2016 round-up and what’s next for M.E. research?

BIG DATA2016 was a bumper year for M.E. research, so what needs to happen next to ensure this progress is built upon to improve the lives of the 17 million people with M.E. worldwide?

This is an article I’ve written for Action for M.E.’s next InterAction magazine. Being a magazine article it’s long, so I’ve provided links to jump to the different sections:

M.E. research in 2016

Although the studies were often only small and need replicating to confirm their findings, strong themes on the underlying pathology were problems with energy production and utilisation, the immune system, the cardiovascular system, muscle, gut bacteria, brain function, and genetics. The highlights are summarised, with links to my easy-read research round-ups for Action for M.E. where possible. Please note that I’ve used the same name for the illness as the researchers publishing the paper.

Energy production and utilisation

Several studies suggest that there are problems with the way energy is generated and used in people with M.E. Naviaux and team suggested that body is in a hibernation state in M.E. after finding several abnormal biochemistry processes compared with healthy controls, affecting energy reactions, cell building blocks, and how vitamins in our food are used. Ron Davis at also found problems with the way sugars and fats are used as a source of energy. Research by Fluge and Mella’s Norwegian team, also trialling rituximab to treat M.E. as an autoimmune condition, found that the way mitochondria, the powerhouses of our cells, generate energy is also at fault in people with the illness, and similar studies also suggested mitochondrial dysfunction.

The immune system

Around 30% of the people with M.E. were found to have high levels of autoimmune antibodies working against part of the autonomic nervous system, which could account for some of the symptoms such as dizziness and palpitations after standing up, digestive and cardiovascular system problems, amongst others, in a subgroup of people with M.E. The patients who responded well in the rituximab trial had these antibodies before treatment but normal levels afterwards.

Hornig and Lipkin discovered differences in cytokines, chemical messengers of the immune system and inflammation in people with ME/CFS, and Fluge and Mella have had success in their B cell depletion trials with rituximab, and a UK trial of this drug has been announced. Natural killer cells, which are a type of white blood cell which destroys cells infected with viruses, were found to be less effective at destroying virus-infected cells than in the healthy controls.

A study found significantly more of one type of mast cell present in the blood of the people with CFS/M.E. and that there are more immune system receptors on the surface of mast cells in people with moderate and severe M.E. Mast cells release histamine, cytokines, and other substances involved in allergic reactions and inflammation, so this finding could account for allergies people with M.E. seem to be more prone to.

Cardiovascular system

Studies found an association between reduced heart and total blood volume in CFS and severity of the illness. A lack of relationship between this and the amount of time living with the illness suggests this is not due to deconditioning, becoming unfit. Another study in the same research round-up found lower levels of the hormones in the renin-angiotensin and antidiuretic hormone systems which control blood volume by reducing how much fluid is lost by the kidneys as urine. Half of the patients in the study responded well to desmopressin, a medicine that increases blood volume by restricting the amount of urine produced.


Muscle studies suggest that muscle strain worsens M.E. and a shorter time for muscles to fatigue in people with the illness. Another study found marked differences between people with M.E./CFS and the healthy controls in biomarkers of the by-products of exercise, muscle function, oxygen use and the immune system, and these differences corresponded with the quality of life scores of the patients.

Gut bacteria

A suggested that gut bacteria differ between men and women with ME/CFS and that this affects symptom severity. These differences have also previously been found in autoimmune diseases, such as MS, lupus, and Type 1 diabetes. A case study comparing a set of twins where one has M.E. found differences between their gut bacteria after exercise.


A Genome-wide association study (GWAS) in compared the DNA of M.E./CFS patients with that of healthy controls to see if there are any differences which could give clues to the underlying causes of the illness, along with a possible genetic predisposition. Several differences were found in the regions which code for components of the immune system, such as T-cell receptors, indicating a possible predisposition to autoimmunity and susceptibility to viral infections. In addition, differences in the genes coding for glutamate receptors in the brain were found. Glutamate is a neurotransmitter which is important for memory formation, learning, and regulation of the body’s systems. Problems with the receptors for glutamate are implicated in many other neurological illnesses, such as chronic pain and MS.

Brain function

Several brain scan studies were published last year which suggest differences in activity in parts of the brain which correspond to the difficulties people with M.E. have in cognitive functioning, for example impaired concentration, working memory loss, inability to focus vision, and poor coordination, along with sensitivity to pain.

Overcoming problems in M.E. research ^back to top^

Looking back through M.E. research over the years, it really stands out that there have been cycles of similar discoveries which have not led to any further progress but buried, until a few years later when similar “discoveries” are being made all over again. There are several barriers or problems which need solving for progress in M.E. research, though M.E. is now considered as a solvable problem by researchers and patients who worked together on a journal article assessing what is already known about M.E.

Bringing in researchers from other areas of medical research where these problems have already been overcome would make sense, as the M.E. research community may be inadvertently reinventing the wheel because of the inward looking nature of a very specialist field.

We’ve really had enough badly designed studies which are too open to bias in interpretation. It may seem like splitting hairs to critique these biological findings but we need to think of the criticisms used to discredit biological findings from M.E. research by those who try to psychologise it, and address them with the next steps. Only then will a breakthrough truly turn into indisputable fact.

Study design

Although studies such as Naviaux’s are promising, Prof Patrick urged caution because the results do not prove that the biological differences are definitely caused by M.E. There are study designs which could enhance this research, such as prospective cohort studies. These are long-term population-based studies, where a very large number of healthy people are recruited and their health is followed over a long time period. Statistically, some of these people will go on to develop M.E. and differences between these and the people who did not go on to develop M.E. can be studied, for example environmental factors.

One criticism of M.E. studies has been the use of appropriate controls. The control groups in studies need to be identical to the participants with M.E. in every way other than the absence of M.E. Sedentary controls have been suggested as this would challenge the criticism that the findings might just be showing up what happens in people who have been inactive for a long time. Using sedentary healthy controls would distinguish the difference and would also prove that M.E. patients are not just physiologically deconditioned.

Difficulty studying severe M.E.

Another problem which needs to be overcome is that of involving patients with severe M.E. in studies. A researcher at the 2016 CMRC conference, Sarah Strassheim, shared her research team’s experience of studying this group. Be inclusive of people with severe M.E. – we’re not the only illness that’s difficult to study because we’re too ill to take part in research. We could learn from the ways this problem has been overcome in other illnesses.

Larger studies and replication

Pretty much every study has concluded that there need to be larger studies and replication to confirm their findings. This is because we can’t be sure that the results from small studies aren’t down to chance, and when scaled up the results may look very different. Researchers have urged caution with the cytokine and energy metabolism findings, as there has been false hope before when a the virus XMRV was suggested as a cause of M.E. in 2005, but further studies could not replicate this and it turned out that there was contamination of the samples leading to false results.

Larger studies such as MEGA and the availability of the UK M.E. biobank, which can be used by researchers from any field of research are some promising developments in research infrastructure. Biobanks also maximise the amount of research from the data patients have sacrificed their health to give.


Another problem often mentioned in research papers, including reviews of treatments for M.E., is the existence of sub-groups leading to inconclusive findings. The observation that there are sub-groups within M.E., even without the confusion of throwing chronic fatigue in with it, goes way back, and is also something that’s really obvious to patients who follow research in our online community.

Asthma, type 2 diabetes and multiple sclerosis are examples of the way defining sub-groups improves treatments and outcomes for patients. Clinicians observed that in some people with asthma their condition has been difficult to get under control and prevent life-threatening asthma attacks. Thanks to “big data” studies looking at a vast number of asthma patients, sub-groups stood out and the way asthma is treated has been revised as a result, tailoring treatment to different sub-groups. Several big data studies are planned for M.E., including the UK’s MEGA study, and Prof Stephen Holgate, who worked on the asthma studies, is part of the team. University of Southampton. Another avenue for treatment is which is currently used to tailor treatments to individual patients, which would be a shortcut to providing treatments for people with M.E. based on their own specific metabolic profile, such as deficiencies. The NHS aims to adopt personalised medicine by 2025.

Research funding

A report assessing research funding for M.E. globally and here in the UK, co-authored by Action for M.E.’s CEO Sonya Chowdhury found that M.E. research receives less than 1% of all active grants given by UK mainstream funding agencies, such as the Medical Research Council and National Institute of Health Research. As a result, patient groups are having to crowdfund research via the M.E. charities. The report calls for a level of central research funding commensurate with the size of the UK M.E. population and the impact it has on the lives of those with the illness and their families, and the impact on the economy. M.E. patients and supporters also signed a petition to the government to increase funding.

Speaking at the 2016 CMRC conference, a representative from the MRC responded to the report by reiterating that there is already an official call for M.E. research applications but that the quality of them is not high enough, and the speaker went on to give ways of improving the funding applications so that they meet the MRC’s standards. Taking this advice will ensure that there is more robust research, so this should be seen as a filter of quality rather than a barrier to more research in the UK.

What next? ^back to top^

For research discoveries, such as diagnostic tests and treatments, to go from “bench-to-bedside” to the point where it can be used clinically to improve patient care is known as translational research. This involves researchers and clinicians from a wide range of specialisms, and preferably patients, working together on the practicalities and logistics of making the knowledge, tests, and treatments derived from research available. The 4 stages of translational research are shown here (click the image to enlarge):

4 step process of translational medicine

Several biomarkers were suggested as diagnostic tests in last year’s research. The expensive and very specialised equipment used in research is not always practical for use for diagnostic tests from GP surgeries but a team of Australian researchers have developed a test and are looking for commercial input to make this available in clinics.

As for treatments, two studies looked at all the medication which has been tried in people with M.E. over the years and concluded that the sub-groups issue confuses trial results. You can read Cort Johnson’s article on trial updates at the IACFS/ME conference here. The announcement of a UK rituximab study in addition to those abroad is promising. In order for M.E. patients to be offered treatments on the NHS, providing the results are successful they need to undergo assessment into the safety and cost effectiveness by NICE, followed by the practical issues of how and where patients could be treated by specialists already familiar with using rituximab, such as rheumatologists who prescribe the drug for rheumatoid arthritis.

One of the research presentations at the 2016 CMRC conference showed that patients’ priorities and goals are very different from those of health professionals. It’s essential to involve patients in this translational process, as we bring our experience and observations of living with our hugely misunderstood illness with very little help from health and social care services. I strongly believe we are at the tipping point in changes to attitudes to our illness and the help available to us, and that we need to take every opportunity to have our say on research and healthcare. You can find UK opportunities in the Get Involved section of my blog.

If you’ve liked this article, please consider sponsoring the CEO of Action for M.E., the charity I volunteer with. Sonya’s walking my million steps as well as her own in this fundraising challenge on the run up to M.E. awareness day in May:

Click to sponsor Sonya
Sponsor Sonya

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