Published in InterAction 80 (Summer 2012)
Prof Stephen Holgate, Chair, Medical Research Council (MRC) M.E./CFS Expert Group, explains how M.E. research is being moved forward.
Anyone with a diagnosis of M.E./CFS will likely be aware of the difficulties in researching this area for many reasons, not least of which is the sheer complexity of the disorder.
There is now a very strong case that M.E./CFS comprises a series of disorders with overlapping symptoms and because of this trying to uncover a single ‘cause’ or therapy is doomed to failure.
The concept of multiple causes for what originally has been labelled as a single disorder is not uncommon in complex chronic disease. For many cancers, chronic inflammatory and degenerative disorders there are multiple routes to the same final disease. The same is true of M.E./CFS.
Multiple disease subtypes with differing initiating factors, symptomatology, natural history and responsiveness to common treatments demand a different research approach that uses modern mathematical and statistical tools (such as machine learning) to explore clusters of clinical features, physiological and laboratory measures to define individual disease subtypes. Connected to this has to be a new approach for uncovering the abnormal cellular, immunological and biochemical pathways that lead to the individual disease subtypes.
A major step forward has been applying new technology platforms collectively named ‘omics – genomics (genetic), proteomics (proteins) and metabolomics (small molecules generated by living cells) – to examine differences in many thousands of molecules to form a pattern (or fingerprint) of the disease subtype, just as one would use a range of different forensic measures to identify a criminal in relation to a specific crime scene. Great progress is already being made in difficult disease areas such as breast, prostate, lung, pancreatic and skin cancer as well as in rheumatoid arthritis, inflammatory bowel disease and osteoporosis.
By identifying causative pathways, specific therapies can be targeted effectively to these with a real chance of a cure. This stratified, individualised or precision approach to diagnosis and treatment uses the technologies described above to find biomarkers for each subtype of the disease, which then forms the basis of diagnostic tests and targeted treatments.
Recognising the parlous state of M.E./CFS research, the MRC’s Expert Group importantly includes scientists from outside the field as well as those interested in M.E./CFS. In addition the Group has major input from Action for M.E. and the ME Association.
When it was set up in 2008, the Expert Group requested a comprehensive literature review and this was followed by a two-day workshop of world class scientists, again with strong representation from outside the M.E./CFS field.
An MRC prioritisation meeting then led to six main research themes being identified (autonomic nervous system dysfunction, cognition, fatigue, immune regulation, pain and sleep disorders) for which a dedicated research call was made. A key feature of this call was a request that each application had extensive input from experts outside the M.E./ CFS research arena.
A special MRC grant panel comprising scientists from the four MRC research boards, plus input from overseas, reviewed the proposals and were greatly impressed by the quality overall. It was able to award five grants totalling £1.6 million covering most of the areas specified in the call.
Other areas were identified that required further proposals: these are M.E./CFS in children, subphenotyping M.E./CFS and immune dysfunction. They have now been inserted into an MRC cross- board highlight notice and any of the MRC’s four boards (infections and immunity board; molecular and cellular medicine board; neurosciences and mental health board; and the population and systems medicine board) will be pleased to receive proposals in these and other areas.
The last three years leading to this successful outcome has required a completely different approach to identifying research priorities. We have sought new research approaches in which multidisciplinary teams, which include top class scientists outside the field, have come together, resulting in the high quality proposals received by the MRC.
Of particular importance is the observation that all the successful grants were from teams embedded in much larger research infrastructures within the universities and health care providers (eg. the MRC centre on aging in Newcastle, the MRC arthritis centre in Liverpool and an MRC disease cohort in Newcastle).
So where do we go from here? The MRC is committed to maintaining close contact with the successful grant-holders and we are hopeful that others will now apply in response to the cross-board highlight notice. But more is needed: it is critical that this momentum is not lost.
One way forward would be to establish an M.E./CFS research collaborative in which all the relevant stakeholders participate. This would include the MRC, the NHS (via the National Institute for Health Research), charities (eg. Action for M.E., the ME Association and others who sign up to peer reviewed processes), industry and any other professional groups who could make a significant contribution.
Action for M.E. has a well developed scheme to fund high quality pilot work to help prepare researchers wanting to apply for larger and highly competitive applications.
Other exciting developments include the M.E./CFS Observatory (set up by Action for M.E. with Big Lottery funding to enable social and epidemiological research) and the newly established biobank for M.E., which is collecting blood samples from people with M.E. to give the research community access to a well-characterised cohort of patients with biological, clinical and laboratory data attached.
Power of collaboration
A similar collaborative body, the UK Respiratory Research Collaborative (UKRRC), was formed five years ago in response to low research activity and capacity. The establishment of the UKRRC has resulted in a three- fold increase in research funding in this field including research projects, programmes, centres, networks, Fellowships and PhD studentships.
I see no reason why this success cannot be replicated in M.E./CFS, having got off to such a promising start. Just as in respiratory disease, charities such as Action for M.E. have an enormous role to play. This could be the stimulus for the step change needed to find new ways to diagnose and treat M.E./CFS.
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