Dr Charles Shepherd reports on the 2016 Invest in ME conference, which was held in London on Friday June 3.
The 11th annual conference saw a change in venue to a much better lecture theatre situated at One George Street – the magnificent Edwardian building near Parliament that houses the Institute of Civil Engineers.
As usual, the audience consisted of a mixture of patients, carers, charity representatives and health professionals from both the UK and overseas. And it was good to meet up with colleagues including Dr Rosemary Vallings from New Zealand, Dr William Weir, Mark Berry and several other members of the Phoenix Rising discussion forum.
Brief reports of each presentation follows. Hot topics included autoimmunity; big data – genomics, metabolomics, proteomics; biomarkers and sub-grouping; European and International collaboration, and rituximab.
DR IAN GIBSON – FORMER DEAN OF THE SCHOOL OF BIOLOGICAL SCIENCES, UNIVERSITY OF EAST ANGLIA
10 years – Looking back, Looking Forward
The conference was chaired by Dr Ian Gibson with his usual sense of humour, along with pertinent observations and amusing anecdotes from his work as both Dean of the School of Biological Sciences at University of East Anglia and as a former Member of Parliament.
Dr Gibson opened the meeting by taking us back ten years to the publication of a report on research into ME/CFS that involved the All Party Parliamentary Group (APPG) on ME and became known as the Gibson Report. This report was prepared with input from Ian’s parliamentary colleagues, charity representatives on the APPG, and collected evidence from a wide spectrum of health professionals and ME/CFS researchers.
Although this was in many ways a compromise report, it was very critical of government in relation to almost all aspects of research into ME/CFS – including the lack of any epidemiological research in relation to recording the number of people who are known to have ME/CFS.
Moving forward to 2016, Dr Gibson said that we now lived in “exciting times” and there were good reasons to feel far more positive about initiatives relating to collaboration, education, funding, and pharmaceutical company involvement along with the establishment of new centres of research excellence – The Crick Institute in London being one example.
Dr Ian Gibson’s report into ME/CFS research: www.erythos.com/gibsonenquiry/Docs/ME_Inquiry_Report.pdf
DR VICKY WHITTEMORE – PROGRAMME DIRECTOR IN THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) AT THE NATIONAL INSTITUTES OF HEALTH (NIH)
Keynote speech: NIH research into ME
Dr Whittemore opened her presentation by telling us about her main areas of neurological interest – which involve epilepsy and a rare genetic disease called tuberous sclerosis – along with a brief summary about what the NIH does and how it operates.
The NIH has 27 separate institutes and centres – each covering a specific area of medicine and health. The NIH, through its various centres funds and carries out medical research both internally (at the NIH site in Bethesda, Maryland) and elsewhere – where NIH funding goes to research in both America and the rest of the world, including a three year grant the ME/CFS Biobank here in London to study the immunology and virology of ME/CFS.
Dr Whittemore joined the NIH about five years ago when there were just two grants relating to ME/CFS. During this time she has seen a very significant shift in opinion at NIH regarding the need to carry out high quality research into this illness.
Support and encouragement has come from a number of key people at the NIH including Dr Francis Collins (Director NIH) and Dr Walter Koroshetz (Medical Director at NINDS). They have accepted that there has been a lack of understanding at the NIH relating to both the severity of ME/CFS and the need to stimulate new research. At present, the US spends around $5-6 million per year (over the past 8 years) on research into ME/CFS – compared to $160 million on epilepsy.
She was very emphatic about the way in which this situation needs to urgently change and went on to outline the short, medium and long-term plans for ME/CFS research at NIH. This includes a call for applications for supplementary grants and the request for public feedback on what sort of research priorities need to be encouraged and pursued by NIH.
Dr Whittemore also spoke about a new intramural study at NINDS that is due to start in the summer of 2016. Led by Dr Avi Nath (Clinical Director at NIH), this research will be looking at in great detail at 40 patients with ME/CFS who have been ill for less than five years.
Dr Whittemore explained that the NINDS is very keen to foster co-operation amongst all the various organisations that deal with ME/CFS in the USA. These are the CDC, FDA, and so on. And she referred to the important NIH Pathways to Prevention Workshop that was held in December 2014 and the consequent Report on ME/CFS research. She is also keen to establish better links with organisations involved in ME/CFS research outside America.
* Dr Whittemore and the NINDS are keen to hear from both patients and researchers about what sort of research needs to be carried out into ME/CFS. Ask for information here: MECFSRFI@nih.gov
* More information on the study being carried out by Dr Avi Nath: www.meaction.net/2016/04/24/transcript-solve-mecfs-interviews-dr-avi-nath/
* The NIH is currently funding a three-year study into the immunology and virology of ME/CFS using blood samples and clinical data at the ME/CFS Biobank here in London: blogs.lshtm.ac.uk/news/2013/06/28/uk-mecfs-biobank-project-awarded-1-million-grant/
PROFESSOR OLLI POLO – CHIEF OF DEPARTMENT OF PULMONARY MEDICINE, TAMPERE UNIVERSITY HOSPITAL, FINLAND
Clinical diagnosis of myalgic encephalomyelitis
Although Professor Polo is a respiratory disease specialist, he also sees patients where a diagnosis of ME/CFS is being queried. He liked the definition of Systemic Exertion Intolerance Disease for ME/CFS that has been prepared by the Institute of Medicine.
Professor Polo referred to the way in which significant proportion of the patients he sees with a possible diagnosis of ME/CFS turn out to have a primary sleep disorder such as sleep apnoea.
After briefly referring to the scepticism about ME/CFS that still exists amongst some doctors and the need to improve the diagnosis in primary (GP) care, the remainder of this presentation was largely devoted to the overlap between ME/CFS and joint hypermobility syndromes, including Ehlers Danlos syndrome (EDS) where he referred to the well-established findings from Professor Peter Rowe. Professor Polo illustrated this aspect with several images of abnormally flexible joints and skin that are found in hypermobility syndromes.
As the overlap with EDS and the examination of hypermobile joints is covered in some detail in the new MEA purple booklet, I will limit this summary to three key points that were made:
* Hypermobility is caused by a defect in the body’s connective tissue (= cartilage, fatty and elastic tissues that helps to bind and support other tissues).
* Hypermobility can affect a wide range of joints – fingers, wrists, elbows, knees, hips.
* The connective tissue defect can also cause the skin and muscles to become more elastic, along with increased dilation of the veins in the presence of hydrostatic pressure. Increased dilation of veins can then lead to venous pooling, varicose veins and dilation of tiny blood vessels (= telangiectasiae) on the skin of the face (nose and cheek in particular), back hump and legs. Clubbing of the fingers can also be found on examination due to hypoxia (=low oxygen levels).
The diagnosis of EDS can be made using the Beighton criteria: hypermobility.org/help-advice/hypermobility-syndromes/beighton-score/
Professor Polo finished his presentation by explaining the rather complex neuroanatomy that underlies his hypothesis on the possible causation of ME/CFS. This hypothesis involves autonomic nervous system (ANS) dysfunction and the regulation of what is called sympathetic tone. This involves messages from the brain to the sympathetic part of the ANS that are then sent to various organs in the body – including heart, bowel and bladder.
PROFESSOR CARMEN SCHEIBENBOGEN – PROFESSOR OF IMMUNOLOGY AND DEPUTY CHAIR, INSTITUTE OF MEDICAL IMMUNOLOGY BERLIN CHARITE, GERMANY
Professor Scheibenbogen explained that autoantibodies are well-established causative factors in a number of autoimmune diseases.
Autoantibodies are harmful antibodies that the body uses against its own tissues and are directed against neurotransmitters (i.e. brain chemical transmitters).
She then described her group’s research that has demonstrated the presence of elevated levels of autoantibodies that are directed against what are called beta2 adrenergic receptors and M3 and M4 muscarinic acetylcholine receptors in a distinct subset of patients with ME/CFS.
The patients with elevated levels of autoantibodies often had increased levels of IgG (immunoglobulin G), ANA titres (anti-nuclear antibody titres) and/or activation of T cells. As a result, her research group has suggested that these autoantibodies can activate immune cells that carry these receptors by imitating adrenaline and acetylcholine stimulation. Other symptoms could be explained by overstimulation of the sympathetic and parasympathetic components of the autonomic nervous system.
These autoantibody findings may also be relevant to the treatment of ME/CFS using rituximab. This is because in patients treated with this drug in Norway the elevated levels of autoantibodies were normalised in those who tended to respond and this was not the case with the non-responders.
Professor Sheibenbogen also referred to a new clinical trial they are conducting which involves the use of plasmapharesis to remove IgG from the serum.
[CS note: Plasmapharesis is a method of removing blood plasma from the body by withdrawing blood, separating it into plasma and cells, and transfusing the cells back into the bloodstream. It is normally performed to remove autoantibodies in treating autoimmune conditions.]
Research paper: Loebel M et al. Antibodies to beta adrenergic and muscurinic cholinergic receptors in patients with chronic fatigue syndrome. Brain Behaviour Immunology. 2016, 52: 32 – 389.
DR GERALDINE (JO) CAMBRIDGE – PRINCIPAL RESEARCH FELLOW INFLAMMATION, DIVISION OF MEDICINE, FACULTY OF MEDICAL SCIENCES, UNIVERSITY COLLEGE LONDON (UCL) AND FANE MENSAH
Dr Jo Cambridge gave an excellent and easy-to-understand presentation on B-cell function in general, how B-cell dysfunction and the production of autoantibodies might relate to the immunopathology of ME/CFS, and the practical aspects of using rituximab to treat non-malignant conditions.
She explained that she belonged to a group of researchers at UCL – including Professor Jonathan Edwards – who have a particular interest in how a drug called rituximab, which was originally used to treat a malignant condition called lymphoma, depletes the population of a specific type of immune cells called B-cells. Rituximab was then found to effectively treat some cases of rheumatoid arthritis (RA) and other autoimmune conditions such as SLE/lupus where inflammation is an important part of the underlying disease process.
Among the key points made in relation to the use of rituximab in RA and to the way in which it might also act in ME/CFS:
* This research has produced information about how rituximab can produce a significant remission of symptoms (in around 70% of RA patients) and the resumption of symptoms (in around 60% of RA patients) once the B-cell population has been restored.
* Patients with high levels of autoantibodies (= antibodies that attack the body’s own tissues) have a far more pronounced and predictable response than those with no evidence of autoantibodies.
* B-cells are killed off very quickly by rituximab; the drug binds to cells that express what is called a CD-20 receptor. This usually occurs within a week of the infusions which are given intravenously over 6 hours. The B-cells therefore start to disappear from the blood within days and from other tissues at varying rates. But the dynamics of the clinical response – which takes from 1 to 5 months after depletion of the B-cells – suggests that for remission to occur it is the constantly generated B-cell product (possibly an autoantibody) and not the B- cells themselves that need to be reduced.
* A considerable proportion of the B-cells are not depleted and remain in protective sites in lymphoid and inflamed tissues.
* Levels of autoantibodies can therefore remain raised, even in the presence of an improvement in clinical symptoms.
* These observations suggest that only a proportion of parent B-cells and autoantibodies are actually ‘pathogenic’ (that is involved in disease causing mechanisms). And, as a proportion of patients then relapse, the autoimmune response underlying the disease causing process must be self-sustaining.
* Patients are not therefore normally ‘cured’ by rituximab and symptoms can worsen when the B-cells start regenerating within 6 to 9 months after the infusion. However, some patients have a more extended period of remission after the B-cells return.
* Side-effects are rare and, although there are reductions in serum antibody levels (which provide protection against infections) , the effects on protective immunity are mild and serious infections are not a problem.
In relation to the use of rituximab in ME/CFS, we are very much at the beginning of a learning process which follows on from the clinical trials that have been carried out and published by Drs Fluge and Mella in Norway.
The UCL research team is concentrating on investigating B-cell biology in order to try and identify differences between people with ME/CFS and healthy controls to see if this can help identify people with ME/CFS who are more likely to respond to this drug.
The group has hypothesised that rituximab may be reducing fatigue levels in ME/CFS as a result of decreasing the production of immune system chemicals called cytokines (i.e interferon alpha) through the removal of autoantibody containing (pro-inflammatory) immune complexes. Rituximab would therefore be working by stopping the production of (as yet) only tentatively identified pathogenic antibodies.
The group has published data on these B-cells and this shows that a specific cell maturation marker called CD-24 is upregulated or retained by the newly generated B-cells. As a result, they have been using cells from patients and healthy controls to follow B-cell development patterns, and interactions with T-cells, in response to certain stimuli. The group has also established an in vitro system (i.e. it is performed in a test tube) where they can compare the metabolic function of B-cells in ME/CFS patients and in healthy controls as well as what is termed mitochondrial mass.
Dr Cambridge did not put any ‘meat on the bone’ regarding which clinicians might/would be involved in a UK trial; where the trial might/would take place; the development of the protocol; and when a clinical trial might/would take place here in the UK until the Q and A session, where she explained the difficulties involved in setting up a UK trial for a drug like rituximab.
According to Dr Cambridge, it is going to be very hard to get a clinical trial going here in the UK due to a combination of developing a protocol, obtaining ethical approval, finding committed clinicians to carry out the work, the work being expensive in both cost and time, and the lack of pharmaceutical backing for a drug that is quite expensive to use. This has also occurred in other clinical trials involving rituximab.
Dr Cambridge also repeated the advice that has come from Drs Fluge and Mella in Norway that in our present state of knowledge rituximab should not be used on patients with ME/CFS outside proper clinical trials.
[CS note: I was going to ask Dr Cambridge over lunch what she thought about the less positive patient evidence from people with ME/CFS who have been treated with rituximab in America outside the Norwegian clinical trial (an important point that was raised during the clinical and research meeting in Sussex with Dr Amolak Bansal and myself three weeks ago) but wasn’t able to do so.
Mensah F et al. Extended B cell phenotype in patients with myalgic encephalomyelitis/chronic fatigue syndrome.
Clinical Experimental Immunology. 2016,184 :237-47.
Most recent MEA statement on rituximab: www.meassociation.org.uk/2016/05/rituximab-update-by-the-me-association-23-may-2016/
PROFESSOR TOM WILEMAN – PROFESSOR OF INFECTION AND IMMUNITY AND DIRECTOR OF THE BIOMEDICAL RESEARCH CENTRE, UNIVERSITY OF EAST ANGLIA
This presentation concentrated on what is called the enteric virome (that is, the viral population of the human gut) and the research that his group in Norwich are carrying out into the enteric virome of people with ME/CFS. This will be looking at whether there are similar changes in the diversity of the enteric virome in ME/CFS to those that occur in inflammatory bowel disease where changes in diversity are linked to an inflammatory response.
Professor Wileman explained that the human body contains large numbers of viruses in the gut even when people are well. The human virome contains what are called eukaryotic viruses (that infect host cells) and prokaryotic viruses (that infect bacterial communities) within the overall gut microbiota.
[CS note: Microbiota is the scientific name given to the collection of micro-organisms in various parts of the human body. Human beings have clusters of bacteria in different parts of the body, such as in the surface or deep layers of skin (the skin microbiota), the mouth (oral microbiota), the vagina (vaginal microbiota) etc. The gut microbiota is the name given to the microbe population in our intestine.]
The gut microbiota contains tens of trillions of microorganisms, including at least 1000 different species of known bacteria with more than 3 million genes (150 times more than human genes). Microbiota can, in total, weigh up to 2 kg. One third of our gut microbiota is common to most people, while two thirds are specific to each one of us. In other words, the microbiota in the human intestine is like an individual identity card and, when this becomes dysfunctional, it has the potential to act as a diagnostic biomarker.
The gut also has its own immune system – which only attacks invading infections. So, as with the rest of the immune system, the gastrointestinal immune system will respond to infections by producing immune system chemicals called cytokines. And it is now thought that if there is an upset in what is called the inflammatory threshold in the gut, this can influence the susceptibility to the development of a wide spectrum of physical and mental disorders – including cardiovascular disease, depression, diabetes, and inflammatory bowel disease – where the diversity of the enteric virome increases and leads to chronic inflammation. This type of inflammatory response in the gut is likely to be influenced by genetic factors as well.
In the case of inflammatory bowel disease (e.g. Crohn’s disease, ulcerative colitis), where there is a definite pathological inflammation in the intestinal mucosa, bacteria can therefore trigger an inflammatory immune response.
In relation to their research into ME/CFS, a faecal sample study is now in progress. This involves collecting stool samples from 16 people with moderate ME/CFS. The research group will then be able to produce a detailed analysis of the enteric virome in people with ME/CFS. If there do turn out to be significant and specific abnormalities in the enteric virome in ME/CFS, this information could form the basis for a diagnostic gut biomarker.
[CS note: This interesting research, which links in with the research described by Professor Maureen Hanson later in the day, is in the very early stages and at this point it is impossible to say whether the human microbiome, or the enteric virome, plays a role in the causation of ME/CFS, or is influenced as a consequence of having ME/CFS. If it does, it could also provide some useful leads in relation to treatment – one aspect of which, the possible use of probiotics, ‘heathy gut bacteria’, which can alter the diversity of the microbiome – was raised during the discussion section.]
Reference to useful review paper: Navaneetharaja N et al. A Role for the Intestinal Microbiota and Virome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)? Journal of Clinical Medicine. 2016, 5(6), 55.
PROFESSOR DON STAINES – NATIONAL CHAIR FOR NEUROIMMUNLOGY AND EMERGING DISEASES (NCNED), GRIFFITHS UNIVERSITY, AUSTRALIA
Professor Staines (pictured left with Professor Sonya Marshall-Gradisnik) is a regular speaker at these conferences. He updated on some of the work that is being carried out at the NCNED in Australia – in particular complex new research which is looking at intracellular signalling and the possibility that there may be a disturbance in the way that people with ME/CFS are handling calcium at a cellular level (ie in B-lymphocytes and NK-cells).
The background to this is that what are called Transient Receptor Potential Ion Channels (TRPs) may be playing a major role in the pathology of ME/CFS. These receptors are located in every system in the body. TRP receptors amplify activations signals, particularly via calcium, to impact on gene regulation and other physiological mechanisms.
This research has revealed genetic changes in important receptors associated with immunological and cellular function that may be contributing to the development of ME/CFS.
These genetic changes can then result in important intracellular signalling mechanisms being disrupted involving the detection and response to threats. These are primitive genes that are involved in many cellular signals in the brain, gut, cardiovascular and immune systems, as well as in the mediation of pain.
[CS note: The attractive hypothesis that part of the underlying disease process in ME/CFS could involve what is called a calcium-ion channelopathy and in the past has been put forward by my neurologist colleague Dr Abhijit Chaudhuri. During the Question and Answer session, I referred to this research and also mentioned the research that Dr John Pearn had carried out in Australia. This involved people who had contracted ciguatera fish poisoning and then went onto develop a fatigue syndrome with similar features to ME/CFS. In this case a sodium-ion channelopathy was found to be involved.]
Marshall-Gradisnik S et al. Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients. Immunology and Immunogenetics Insights, 2015; 1 DOI: 10.4137/III.S25147
Nguyen T et al. Novel identification and characterization of transient receptor potential melastatin 3 ion channels on natural kiler cells and B-lymphocytes: effects on signaling in chronic fatigue syndrome/myalgic encephalomyelitis patients. Biological Research 2016, 49, 27.
Press release on 2016 paper: www.scimex.org/newsfeed/closer-to-a-full-understanding-of-chronic-fatigue-syndrome
Useful review of ion channelopathies from the National Institutes of Health: www.ncbi.nlm.nih.gov/pmc/articles/PMC3935107/
Hypothesis from Dr Abhijit Chaudhuri et al relating to ion channels and ME/CFS:
PROFESSOR SIMON CARDING – LEADER, GUT HEALTH AND FOOD SAFETY PROGRAMME, INSTITUTE OF FOOD RESEARCH, NORWICH RESEARCH PARK
Professor Simon Carding wrapped up the morning session with a brief update on what is happening to two important European initiatives that are increasing co-operation and co-ordination of ME/CFS research in a number of EU countries. He explained that despite excellent research being carried out in several European centres this work still remains fragmented and not properly co-ordinated.
First he spoke about the work of the European ME Research Group (EMERG). Following an inaugural meeting in October last year, EMERG has set up three work streams. They cover diagnosis and patient stratification (led by Alex McGregor), biomarkers (Carmen Scheibenbogen) and sample collection/standardization (Luis Nacul, Jonas Bergquist and Jo Cambridge).
Secondly he referred to the work of EUROMENE (the European ME Network).
[CS note: This group involves researchers from 11 EU countries: Belgium, Bulgaria, France, Italy, Latvia, Norway, Romania, Serbia, Spain and the UK. EUROMENE has UK representation from Professor Jonathan Edwards, Professor Derek Pheby and Dr Eliana Lacerda (from the ME Biobank). Dr Lacerda was elected vice-chair of the group at the last EUROMENE meeting. EUROMENE now has 6 million euro funding from the EU over the next two years and their aim is to build a sustainable and integrated network of ME/CFS researchers.]
EMERG and EUROMENE have recently held a joint meeting where it was agreed that EMERG would focus on research infrastructure and setting up a European research agenda. EUROMENE will concentrate on the establishment of European network of researchers and stakeholders.
PROFESSOR MADY HORNIG – DIRECTOR OF TRANSLATIONAL RESEARCH, CENTRE FOR INFECTION AND IMMUNITY (CII), COLUMBIA UNIVERSITY, NEW YORK
Professor Mady Hornig, another regular presenter at these conferences, is researching the role of microbial, immune and toxic stimuli in the development of a range of neuropsychiatric conditions including autism, mood disorders and ME/CFS. She also directs the chronic fatigue initiative pathogen discovery and pathogenesis project at the CII, Columbia University.
In relation to ME/CFS, she is currently working on projects that will help to establish immune profiles and the identification of pathogens (i.e.infections) that are linked to the disease.
She opened by explaining how gastrointestinal problems occur in a number of neurological conditions (i.e. the gut-brain axis) and how the make up of normal gut microbiota helps to modulate brain development and behaviour.
Her group has already published results from recent research looking at cytokine networks. This research has demonstrated that there are different immune system signatures in the early stages of ME/CFS that differ from those seen later on.
Her group are now carrying out a study looking at immune system profiles and microbiome results in people with ME/CFS.
PROFESSOR MAUREEN HANSON – DEPARTMENT OF MOLECULAR BIOLOGY ASND GENETICS, CORNELL UNIVERSITY, NEW YORK
Professor Maureen Hanson already has an impressive track record in ME/CFS research. Her lab was part of the 2012 multicentre study organised by Prof Ian Lipkin’s group at Columbia University to assess the role of XMRV in ME/CFS (none found).
Her current research projects involve the examination of the microbiome in people with ME/CFS and controls with Dr Ruth Ley (Cornell Microbiology) and Dr Susan Levine. She is also collaborating with Dr Levine on an immune cell gene expression study. A third project is in collaboration with Dr Betsy Keller at Ithica College. This involves the collection of blood samples from people who are performing a two-day cardiopulmonary exercise test.
Professor Hanson’s presentation concentrated on one of the main themes running through the conference – the search for an objective biomarker that can be used to diagnose people with ME/CFS. In the current situation there are various potential candidates: immune cell dysfunction – especially NK cell dysfunction and cytokines; the two-day cardiopulmonary exercise test, abnormalities on brain/neuroimaging; changes in gene expression in immune system cells.
Professor Hanson described how her group are now exploring the possibility that levels of inflammatory proteins in the blood, in conjunction with bacterial species in the gut microbiome, might serve as biomarkers if the intestinal microbiome is disturbed in ME/CFS – as some researchers believe is the case.
Background info from this presentation: The human microbiome (HMB), situated in the large intestine, plays an important role in the protection against infection and disturbances in the HMB are now been implicated in obesity, type 2 diabetes and inflammatory bowel disease. The HMB is also influenced by diet, health status, genotype (= genetic make up) and age. With gastric and bowel symptoms commonly being present in ME/CFS, it is therefore possible that the HBM plays a role in ME/CFS. Gastrointestinal symptoms are also commonly reported in ME/CFS. In her own study, 32/47 ME/CFS patients had intestinal discomfort compared to 8/39 controls.
The group has examined the gut microbiome in 48 ME/CFS patients and 39 healthy controls by sequencing regions of DNA (i.e. genetic material) that allow for the identification of the different bacteria that are present.
Preliminary results indicate that people with ME/CFS have a reduction in the diversity of the bacterial population compared to healthy controls – something that is also found in inflammatory bowel disease such as Crohn’s disease and ulcerative colitis. And, while there is no specific species of bacteria that is present in the ME/CFS group and absent from healthy controls, the group were able to identify a number of taxonomic groups that were present in a different ratio in people with ME/CFS compared to healthy controls.
They have also found an increase in inflammatory markers in the plasma in the ME/CFS patients known as lipopolysaccharides. This may may be related to intestinal function and intestinal inflammation.
By using careful statistical analysis involving blood and gastrointestinal sample analysis, her group were able to correctly classify 83% of subjects as having ME/CFS or being a healthy control.
These are clearly interesting findings that are consistent with a hypothesis that involves involvement of the gastrointestinal tract, microbe transmission into the blood, and an activated immune system response. The difference in the microbiome population could also be contributing to both ME/CFS symptoms and severity. However, the present evidence does not suggest that these abnormalities are involved in causation of ME/CFS – they are more likely to be a consequence of the disease process.
PROFESSOR ELISA OLTRA – PROFESSOR OF CELL AND MOLECULAR BIOLGY, UNIVERSIDAD CATOLICA DE VALENCIA, SPAIN
Professor Oltra specialises in cellular and molecular biology and has a specialist interest in stem cell-based therapies and cancer. Her team has also been seeing patients with fibromyalgia (FM) for many years and investigating the molecular basis for FM.
Back in 2009, she started work on a project to investigate the molecular basis of fibromyalgia (FM) where they identified irregularities in what are known as RNAseL expression and profile changes in miRNAs – both of which could increase our understanding of underlying disease mechanisms in both FM and ME/CFS.
Professor Oltra’s presentation was mainly about the search for an objective biomarker for ME/CFS.
Background info from this presentation: MicroRNAs, also known as miRNAs or miRs, are a set of small molecules that are present in all body fluids. They act as important modulators of gene expression in tissue specific pathways in response to environmental triggers and in disease. These small nucleic acids have been shown to be helpful in the diagnosis and prognosis of certain forms of cancer. They may also have a role as potential biomarkers in FM and ME/CFS. Once identified, they are easy to make use of in diagnostic tests.
Encouraged by the idea that miR profiling may be altered in ME/CFS, her group have been looking at blood samples, and other body fluids, to see if there are any significant abnormalities. In their initial study, they have looked at miRs in peripheral blood mononuclear cells (PBMCs) in patients with both ME/CFS and age-matched controls and those with FM.
They are now extending this study to include a larger group of participants with a more varied symptom profile with the aim of symptom profiling and producing symptom severity miR profiles. This is being done in collaboration with Dr Nathanson (who works with Dr Nancy Klimas in the USA) and Dr Alegre’s group in Barcelona, Spain.
PROFESSOR JAMES BARANIUK – PROFESSOR OF MEDICINE, GEORGETOWN UNIVERSITY MEDICAL CENTRE, WASHINGTON DC, USA.
Professor Baraniuk gave a rather diverse presentation that jumped around a number of subjects. This involved nomenclature, definition and the overlap of ME/CFS with other conditions involving fatigue and pain – especially fibromyalgia and Gulf War Syndrome – from both an historical perspective and from our current understanding of the subject.
In relation to FM, he discussed the role of the Pain Catastrophizing Scale in FM and the way in which the objective measurement of pain differs in FM from ME/CFS. This involves using a technique called dolorimetry, which measures pain threshold and tolerance
In relation to GWS, he described how a combination of factors relating to troop deployment – vaccinations, heat, stress, the use of pyridostigmine bromide tablets, and exposure to sarin and nerve agents – played a role in the causation of this syndrome, which has some interesting clinical overlaps with ME/CFS.
Professor Baraniuk concluded by describing his on-going study of brain MRI before and after a submaximal exercise test and some new research that his group is carrying out into postural tachycardia (where the pulse rate increases following a change in posture from lying to standing) in ME/CFS.
PROFESSOR RON DAVIS – PROFESSOR OF BIOCHEMISTRY AND GENETICS, STANFORD SCHOOL OF MEDICINE, USA
The final presentation of the day came from Professor Ron Davies, who is a world authority in biotechnology ≠ especially in the use of recombinant DNA and genomic methodologies and their application to human disease.
Professor Davis started off by describing how his interest in ME/CFS stemmed from the fact his son – Whitney Dafoe – had become seriously ill with ME/CFS.
The focus of his presentation was the collection of ‘Big Data’. This is the new medical buzzword that describes the collection of all kinds of biological and clinical data, using new techniques such as genomics, metabolomics, proteomics (i.e. the production and interplay or proteins) to see what sort of abnormalities can be found in large numbers of people with a particular condition.
Professor Davis is embarking on a study that will involve 20 people with severe ME/CFS and 10 controls and will collect billions of bytes of information. He explained that this type of study is very expensive to carry out (approximately $70,000 per patient) and he is working with the Open Medicine Foundation in America to raise private funds.
The blood, sweat, saliva and faecal/stool samples will be analysed in minute detail for a whole range of abnormalities including the immune system (NK cell activity and gene expression, cytokine analysis etc), metabolomics (i.e. small molecules, also known as metaboliites, that are found in body fluids, tissues etc) and proteins (proteomics).
Fortunately, through a generous donate from Metabolon – a high tech company that deals in metabolomics – the cost of this particular part of the project has been reduced significantly.
Professor Davis concluded by presenting slides of some very interesting pilot data on serum – by using a map model of known biochemical pathways – from 3 patients.
In his opinion, these initial findings show a severe and fundamental problem involving complex biochemical pathways, including the citric acid cycle in the mitochondria, that are involved in energy generation from sugars and fats at a cellular level in ME/CFS.
Professor Davis also referred to some specific abnormalities in the biochemical pathways and specific deficiencies (including biotin and tryptophan) that have been found in this preliminary analysis of the data. And as many of these key functions and activities take place within the mitochondria, where energy generation takes place, Professor Davis believes that mitochondrial dysfunction is a key component of this illness.
Professor Davis also referred to the use of mice models in the investigation of disease causation and treatment in ME/CFS and pointed out that when new drugs are assessed in mice the results may be very different to those seen in humans.
[CS note: Here in the UK a ‘big data’ study is in the process of being put together by Professor Stephen Holgate and the CFS/ME Research Collaborative. A workshop was held in Bristol in April 2016 that brought together an impressive collection of researchers working in genetics, epigenetics, proteomics and metabolomics. The aim is to collect clinical data plus blood and urine samples from 10,000 people with ME/CFS and a research grant application for this study will be submitted later in the year.]
More information on this presentation can be found on the ME Action site: www.meaction.net/2016/06/04/ron-davis-errors-metabolism/
Article in the Washington Post on Whitney Dafoe: www.washingtonpost.com/national/health-science/with-his-son-terribly-ill-a-top-scientist-takes-on-chronic-fatigue-syndrome/2015/10/05/c5d6189c-4041-11e5-8d45-d815146f81fa_story.html
The meeting closed with a review of the day from Dr Ian Gibson followed by general discussion on a range of clinical and research topics.
This was an interesting, encouraging and informative conference that covered a number of important new approaches to the way in which the investigation of the underlying disease process in ME/CFS, as well as the development of diagnostic biomarkers, is now moving forward. Hopefully, these developments will also lead to much needed treatments that are aimed at causation rather than symptoms control – as is currently the case.
Thanks to everyone involved in both the organization of this event and the people who gave the presentations.
* I can also recommend another comprehensive conference report from Mark Berry. This is available on the Phoenix Rising website: forums.phoenixrising.me/index.php?threads/a-new-decade-of-me-research-the-11th-invest-in-me-international-me-conference-2016.45189/#post-734738
* The conference journal is available to download as a pdf: www.investinme.org/Documents/Journals/Journal%20of%20IiME%20Vol%2010%20Issue%201.pdf
* A DVD of the conference proceedings can be pre-ordered here: http://www.investinme.eu/IIMEC11-DVD-Order.shtm1
Dr Charles Shepherd
Hon Medical Adviser, ME Association
20 June 2016