The award by the MRC of almost £1 million to Professor Julia Newton, Dr Wan Ng and colleagues (Newcastle Biomedicine, Newcastle University, UK) for two biomedical projects is a great boost for research into ME/CFS in the UK. The initial call for applications Understanding the Mechanisms of CFS/ME was issued by the MRC in February 2011, with a submission deadline in June 2011. In total, the MRC has made five discrete grant awards under this call, at a cost of approximately £1.65 million.
The MRC had invited “
proposals for high-quality, internationally competitive research partnerships addressing CFS/ME… focusing on one or more of the following areas:… Autonomic dysfunction; Cognitive symptoms; Fatigue; Immune dysregulation; Pain; and Sleep disorders”. The awards given to Professor Newton, Dr Wan Ng and colleagues were allocated under MRC-identified focus areas of “Autonomic dysfunction” and “Immune dysregulation”, and the funded projects aim to explore in greater depth:
- Autonomic dysfunction, a phenomenon observed in the majority of patients investigated in Newcastle [see Note 1 below]. The researchers plan a detailed exploration of its pathogenesis, including its relationship with the neurocognitive impairments seen in patients [see Note 3 below].
- Biological fingerprints of fatigue using whole blood gene expression profiling. Using primary Sjogren’s syndrome (an autoimmune condition with several clinical features similar to ME/CFS) as a disease model, the researchers will undertake a comprehensive analysis of the immune system to identify biological fingerprints. Subsequently, they will explore whether these biomarkers are present in ME/CFS patients, and whether they have a role in improving diagnosis and treatment.
As Prof. Newton says, “
I am delighted at this outcome, which arrives after many years of hard work for my colleagues and myself. I’d like to particularly thank the charity ME Research UK. The charity provided the pilot/seedcorn funding for four distinct projects from 2006 to 2011, which have allowed us to accumulate the data on which these successful applications to the MRC were based. In addition, ME Research UK has supported our research programme in a variety of ways, not least by providing formal support letters for our grant applications to the MRC. The success of these applications shows what can be achieved by biomedical researchers working closely with the medical research charities in a supportive and collaborative way.”
Dr Neil Abbot, on behalf of ME Research UK, said [see Note 2 below], “
The allocation of these monies under a ‘pathophysiology’ call, culminating in the award of grants for research that is overwhelmingly ‘biomedical’ rather than ‘psychosocial’ in nature, is a significant achievement for which Prof. Stephen Holgate, the ME/CFS charities and the MRC itself deserve congratulations. The task now is to ensure that Class I funding continues to be available, year-on-year, for biomedical research into a disease that has been overlooked for far too long.”
1. Scientific progression at the University of Newcastle
The research headed by Prof. Julia Newton and Prof. David Jones of the School of Clinical Medical Sciences, University of Newcastle (Newcastle Biomedicine) is one of the very few research programmes anywhere in the world on ME/CFS – and a rare example of a consistent, directed, problem-solving approach to tackling the illness.
Since 2006, the group has received three separate grants from ME Research UK to look at:
In addition, the researchers received a large grant (2007) from ME Research UK, the John Richardson Research Group and the Irish ME Trust for “Autonomic nervous system dysfunction: a two-year investigation” to examine muscle, liver and heart function in a large patient cohort.
These investigations have resulted in a series of novel, incremental, scientific papers showing that, compared with healthy people, ME/CFS patients can have:
- Dysfunction of the autonomic nervous system (three-quarters of patients) (QJM 2007)
- Fatigue and functional impairment that is directly related to the burden of autonomic nervous system symptoms (QJM 2010)
- An abnormal heart rate response to standing (QJM 2008)
- Lower blood pressure, and abnormal blood pressure regulation (Psychosom Med 2009)
- Impaired cardiovascular responses to standing (Eur J Clin Invest 2010)
- Substantially slower recovery from standarised exercise of the skeletal muscles (Eur J Clin Invest 2011 and J Intern Med 2010)
- Impaired cardiac function, including markedly reduced cardiac mass and blood pool volumes (J Intern Med 2011)
- Alternative diagnoses to the diagnosis of ME/CFS originally given by their GPs, with around 40% of patients being diagnosed with other chronic diseases, such as primary sleep disorders, and psychological or cardiovascular illnesses (J R Coll Physicians Edinb 2010)
Such a progression is the norm for scientific investigation – whether towards positive findings or away from negative ones. In fact, in most chronic diseases, real breakthroughs come only after years of painstaking work by specialist groups of researchers across the world – after a ‘critical mass’ of investigators has produced a ‘critical mass’ of biomedical data. For the scientific enigma(s) of ME/CFS to be solved, the disease must become the main focus of a wide range of investigative programs across the globe.
2. ME Research UK comment: MRC and funding for ME/CFS research
The issue of MRC funding for ME/CFS research has been a ‘hot potato’ for many years. So hot, in fact, that the fractiousness of the debate has been a marvel to outside observers whether scientists, healthcare professionals or journalists.
In brief, ME/CFS patients, support groups and charities have opposed the allocation of MRC funds for the investigation of ‘biopsychosocial models’ at the expense of ‘biomedical’ investigations designed to find the causes of the underlying physical illness. Indeed, in an analysis entitled The Medical Research Council: a case to answer?, ME Research UK showed that approximately 91% of the total grant-spend on ME/CFS by the MRC from 2003 to 2008 (at least £3,180,900 at the time) had gone on trials of non-specific management and coping strategies. As this essay said, “
In an ideal world in which £100 million had been invested over five years in ME/CFS research, a 3% spend on assessing the usefulness of various coping strategies, such as CBT, relaxation or meditation, might have been acceptable. The point at issue is that most of the MRC’s inadequate grant-spend has gone on this aspect at the expense of truly biomedical research, the reverse of the situation in other illnesses such as multiple sclerosis or rheumatoid arthritis.”
Since 2008, however, there has been a much greater level of engagement between the MRC and ME/CFS charities at a professional level. First, the arrival into the field of Prof. Stephen Holgate (MRC Clinical Professor of Immunopharmacology at the University of Southampton School of Medicine), who had previous experience of organising a successful research collaborative in respiratory illnesses, brought new momentum, not least through his chairmanship of a novel MRC CFS/ME Expert Group to consider how new high-quality research into CFS/ME might be encouraged. Then, a Research Workshop was held in November 2009, at which established researchers and scientific representatives of charities – including Dr Vance Spence and Dr Neil Abbot of ME Research UK – met to set research priority areas. This was followed by the formation of an MRC CFS/ME Research Prioritisation group to prioritise the research topics raised at the Research Workshop as a prelude to action. The culmination of this process was the Call for proposals: Understanding the Mechanisms of CFS/ME in February 2011, under which Prof. Julia Newton and her team, and three other research groups in the UK, have now been awarded grants totalling £1.65 million.
Medical research funding of £1.65 million for ME/CFS is not a huge sum; the MRC’s gross research expenditure was £758.2 million in 2009/10, for example. However, the allocation of these monies under a ‘pathophysiology’ call, culminating in the award of grants for research that is overwhelmingly ‘biomedical’ rather than ‘psychosocial’ in nature, is a significant achievement for which Prof. Stephen Holgate, the ME/CFS charities and the MRC itself deserve congratulations. The task now is to ensure that Class I funding continues to be available, year-on-year, for biomedical research into a disease that has been overlooked for far too long.
3. Neurocognitive impairment in ME/CFS
Neurocognitive problems are one of the most frequent and disabling symptoms associated with ME/CFS. In one investigation, 89% of patients reported memory/concentration problems, while in another large study, memory/attention deficit problems were reported by approximately 90% of 2,073 consecutive patients. Crucially, patients often report that their cognitive problems are made worse by physical or mental exertion. But do such self-reported anecdotes about cognitive symptoms also show up as measurable deficits on objective cognitive testing in a clinical setting?
Meta-analysis is a method of combining results from a range of studies to obtain an overall estimate of the ‘true’ effect of a treatment. In 2010, researchers at the University of Adelaide, South Australia published a meta-analysis (Cockshell et al, Psychol Med 2010) of all relevant clinical trials examining cognitive functioning in people with ME/CFS, with the aim of identifying the pattern and magnitude of these deficits. Overall, they found a very mixed bag of 50 studies (made up of 1,577 patients and 1,487 controls) published between 1988 and 2008 from which, nevertheless, a clear and very revealing pattern emerged on detailed examination.
The most significant cognitive deficits were found in ‘attention’ (encompassing attention span and working memory), ‘memory’ (examined from verbal and visual memory tests, mostly memory for word lists) and reaction time (assessed as responses to both simple and complex choice stimuli) – consistent with the memory and concentration problems that patients themselves complain about. In contrast, deficits were not statistically apparent on tests of ‘fine motor speed’, ‘vocabulary’, ‘reasoning’ and ‘global functioning’ – suggesting that the ‘higher-order’ cognitive abilities, such as language, reasoning or intelligence remain unimpaired. And, importantly, the majority of studies that examined the impact of self-reported depression on cognitive functioning failed to find a relationship, indicating that depression was not responsible for most cognitive impairments.
The range of these studies and the clarity of the findings leave no doubt that people with ME/CFS have moderate to large impairments in simple and complex information processing speed and in tasks requiring working memory over a sustained period of time. As the authors point out, the deficits in performance are around 0.5 to 1.0 standard deviations below that of healthy people, a fact which explains the significant impact cognitive problems have on patients’ day-to-day activities and quality of life.