though in his talk, Stephen Holgate, emphasised how now was the time to study ME/CFS because of the emergence of new techniques, so I don't know if such an in-depth study has been done before, since this is the cutting edge. Maybe that's part of the appeal. Will try to find out if the approach has been used before.

 

It's an important point about how information gleaned from clinical trials integrate into big research cohorts like this. I don't know how practical it is to combine them directly: over on the Rituximab thread, Jonathan Edwards commented on the possibility of combining the proposed UCL study with the Norwegian one and said that while it makes good theoretical sense, the more complicated any study becomes, the harder it is to get high quality data. He said in practice it works better to do such things separately.

I agree that trying to add on to a pre-existing trial would have the downside of complicating matters but enrolling patients in what are essentially two separate studies (the trial and this cohort) wouldn't add complexity to either, just more scope for additional analysis. I think it would make sense to include the trial participants in the cohort before they get treated, as a further opportunity to distinguish responders from non-responders, and to have them in a study where they'll be getting longitudinal follow-up (I think) at no extra cost to the Rituximab trial.

 

I agree that trying to add on to a pre-existing trial would have the downside of complicating matters but enrolling patients in what are essentially two separate studies (the trial and this cohort) wouldn't add complexity to either, just more scope for additional analysis. I think it would make sense to include the trial participants in the cohort before they get treated, as a further opportunity to distinguish responders from non-responders, and to have them in a study where they'll be getting longitudinal follow-up (I think) at no extra cost to the Rituximab trial.

It's hard to know how feasible this is, not least because right now, neither study is funded (or even applied for in the case or Rtx) so we don't yet know the mechanics. My guess is that, because the 5k cohort is so big, it's tapping into clinics in a big way - which presumably means the BACME clinic network. If so, they will be gathering data from their own regular patients, probably new patients so the time spent on diagnosis etc is time already budgeted for. That means they wouldn't automaticlly welcome having to add a separate group to their study, esp if it meant taking clinician time away from regular clinic work.

Thinking aloud here, one possibility is, if UCL contacts whoever plans the cohort (it's not Stephen Holgate's study AFAIK), they could arrange to recruit for that study via clinics particpating in the cohort (they have to find the patients somewhere, and there are BACME clinics in London). That would minimise any duplication of effort in having patients in both studies. There may be many practical reasons why this wouldn't work, but might be worth discussing the possibility with JE on the Rituximab thread.

I agree that it would be good if the same patients figured in both studies. And potentially, if a mechanism to cooperate easily can be found, it could apply to other UK studies too, eg Julia Newton's work - which is what you were originally suggesting, I think. So that would be another reason to explore this now.

 

No interest in this unusual incident = No interest in the incident that started CFS.

"This seemed to be evolving, before our eyes, from a flu-like illness into something else"
-Dr Paul Cheney

"... and it seemed to be spreading. Through the local hotel and casino, two area high schools, members of a girls basketball team."
-Dr Nancy Snyderman

"That's when we wondered, Hey, maybe we better call somebody. This is really unusual."
-Dr Paul Cheney

 

Hi Rick,

Thank you for this. It is Important to inform people of what really happened. I just finished reading "Osler's Web" for the second time and I'm very interested to hear more a out it.
I feel though that this is important enough to have its own separate thread.

 

If Professor Holgate were serious, reading Osler's Web would be a good start.
Then he would know that CFS was not begun as an umbrella term for "anything and everything"

 

I believe that by the conclusion of the CFI:Lipkin study there will be a significantly new set of players in the field of diagnostic criteria due to the strong advancement in technology and testing medium (serum, urine, saliva, tissue and spinal fluid). Diagnostic testing has ran out of room by trying to find everything in serum for sure. There is probably room in urine and saliva, but spinal fluid and tissue samples will have to be a part of a definitive analysis at some point. Unless some new types of analysis are developed which is very possible. Ultrasound, forms of MRI's and very small tissue samples of tissue and spinal fluid.

 

Thanks Simon - great article - 15 sounds about right !
Not read all posts but here in Australia lots are now being re- diagnosed with LYME, POTS/OI and EDS -
Ehlers-Danlos Syndrome so these are likely among the 15 along with other CTDs it seems

Lyme had been dismissed here for years

cheers

Ally

 

And I should add that as EDS makes y ou more prone to other illnesses it may be likely that some have EDS AND Lyme disease - the overlap in symptoms will make it hard to differentiate but may explain why some seem to respond well to Lyme treatment while others do not - they may have underlying POTs or EDS so the symptoms never disappear even if the Lyme is treated


ALly.

 

It had been my impression that researchers wanted to know what happened in the local area high schools, a casino, and a girls basketball team, because it was really unusual.

25 years of utter unresponsiveness and lack of any questions or investigation indicates otherwise.

 

Am wondering if there has been anything with which we might compare. Some other disease that was looked at in this way, in the recent past on such a large scale? What say you Simon my man?

I asked Stephen Holgate who replied:

Cancer is leading the way here. Other complex diseases are following especially Rheumatoid Arthritis, Inflammatory Bowel Disease, Psoriasis, Type 2 Diabetes, Multiple Sclerosis and Alzheimer's Dementia. All very exciting!

So it is being done, though I'm afraid I don't have any more specifics from the Professor. However, a recent Nature paper on Cancer gives an idea of the approach:

Like the proposed ME/CFS study, it was on a huge scale - looking at 7,000 indiviudal cancer genomes for 30 different types of cancers (ie looking at the specific mutations in each of 7,000 individual's cancer). From this they identified 21 common 'mutational signatures' - a common pattern of DNA mutations eg there is one mutational signature caused by damage from UV radiation. Which is pretty cool.

But it wasn't a case of one mutational signature being linked to one type of cancer. Each person's cancer carried at least two different mutational signatures (and not every individual with the same type of cancer would have exactly the same mutations).

What they found was that some mutational signatures cropped up in many different types of cancer. For instance, one mutational signature common in breast cancer was also found in 16 of the 30 types of cancer studied. Wheras some of the mutational signatures were only ever found in one type of cancer.

So they started off with 30 different types of cancer. But when they looked at the molecular level - specifically at the types of DNA mutations underlying the cancers, they found a very different pattern, with some DNA mutational signatures cropping up in lots of different cancers.

The scientists think that by better understanding the precise mutations involved they will learn a lot about the causal mechanisms of cancer.

This cancer study used some pretty-intensive mathematical computational approaches, which is just the sort of approach that Stephen Holgate has advocated to make sense of a lot of data from 5,000 ME/CFS patients.

Look like ME/CFS is moving to the forefront of science - which is probably where it needs to be if such a complex illness is ever going to be cracked.

Short video about the Nature Cancer study:

 

Simon appreciate it. And do pass my (our) thanks to Prof. Holgate as well

 

And suppose I were to refuse to agree that whatever Professor Holgate is calling CFS is exactly the same as the illness that started CFS?

Which I see no reason to do, until researchers agree to incorporate all of the actual evidence which led to Dr Peterson and Dr Cheney calling the CDC for help with our little problem.

 

Plenty of time to get used to any findings
Putting together the cohort of 5,000 will probably take a few years, (assuming it does secure funding); then probably at least another 2 years before the results of any research on the cohort is available. That will hopefully reveal clusters and give clues at to molecular pathways.

Then at least another few years to nail down the first pathways (assuming they exist). And at least 5 years to find a drug and get it to market. So well over a decade in total, and that's just to tackle some of the disease clusters. We won't be waking up any day soon to discover that we all have one of several new, previously undisovered diseases within ME/CFS - or are orphaned in an undiagnosed mishmash of leftovers.

Hopefully not only drug treatments will be considered. I would expect that some of the clusters would be amenable to other treatments which do not have such long lead times as drugs, and better safety profiles. Also, some existing drugs with known safety profiles may be useful ('repurposing'), which again can be brought into use relatively quickly.

 

Hopefully not only drug treatments will be considered. I would expect that some of the clusters would be amenable to other treatments which do not have such long lead times as drugs, and better safety profiles. Also, some existing drugs with known safety profiles may be useful ('repurposing'), which again can be brought into use relatively quickly.

Yes, drug repurposing could be a shortcut eg rituxmab, if there are any suitable available. What other treatents did you have in mind?

 

Yes, drug repurposing could be a shortcut eg rituxmab, if there are any suitable available. What other treatents did you have in mind?

I was thinking of things that some of us already find helpful such as dietary changes and supplements. It's a difficult process working out which foods and supplements help which people, and we may never quite find the optimal mix. Subgrouping patients might help us to do this, so that the interventions are more effective, and maybe even bring about remission or that four-letter c-word...(says to self - go on - say it - OK - cure!)