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A New Decade of ME Research: The 11th Invest in ME International ME Conference 2016

Mark Berry presents the first in a series of articles on the 11th Invest in ME International ME Conference in London …
11th Invest in ME Conference Logo

The 11th Invest in ME International ME Conference (IIMEC11) was held at One Great George Street, just down the road from its previous home on Birdcage Walk, on Friday June 3rd, 2016.

You can view the full conference agenda (with photos and biographies of the speakers) here and the Conference Journal is available to download as a PDF. The highly-recommended DVD of the conference is now available for pre-order, and Kina did an incredible job tweeting the conference live for Phoenix Rising.

This article, the first in a series covering the conference, summarises all of the presentations. Future articles will explore selected presentations in more detail.

Conference Agenda

Richard Simpson: “Welcome and Introduction to IIMEC11”

Dr Ian Gibson: “10 Years – Looking Back, Looking Forward”

Dr Vicky Whittemore: Keynote: “A new research initiative into ME at NIH”

Professor Olli Polo: “Clinical Diagnosis of Myalgic Encephalomyelitis”

Professor Carmen Scheibenbogen: “Autoantibodies to adrenergic and acetylcholine receptors in CFS/ME”

Dr Jo Cambridge: “Immunoregulation in patients with ME”

Professor Tom Wileman: “Gut Virome in ME”

Professor Don Staines: “Update from NCNED: Receptor identification and intracellular signalling”

Professor Simon Carding: “The European ME Research Group (EMERG)”

Professor Mady Hornig: “Pathogen Discovery in ME”

Professor Maureen Hanson: “The Search for Biomarkers for Myalgic Encephalomyelitis”

Professor Elisa Oltra: “Molecular Biomarkers of Myalgic Encephalomyelitis”

Professor James Baraniuk: “Exercise Testing and Orthostatic Tachycardia”

Professor Ron Davis: “Big Data Approach: Severely Ill ME Patient Cohort”

Plenary and Personal Reflections

Welcome and introduction to IIMEC11

Invest in ME’s Richard Simpson kicked off proceedings by welcoming conference-goers to IIMEC11, and took us through the usual conference house-keeping information.

Warning of the scheduled fire-alarm test in the afternoon, he reassured us, “I’m told that the only person with a gun in London today is Ian Gibson, our chair.”

Noting the new venue, with much-improved accessibility, he hoped we would find it an improvement, and he advertised the conference DVD, warning that Early Bird ordering would be closing in the next day or so — but it’s still available for pre-order at a knock-down price.

Simpson thanked the speakers from various parts of the world, recalling again how much they now feel like a family. About 18 countries were represented here today, he said, and he noted in particular the European ME Alliance (EMEA), whose AGM was hosted by Invest in ME the following day.

Simpson hoped that in future they would be able to develop that link and “wrap around” to make these “a set of events which really make progress”. Invest in ME’s Centre of Excellence is “nearly there”, he added, and he advised of the new Twitter hashtags for the final push to get it over the line: #letscresearch and #cofeforme.

With the housekeeping and business quickly out of the way, Simpson introduced a man who, as he rightly said, does so much, out of the headlines, not just for the cause of ME patients but for other causes as well: “the guy with the gun …”

10 Years – Looking Back, Looking Forward

Dr. Ian Gibson — Former Dean of Biological Sciences, University of East Anglia, UK

Picture of Dr Ian Gibson

Dr Ian Gibson

Dr. Gibson recalled his introduction to the world of ME politics 10 years ago, and said that 10 years later “we’re still fighting on … but there’s a new atmosphere around.”

He admitted that the Gibson report had compromised, and explained why. He expressed strong feelings about the admission that the UK doesn’t keep data on the numbers of ME patients, and about the lack of support for carers: “the world is full of people who want to care and don’t get care and support themselves.”

Gibson suggested five political themes to focus on as part of a “Pledge Card”: European and International Collaboration, Education, Substantial Funding, United Nations, and Centre of Excellence.

And he said he is “never one who thinks this money’s not around, it can be found if you look hard enough,” before asking keynote speaker Dr Vicky Whittemore: “What have you got to offer? …”

Keynote speech: ‘A new research initiative into ME at NIH’

Dr. Vicky Whittemore — Program Director, National Institute of Neurological Disorders and Stroke, National Institutes of Health, USA

Picture of Dr Vicky Whittemore

Dr. Vicky Whittemore

Dr. Whittemore from the US National Institutes of Health (NIH) made a big statement just by attending the conference, signaling her intent to encourage international collaboration in ME research.

She hailed the “new dawn” and “new vision” for ME/CFS research in the U.S. government agencies, acknowledging historical problems like the “shocking and disappointing” funding levels.

But she explained how individuals like Ron Davis and Francis Collins had become impatient with the lack of progress and the lack of understanding within NIH of the importance and severity of ME/CFS, and had brought this issue to the attention of the director of NINDS, Walter Koroshetz.

She outlined the emerging agenda for the NIH’s short, medium and long term plans for ME/CFS research. She described recent initiatives including the “deep dive” intramural study, the revitalization of the Trans-NIH ME/CFS Working Group, the call for applications for supplementary grants, efforts to encourage research collaboration, and the public request for feedback on what the research priorities should be.

She said that her “hope and vision” was to return to IiME in the next two years and present a graph showing levels of government funding for ME/CFS research “off the charts.”

‘Clinical Diagnosis of Myalgic Encephalomyelitis’

Professor Olli Polo — Chief of the Department of Pulmonary Medicine, Tampere University Hospital, Finland

Picture of Professor Olli Polo

Professor Olli Polo

Professor Olli Polo focused on the importance of identifying clinical signs in order to establish the credibility of ME in the minds of often-sceptical medical practitioners who “need to see to believe.”

He presented some examples from his own experience as an expert in sleep apnea who sees a lot of ME/CFS patients in the course of his work.

Running through a list of ME/CFS symptoms, he said that they affect the whole of the sympathetic trunk, making ME/CFS a whole-body condition that doesn’t fit well with the prevailing model of medicine.

He drew attention to a paper from Peter Rowe which concluded that a subset of patients with ME/CFS and OI also have EDS.

After describing (with photos) a variety of signs indicating disorders of the connective tissue in his ME/CFS patients, he proposed that connective tissue disorders can allow veins to distend excessively causing venous pooling and problems with blood flow, resulting in multiple symptoms.

He explained how whiplash or hypermobility can interfere with ‘central descending sympathetic tone’ and how excessive firing of damaged C-fibers causes excessive ‘peripheral ascending sympathetic rescue activation’, both of which can disrupt the sleep-wake cycle.

In this way, elastic veins or arteries can result in a phase of prolonged sleep duration followed by a phase of insomnia, he concluded.

‘Autoantibodies to adrenergic and acetylcholine receptors in CFS/ME’

Professor Carmen Scheibenbogen — Professor for Immunology and Deputy Chair, Institute of Medical Immunology, Berlin Charite, Germany

Picture of Professor Carmen Scheibenbogen

Professor Carmen Scheibenbogen

Professor Scheibenbogen summarised the efforts of her team at Berlin Charite to identify autoantibodies in ME/CFS patients. She reviewed the hypothesis that ME/CFS is an autoimmune disease, and the evidence supporting that hypothesis, and explained why antibodies to neurotransmitter receptors are an obvious starting point, supported by the findings of a Japanese study in 2003.

She described her exploratory work with Gerd Wallukat, and her study published in February 2016, which found that antibodies against Beta-2 adrenergic, and M3 and M4 muscarinic acetylcholine receptors, were significantly elevated in 29.5% of the ME/CFS patients.

She explained that they had also found a correlation between elevated levels of these antibodies and immune activation, and noted some strikingly familiar symptoms that result from acute Beta-2 and M3 stimulation.

Intriguingly, these two receptors are complimentary, so one might expect to see opposite effects in different individuals and even fluctuating opposite effects in an individual patient.

The research also found that responders to Rituximab had reduced levels of these autoantibodies, whereas non-responders did not. Scheibenbogen finished with some suggestions for possible treatments for those with elevated levels of these autoantibodies: Intravenous gamma-globulin, immunadsorption therapy (now being trialed in Berlin), and of course, Rituximab.

Questions focused on the difficulty of obtaining insurance coverage for ME/CFS and how to overcome this, possible explanations for ME/CFS occurring in outbreaks, potential parallels with organophosphate poisoning, and whether the length of a patient’s illness might affect treatment.

‘Immunoregulation in patients with ME’

Dr. Jo Cambridge — Principal Research Fellow, Inflammation, Div. of Medicine, Faculty of Medical Sciences, UCL, UK

Picture of Dr Jo Cambridge

Dr. Jo Cambridge

After a tea break, Dr. Jo Cambridge explained that as part of the group which had introduced the idea of B cell depletion as a treatment for rheumatoid arthritis about 10 years ago, and which has since been exploring in more detail how the technique works and why response varies between patients, she’s “pretty rituximab.”

As a relative newcomer to ME/CFS research, prompted by Fluge and Mella’s successful treatment of ME/CFS patients with Rituximab in Norway, she “accepted fully that ME is an organic illness” and she presented a simplified version of her model of ME/CFS.

She explored possible mechanisms to explain why Rituximab is effective in ME/CFS, showing how it works by binding to B cells that express the CD-20 receptor and killing them (“Splat!”), and explained that memory B cells, and B cells in certain tissues (and especially in bone marrow) are more resistant, potentially explaining the variability of response to treatment.

Cambridge showed how response varies across autoimmune diseases, depending on the significance of autoantibodies in the disease process. She pointed out that response rate and speed of response are always variable in diseases where it’s used as a treatment, with response almost always taking at least a few months to kick in.

She said that fears about people dying of infections when their immune system is knocked out have proved unfounded in practice. She clarified that when the B cells return after Rituximab wears off, this may or may not trigger a relapse. For some people, there is no relapse when the B cells return, and it’s a long-lasting cure.

Main hypotheses as to how Rituximab works are that it may stop B cells from differentiating into plasma cells, or it may stop interactions of B cells with other cells (for example, T-regs).

At UCL they have been investigating phenotype sub-populations of naive and memory B cells in ME/CFS patients. Cambridge introduced Ph.D. student Fane Mensah who has been working on this.

Mensah presented a preliminary conclusion that they believe they have confirmed dysregulation of B cells associated with the CD24 marker in ME/CFS patients. He explained that they are now investigating interactions between B cells and T-cells in patients, using an in vitro system to explore soluble serum factors, and looking at mitochondrial mass, proliferation, CD23 differentiation and antibody production.

‘Gut Virome in ME’

Professor Tom Wileman — Professor of Infection & Immunity at the University of East Anglia, Norfolk, UK

Picture of Professor Tom Wileman

Professor Tom Wileman

Next, Professor Tom Wileman introduced the concept of the enteric virome: the viral population of the gut, which has its own immune system, with a homeostasis existing between microbes in the gut and the host’s immune system.

Interactions between the immune system and the microbiota can set an inflammatory threshold which can influence disease. He discussed how viruses which infect bacteria — phages — can affect these interactions, and explained that only recently has it become possible to study this.

In 2014, some U.S. groups proposed the Virotype Hypothesis, whereby these interactions affect the inflammatory threshold and may cause disease.

Wileman’s lab has been investigating this in IBS and they are finding that when the gut is upset, bacteria move into the immune system, create infection, and upset the inflammatory threshold, characterised by a decrease in the diversity of viruses in the gut.

Maureen Hanson has found a similar reduction in diversity of the microbiome in ME/CFS (Hanson presented this data later in the conference). Bioinformatic analysis is now required to explore the details.

With sponsorship from Invest in ME, Ph.D. student Daniel Vipond has been exploring this with them and they are now working through the bioinformatics based on samples from 16 moderate ME/CFS patients.

“Every flea has a flea that lives on a flea,” he explained. Each phage can be assigned to a member of a bacterial family living in the gut. Work elsewhere is moving in the direction of attempting to correlate the phage population with disease, and to explore how the phages influence the metabolism of the microbes that they affect.

Working up this data through stool samples could potentially lead to a very quick and easy biomarker. A few days after the conference, Wileman published a review of the evidence about all this, together with Professor Simon Carding, Invest in ME-funded Ph.D. student Navena Navaneetharaja and others, which is an excellent starting point for anyone interested in exploring this topic.

‘Update from NCNED: Receptor identification and intracellular signalling’

Professor Don Staines — NCNED, Griffith University, Australia

Picture of Professor Don Staines

Professor Don Staines

Professor Don Staines ran through the work of his group at Griffith University, presenting evidence for a channelopathy in B lymphocytes — specifically, a calcium channelopathy.

Last year Dr. Sonya Marshall-Gradisnik had presented their findings of SNPs (single point genetic mutations) that affect transient receptor potential (TRP) function, changing how cell signalling happens.

They next wanted to know what it might be about this signalling that may cause the immune system’s Natural Killer cells to fail to do their job of killing their target cells.

Five of the 15 SNPs they found were related to the TRP-M3 receptor. Investigating immune cells where that receptor was expressed, in ME/CFS patients they found reduction in the expression of that receptor on isolated B cells (CD19) and Natural Killer cells (CD56+ bright).

If these SNPs translate into damaged receptors, Staines said, that in itself may harm the immune system, but  calcium signalling pathways within cells may also be affected.

He added that their group are currently preparing “nine or ten” further papers exploring the changes that then follow within the cells. They have found protein kynase p38 MAPK to be upregulated, which in turn will upregulate various inflammatory cytokines — notably TNF-alpha and IFN-gamma, which can open the blood-brain barrier and cause a sustained inflammatory response.

They also see downregulation of ERK 1 and 2, which would affect how NK cells and granzymes migrate along the cytoskeleton and impair their ability to do their job. Investigating the calcium within the cell, they see reductions in calcium levels in the cytoplasm and storage of calcium at the endoplasmic reticulum.

Their conclusion: “Impaired TRP receptor function and impaired calcium signalling and stores is suggestive of a pathology for ME.” Among the effects one would expect from impaired TRPM3 expression are impaired pain sensation and pain signalling, and impaired regulation of body temperature, both of which fit with the symptomology of ME/CFS.

‘The European ME Research Group (EMERG)’

Professor Simon Carding — Leader, Gut Health and Food Safety Programme, Institute of Food Research, Norwich Research Park, UK

Picture of Professor Simon Carding

Professor Simon Carding

Professor Simon Carding finished the morning’s presentations with a brief introduction to the new European ME Research Group (EMERG), a trans-European network of research groups which aims to jointly define a co-ordinated research strategy to be agreed and adopted by those research centres.

Following its inaugural meeting on 13th October 2015 in London, three work packages had been agreed upon:

Clinical diagnoses and patient stratification (led by Alex McGregor)

– Biomarkers – nature and validation (led by Carmen Scheibenbogen)

– Sample Standardisation (led by Luis Nacul, Jonas Bergquist, and Jo Cambridge).

A separate network, EUROMENE, was launched in Easter of 2016, aiming to build a sustainable, integrated network of ME/CFS researchers in Europe. Its 6 million euros of funding runs for the next four years, 15 countries are represented, and Dr. Eliana Lacerda is the UK representative on that group.

EMERG and EUROMENE have met together to clarify their different roles: EMERG will focus on infrastructure and establishing a European research agenda; EUROMENE will establish networks of researchers and stakeholders.

Regarding practical research, early feasibility projects are looking at infectious origins (environmental and microbiome alterations), and clinical trials and supporting research (e.g., Rituximab and bacteria-based therapy).

Carding ended with a quote from Henry Ford: “Coming together is a beginning; keeping together is progress; working together is succcess.”

‘Pathogen Discovery in ME’

Professor Mady Hornig — Associate Professor, Center for Infection and Immunity (CII), Columbia University Mailman School of Public Health, New York, USA

Picture of Professor Mady Hornig

Professor Mady Hornig

After a lunchtime during which an extraordinary collection of the world’s top ME/CFS researchers and physicians networked extensively with every conceivable kind of stakeholder in the world of ME/CFS, Professor Mady Hornig began the afternoon’s presentations.

She started out with a summary of the ME/CFS research programme at Colombia University, together with a rationale for their mission.

The group there has been working to identify pathogens and triggers for ME/CFS for quite some time. Her talk illustrated the complexity of the task.

With a long list of suspected viral triggers (many of them already implicated in a variety of brain disorders), and a variety of microbial and immune factors involved in a complex disorder, some major problems are: how to make a connection specifically to ME,  how to explain multiple viruses triggering one disease, and how to tie everything together in a way that makes sense in terms of diagnosis and treatment.

Much of her wide-ranging and complex presentation aimed to explain why her group’s model of ME is an immune-mediated brain disorder, with a significant connection to the gut. When the microbiota (gut microbes) are disordered, disorders of brain function are among the many consequences.

Organophosphates, viruses and intoxicants can all disrupt the microbiota, and even cause epigenetic changes in the gut microbes themselves, with long-lasting effects. She spoke of how a disrupted microbiome could induce changes in the metabolome and how a skewed microbiome might make development of an autoimmune condition more likely.

Expanding on the gut-brain axis, Hornig presented a more complex slide illustrating the gut-microbiota-metabolomic-brain axis. She and her team are trying to piece together how all these complex interactions may ultimately affect the brain.

The numerous strands of their ‘staged strategy for pathogen discovery in immune-mediated disorders’ includes studies in association with NIH (NINDS and NIAID), the Chronic Fatigue Initiative, Dr. Montoya at Stanford and Dr. Peterson.

Hornig highlighted the group’s 2015 study “Cytokine network analysis of cerebrospinal fluid in ME/CFS” in which they found IL-6 at nearly undetectable levels, and said that further studies were investigating this and trying to tie the cause back to the microbiota.

In this effort, she was particularly interested in the potential for disruption to the tryptophan degradation pathway in response to infections and other stressors.

But in summing up, she again indicated the complexity of the disease models that are emerging. From the classical model of “one microbe, one disease,” it is now becoming clear that a much more complex set of questions must be answered in order to understand complex diseases: who (genetic susceptibility),  what (shared epitopes), when (triggers), where (in the placenta, GI tract, or elsewhere), why, how (e.g., breakdown of blood-brain barrier).

All of these factors, in multiple combinations, come together to form a disease profile — a complex picture indeed!

‘The Search for Biomarkers for Myalgic Encephalomyelitis’

Professor Maureen Hanson — Liberty Hyde Bailey Professor, Department of Molecular and Genetics, Cornell University, New York, USA

Picture of Professor Maureen Hanson

Professor Maureen Hanson

Professor Maureen Hanson was next up, and she started by looking at definitions of a biomarker and why it is so important to identify biomarkers for ME/CFS:

– To distinguish it from other diseases

– To provide objective measures for interventions and drug therapies

– To select participants for studies, and to provide information to help identify the underlying cause (or causes)

Long-standing candidates for ME/CFS biomarkers include abnormal immune function (such as altered NK cell activity), physiological measures varying abnormally after exercise challenge, abnormalities in brain imaging, and more recently other candidates including changes in gene expression and cytokine levels.

Together with Susan Levine and others, Hanson has a 2-year grant to search for biomarkers in the bacterial microbiome. She presented the findings so far from her study of 49 of Levine’s patients and 39 control subjects.

Focusing on inflammatory markers in plasma that may be related to intestinal function, they found a big increase in levels of lipopolysaccharides (LPS), as well as LBP and soluble CD14 (which are a natural consequence of high levels of LPS).

Hanson has also looked at the overall bacterial population of ME/CFS patients, where they found a difference in the number of bacteria between patients and controls. This overall difference was not enough to distinguish between patients and controls, but this is not surprising as they found the same to be true in Crohn’s disease.

However, when they compared bacterial diversity — the number of bacterial families present in the gut — this was a lot lower in ME/CFS patients. There was a clear “loss of species richness” (which has been found in Crohn’s disease as well).

They also found an association of specific bacterial groups with ME/CFS, as distinct from controls: they found that anti-inflammatory bacterial species (ruminococcae, which produce butyrate, an anti-inflammatory fatty acid) and species of bifidobacterium (which produce lactic acid) were reduced in ME/CFS patients. And with a combination of blood and gut assays they could classify 83% of samples correctly as coming from patients or controls.

Hanson drew laughter and applause from the audience when she added that she did want to say that “I don’t see how these different biomarkers in the gut could possibly be explained by the psychosocial model of CFS.”

Although her study was small, she does believe that they could use these metabolites to distinguish 100% of patients from controls, and she is hopeful that they will be able to develop this research into a real biomarker test for ME/CFS.

‘Molecular Biomarkers of Myalgic Encephalomyelitis’

Professor Elisa Oltra — Professor of Cell and Molecular Biology, Universidad Católica de Valencia “San Vicente Mártir”, Spain

Piture of Professor Elisa Oltra

Professor Elisa Oltra

Professor Elisa Oltra began her first presentation at the Invest in ME conference with a bit of background information. Her introduction to ME research came when she joined The University of Valencia.

The team there has been treating fibromyalgia and ME patients for about 20 years, and they make sure that every student going through the medical programme learns about the disease, and learns that many people are suffering.

Since 2009 she has been looking for biomarkers and investigating the molecular basis of fibromyalgia. So far she has identified irregularities in RNAseL expression and the profile of micro RNAs.

Now as Professor of Cell and Molecular Biology at the Universidad Catolica de Valencia, she continues her search for biomarkers and her study of micro RNAs in particular, and she echoed Maureen Hanson’s list of reasons why the search of biomarkers is so important.

Micro RNAs (non-coding RNAs that regulate gene expression) are particularly promising, she believes, for a number of reasons.

They have been established as proven biomarkers of other diseases. They are relatively stable compared to other RNAs meaning that long-term samples can be analysed. They are relatively easy to implement in diagnostic tests in clinics once they have been identified. And they have barely been explored for the diagnosis of ME and related diseases. Micro RNAs are also present in all body fluids.

Oltra’s work to date has focused on fibromyalgia, and in a small study of FM patients who also have chronic fatigue, who have been ill for over 10 years and diagnosed by more than one specialist, she believes her work has identified a micro RNA profile that, if validated, could be developed into a biomarker.

Using genome-wide expression profiling with a new Japanese sequencer (and validated by real-time PCR), in the patients they studied they saw 193 of 1212 miRNAs (16%) at less than half of the levels found in controls, and the handful of similarly upregulated miRNAs (3%) that they saw were only present at very low levels.

At the end of this preliminary analysis, they concluded that a signature of five strikingly downregulated miRNAs in particular could be used as biomarkers of “FM/CFS”. Interestingly, two of these five have independently been shown to be inhibited in cerebrospinal fluid of FM patients (Mannerkorpi et al, PLoS One, 2013), and one was identified as abnormal in plasma of CFS patients (Marshall-Gradisnik et al, PLoS One, 2014).

The next step is to validate these findings in a larger study group, which they are planning to attempt in association with Dr. Nathanson (from Dr. Klimas’ group at Nova University) and Dr Alegre’s group at Val D’Hebron Hospital in Barcelona.

Pondering the possible meaning of the miRNA downregulation in ME, Oltra noted that viruses can manipulate the cellular processes required for their replication, by targeting the RNA interference machinery of the host. She speculated that chronic recurrent infections might lead to well-defined miRNA profiles – but cautioned that this idea is speculative at present.

Another possible explanation she proposed was that stress to the endoplasmic reticulum (also mentioned earlier by Staines), associated with viral infections, environmental factors and aging, is also connected to miRNA metabolism.

‘Exercise Testing and Orthostatic Tachycardia’

Professor James Baraniuk — Professor of Medicine at Georgetown University Medical Centre, USA

Picture of Professor James Baraniuk

Professor James Baraniuk

Professor James Baraniuk returned to IiME with a presentation that was typically provocative, idiosyncratic, and peppered with amusing asides. He started with a look at the historical “drift” of diagnostic criteria in fibrositis (later known as fibromyalgia, and “stripped down” by Wolfe in 1990), benign myalgic encephalomyelitis (later, ME/CFS), and Gulf War Illness.

Baraniuk has suggested before that the distinction between fibromyalgia and ME/CFS is fuzzy at best, and he drew attention to the criteria he still thinks are the best: RM Bennett’s 1981 definition of ‘fibrositis‘.

He also applied his dry humour to the Pain Catastrophising Scale (PCS), on which, if you score above 16, you’re deemed to be catastrophising – “Thank you, thank you very much.”

The PCS had been applied to fibromyalgia in particular as the diagnostic criteria “drifted,” and he wryly highlighted the downregulated and upregulated genes shown to be associated with high levels of “catastrophising” in fibromyalgia sufferers.

As his slide illustrating the PCS scale “failed to reproduce” very well on the projector, Baraniuk mused: “maybe the fuzziness is telling you something.”

Regarding the name “myalgic encephalomyelitis,” which goes back to epidemics of nurses caring for polio patients, he noted that five epidemics from the 1920s and 1930s had been re-evaluated as hysteria — “an unfortunate link that is a legacy … an asterisk tagged on to the ME name … I can only hope that we do justice to you by re-evaluating this link and getting away from ‘hysteria.’”

He added that it was Carruthers who had brought the title back, and praised his contribution of identifying post-exertional malaise as the key factor, and emphasising autonomic dysfunction. Regarding Gulf War Illness (a major focus of his research), he drew gasps from the audience when he asserted that between 25 and 32% of those deployed are now affected — “if there were a similar attack rate on the House of Commons, maybe there’d be some funding for it” — and described some of the notable chemical exposures suffered by the troops.

Between FM, ME, CFS and GWI, there are a number of overlapping conditions here. Can we separate them, he asked?

Looking at frequency analyses in women of systemic hyperalgesia (the classical diagnostic criteria for fibromyalgia: striking tenderness measurable by a significant pain response to a small amount of pressure that would not normally cause pain, and which can now be tracked through to the brain) presented a confusing picture when comparing the distribution of responses in patients with these different diagnoses.

Women with fibromyalgia stood out on the graph, but this was not surprising given that they had been diagnosed on that very basis. Baraniuk had expected that women with CFS would also be very sensitive, but the results here were fairly equivocal in comparison with controls. The one group for whom the measure seemed useful was women with GWI: their pain sensitivity was extreme.

Turning to his own recent research, Baraniuk mentioned his ongoing study of brain MRI before and after a submaximal exercise test.

Their stressor is not enough to see the 15% drop in VO2 max on Day 2, as reported in maximal exercise tests, but it’s enough to see changes in the blood flow in the brain, especially after a cognitive test.

A few more participants are required for the study, and can contact baraniuklab@georgetown.edu if interested — they’ll even throw in a lumbar puncture for free!

About half of the CFS subjects he has tested — and none of the controls — exhibit Baraniuk’s Stress Test Activated Reversible Tachycardia (START): postural tachycardia following exercise challenge.

They are now assessing the details of heart rate variability in this group, but so far they see greater activation of the sympathetic nervous system in this group. They enter “fight or flight” mode just because they stand up.

START is contrasted with STOPP (Stress Test Originated Phantom Pain) in Baraniuk’s terminology … but as he ran out of time, and Dr. Gibson demanded that he “climax,” Baraniuk hastily summarised: the ‘tenderness’ in fibromyalgia may turn out to be an artefact; in Gulf War Illness, it may prove to be more significant; GWI patients have many symptoms distinguishing them from ME patients; and START is telling us that there is something wrong with the brain stem in these patients.

‘Big Data Approach: Severely Ill ME Patient Cohort’

Professor Ron Davis — Director, Stanford Genome Technology Center, Palo Alto, California, USA

Picture of Professor Ron Davis

Professor Ron Davis

As is customary, Invest in ME saved the best for last: Professor Ron Davis delivered a mind-blowing presentation that drew the day’s longest round of applause by far.

Most in the audience were already aware of his motivation for entering the ME/CFS research arena: his son Whitney Dafoe “has been missing for 5 years, I have to do this research”.

Davis’ starting point is to gather data, and lots of it. After taking part in the IOM panel’s efforts, spending a year and a half looking at about 9000 publications mentioning ME/CFS, what shocked him was how little useful data there was, meaning that he was unable to complete his task of identifying a biomarker.

Since the necessary data was missing, he decided to collect it himself …

Research proceeds by making observations, forming hypotheses based on them, and then testing them, but as Davis explained, there’s a problem forming hypotheses when you don’t have adequate data.

Historically, the NIH had been conducting a series of “trial and error” studies, and has now stipulated that there must be a clear hypothesis, which seemed reasonable enough, but as a result, Davis’ own grant submissions to collect the crucial data were rejected for lack of a hypothesis.

So he teamed up with the Open Medicine Foundation to raise private funds to collect the data — and he pledged that he would put up all the data for scientists to view, even ahead of publication of his results; he would try to make it easy for people to download the data, and is working on the software to make that possible for such enormous data sets.

His approach collects all the data at the same time point, from a small number of patients. By collecting data at the same time point, it becomes possible to identify composite biomarkers.

One data point may be problematic as a biomarker, while two or more independent molecules caused by different processes but both caused by the same disease “can make a big difference.” The kind of vast data collection Davis is embarking on doesn’t come cheap, however. At about $70,000 per patient, it becomes very difficult to fund studies with large numbers of patients.

Part of Davis’ solution to this is to focus on severely ill patients. Apart from the fact that they’ve never been studied before, the larger molecular signals should make it easier to find something important, he believes. One can then go back and study those signals in larger groups of patients.

Davis’ project studying 20 severely ill patients is under way. The samples have been collected, and he’s made a lot of progress cutting costs on the data analysis through favours from his students who’ve set up startup technology companies and found ways to bring down the costs of previously expensive technologies. One student built a cell-sorter that used to cost about $150,000 for ten cents, using materials from 3-D printers!

They do already have lots of data from three patients and 43 controls (sourced cheaply from staff members at one of the companies he’s collaborating with). And if three patients sounds like a small sample, Davis questioned: if you’re hunting for a biomarker, if that signal doesn’t show up in those three patients, what use is it?

And as a hint of the kind of scale of the data collection exercise here, Davis referred to a study he previously ran relating to trauma, which collected over 2 billion data points — a real challenge when considering how to visualise, interpret and publish such a dataset!

Davis showed a few illustrative slides to show how he is approaching the problem, by mapping the data collected onto a 30-year old (but probably accurate) model of known biochemical pathways.

Results with abnormally low or high values are coloured red or blue on this map, and the researchers can then zoom in to inspect areas where the pathways are severely disordered, to get a look at what’s going on.

And in the metabolomics data they have so far, it’s clear that some of these pathways are severely disordered: several markers are five standard deviations away from the normal, and one is 16 SDs lower than the level typical in healthy controls.

One big emerging theme so far, Davis revealed, is disruption of the citric acid cycle, inside mitochondria, the source of energy for the body. The body has three ways to make energy, he explained: burn glucose, burn fats, or burn amino acids.

In the patients he’s been studying, it looks like glycolosis is badly broken; glucose is just getting turned into fatty acids, which are then probably just being stored because it seems these patients can’t burn fat very well either. Eating amino acids, then, might be a useful source of energy for some patients: his son Whitney used to sit there eagerly eating spoon after spoon of them: horrible though they tasted, he seemed to get a lot of energy that way.

Davis has also found an ‘unbelievable’ biotin deficiency in Whitney, and said that when one patient added biotin to his treatment, that “totally turned him around.” Showing detail from the analysis of another patient, he presented a slide showing tryptophan deficiency (a pathway highlighted earlier by Mady Hornig), from which they concluded (correctly, as it turned out) that the patient must have an infection.

Looking for infectious agents is important, he said, but also it seems to Davis that in ME/CFS patients the mitochondria have just shut down somehow, perhaps as part of a natural protective process. He speculated that perhaps this becomes the most efficient way to function once there are so many deficiencies that the body is unable to “restart.”

Excited by this possibility, he thinks that if this is correct, it might turn out to be relatively easy to fix: we just have to know what to do.

“I think we’re going to figure this out,” he said, “and it could turn out to be easy … what’s wrong is that we don’t know enough … and what’s wrong is that we haven’t been looking at this seriously in the past.”

But there are a lot of really good people looking at this now, he added, and he said he thought he’d be focusing on that a lot now: recruiting more people, with the help of Dr. Whittemore and the leadership of Francis Collins.

He was cautious about mouse models, demonstrating some data points from his trauma study where results in mice were opposite to results in humans. This has been an FDA requirement, to validate treatments in a mouse model, but this has probably ruled out some effective treatments, and of 150 drugs validated in mice, not one worked in humans.

For complex diseases, this approach just doesn’t work. Instead, he is aiming to work by taking cells from human patients with ME/CFS and use them as a model.

Davis finished by highlighting one more pathway where he has observed severely abnormal data points in the ME/CFS patients: the GTP cyclohydrolase pathway. GTP looks to be low in ME/CFS, and downstream from that, as a consequence BH4 also seems to be low.

BH4 is used to make dopamine and serotonin, and he’s also seeing low dopamine in the kidney — it seems that his subjects may be unable to secrete salt, which would have all sorts of effects, including low blood volume and restrictions of blood vessels … which could account for a lot of symptoms.

But why is the GTP low, he wonders. This is all very fundamental biochemistry of the human body. Ending a spectacularly optimistic presentation on an optimistic note, Davis suggested that the symptoms of ME/CFS may well turn out to have a simple and common origin … and he’s clearly going to continue throwing all his considerable weight at the problem.

For more about Ron Davis’ presentation, see this excellent report from MEAction.

Plenary and Personal Reflections

After a few questions from the audience, Dr. Ian Gibson opened up a lively and wide-ranging plenary session, saying that he’s now going to have to go away and completely rewrite Chapter 3 of his forthcoming book on the politics of ME.

His excitement was evident. He hadn’t wanted to go to sleep for about five days now, he said, because there was just so much excitement and people are getting so involved: “things have really moved on.” He was willing to bet that within two years, big pharmaceutical companies would be turning up to the conference.

He’d take that bet now at 5,000 to 1, and recommended that Invest in ME charge their representatives double to attend. The level of commitment he sees from people in the world of ME/CFS is just amazing, and rare, he added: and “I will never stop … I’ll tell you that …”

For my part, how can I sum up my personal reflections from another incredible conference? Firstly, the above looong article is just a summary of my notes (and there will be more detail to follow soon in further articles), so I urge anyone interested enough to have read this far to buy the conference DVD and learn more.

Secondly, although most of the science presented was not brand new, and has been discussed already on Phoenix Rising’s forums, the opportunity to learn more about that science from the researchers themselves is always priceless.

Thirdly, and perhaps most importantly of all, the networking that goes on at Invest in ME just goes from strength to strength. This year I chatted with Jonathan Edwards, Dan Peterson, Vicky Whittemore, Charles Shepherd, and a few Phoenix Rising members who I’d never met before.

The way that Invest in ME continues to build international collaboration in ME research is game-changing, and we are really starting to see the fruits of that now.

And finally, while I’m writing up these articles about the conference, I often find myself thinking about pieces of a jigsaw puzzle, and how well they are fitting together. Each conference seems to me to get more and more coherent, with more connections being made between apparently disparate areas of research.

I now see a few areas of the puzzle where a few pieces can be plugged together with reasonable confidence. Increasingly our researchers are “singing from the same hymn sheet,” and we have an outline picture emerging of what is clearly an incredibly complex disease, but one which may well turn out to have some quite simple and effective solutions in terms of real (as opposed to psychosocial) treatments.

Even without the knowledge of the appalling and widespread suffering that our community of patients and carers has to endure, and the grotesque injustice of how the political and medical systems continue to denigrate and disregard that suffering, my excitement about what the next few years have in store for the world of ME/CFS research would keep me engaged.

We are on the march, and I just can’t wait to see what happens next! Roll on IIMEC12 …

 

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{ 96 comments… add one }

  • M Paine June 20, 2016, 1:41 pm
    msf

    Yeah, they need to watch out or it will be all over Pirate Bay and YouTube.

    I guess I'll be buying a DVD player then. I'm not sure how being on DVD prevents people from redistributing them. DVD's can easily be trans-coded into any format you wish. If the aim is to distribute the conference material to as many stakeholders as possible, at the lowest cost, then online hosting or streaming is not a bad option. Paying for four DVD's and international postage is costly.

    "The DVD's are heavily subsidised in order to make them available to as many patients, patient groups, carers and researchers, healthcare, media and politicians."

  • BurnA June 20, 2016, 2:13 pm
    M Paine

    I guess I'll be buying a DVD player then. I'm not sure how being on DVD prevents people from redistributing them. DVD's can easily be trans-coded into any format you wish. If the aim is to distribute the conference material to as many stakeholders as possible, at the lowest cost, then online hosting or streaming is not a bad option. Paying for four DVD's and international postage is costly.

    Could they monetize streaming ? I presume one of their aims is not to loose money either.

  • Bob June 20, 2016, 2:13 pm
    M Paine

    I guess I'll be buying a DVD player then.

    DVDs play in personal computers if you have access to one.

  • Bob June 20, 2016, 2:15 pm
    M Paine

    I'm not sure how being on DVD prevents people from redistributing them. DVD's can easily be trans-coded into any format you wish. If the aim is to distribute the conference material to as many stakeholders as possible, at the lowest cost, then online hosting or streaming is not a bad option. Paying for four DVD's and international postage is costly.

    I think it might simply be a case of being a bit old fashioned, and trusting what you know.

  • BurnA June 20, 2016, 2:15 pm
    Bob

    They play in personal computers if you have access to one.

    and playstations too ?

  • M Paine June 20, 2016, 2:15 pm

    Oddly enough, I have several computers, none of which have a DVD drive. These days you can get by without one.

  • Bob June 20, 2016, 3:02 pm
    M Paine

    Oddly enough, I have several computers, none of which have a DVD drive. These days you can get by without one.

    Yes, DVDs are a bit old fashioned these days. I wish they'd place the videos on Vimeo, or similar. The production costs would be cheaper too. But it's just a minor grumble. The DVDs are an amazing resource. I've watched every conference since they began.

  • Bob June 20, 2016, 3:03 pm
    BurnA

    and playstations too ?

    I think so? But I've never owned one, so I'm not certain.

  • AndyPR June 20, 2016, 3:04 pm
    Bob

    I think it might simply be a case of being a bit old fashioned, and trusting what you know.

    I've emailed them to ask the question, I'll let people know the answer when I get it.

  • Kati June 20, 2016, 6:16 pm

    Invest in ME's revenue relies on sales of DVD. SOmeone managed to post the videos online one year which did not please the conference organizers.

    There are costs associated with organizing an international conference. Room rental alone/catering the technical crew (A/V, filming) it's all a lot of money.

    Buy the DVD. Support the conference. Don't post the video content online (it's copyrighted) It's a win win situation.

  • M Paine June 20, 2016, 6:35 pm

    The idea that the DVD's generate revenue, while being heavily subsidized just doesn't make sense.

  • taniaaust1 June 20, 2016, 7:21 pm
    M Paine

    The idea that the DVD's generate revenue, while being heavily subsidized just doesn't make sense.

    many of us wouldnt buy them at all myself included, I have brought these ones before… if they werent cheap enough for us to do so due to being on disabilty pensions (the profit still goes back to them)

  • AndyPR June 20, 2016, 9:35 pm
    Kati

    Invest in ME's revenue relies on sales of DVD. SOmeone managed to post the videos online one year which did not please the conference organizers.

    There are costs associated with organizing an international conference. Room rental alone/catering the technical crew (A/V, filming) it's all a lot of money.

    Buy the DVD. Support the conference. Don't post the video content online (it's copyrighted) It's a win win situation.

    I believe the point is actually whether the conference footage is available to download/stream for a fee, not whether a pirated version is available for free.

    Personally, I ordered the DVDs last week, but I can understand how having them available in a digital format would make them more widely accessible to more people – equally, from the IiME side of things, it would be another task to add to what is probably a long to-do list already, and either they haven't thought of it before or they just don't have a volunteer to take the task on.

  • Simon June 21, 2016, 2:57 am

    Professor Elisa Oltra (Valencia), microRNAs

    Just thought it's worth explaining a little bit more about microRNAs, miRNA, partly for my own benefit. It's a new a rapidly expanding area of research. These small molecules (usually 22 nucleotides long) were only discovered in 1993, and reseach on them only really got going since 2000. They play a critical role in regulating gene expression by stopping messenger RNA, mRNA being translated into proteins. Just to recap:
    genes == transcription ==> mRNA === translation ==> proteins

    miRNA bind to mRNAs and either cause them to get broken down faster, or stop them being translated to proteins: either way the results is less protein is made from the same amount of mRNA.

    While mRNA is very unstable, these small miRNA molecules are very stable and occur in most body fluids, making them good potential biomarkers.

    Mark

    They have been established as proven biomarkers of other diseases. They are relatively stable compared to other RNAs meaning that long-term samples can be analysed. They are relatively easy to implement in diagnostic tests in clinics once they have been identified. And they have barely been explored for the diagnosis of ME and related diseases. Micro RNAs are also present in all body fluids.

    Did she say which diseases? I did a quick google (yeah, flakey or what) and couldn't find anything specific on a disease, though lots of signs of activity trying to find biomarkers, including this published in January
    MicroRNA as Biomarkers and Diagnostics –

    Wang 2016 Conclusion

    Several studies have shown that miRNAs are differentially expressed in diseased tissues and differentially enriched in plasma, serum and other body fluids, potentially making them useful for routine clinical diagnosis.

    Researchers have mainly focused on finding miRNA signatures that are representative of diseases, including cancer, viral infections, nervous system disorders, cardiovascular disorders, muscular disorders, diabetes, and other diseases, and several studies have been specifically designed to validate miRNAs as biomarkers and clarify their role in regulating physiological and pathological processes.

    However, a greater understanding of the biological characteristics of these miRNAs in these diseases is needed to improve their use as biomarkers. The main challenges in the use of miRNA signatures in in vitro diagnostics are discovering specific miRNAs that can be consistently used as specific and reliable “ideal” biomarkers for diseases in a broad range of patients and the development of simple and inexpensive detection methods.

    Mark

    At the end of this preliminary analysis, they concluded that a signature of five strikingly downregulated miRNAs in particular could be used as biomarkers of "FM/CFS". Interestingly, two of these five have independently been shown to be inhibited in cerebrospinal fluid of FM patients (Mannerkorpi et al, PLoS One, 2013), and one was identified as abnormal in plasma of CFS patients (Marshall-Gradisnik et al, PLoS One, 2014).

    The next step is to validate these findings in a larger study group, which they are planning to attempt in association with Dr. Nathanson (from Dr. Klimas' group at Nova University) and Dr Alegre's group at Val D'Hebron Hospital in Barcelona.

    Worth noting that FM/CFS study had only 11 patients vs 10 controls, but great that they are looking to validate the findings – that's the crtical step that's been left out in so many earlier biomarker studies.

    Fingers crossed for this one.

  • AndyPR June 21, 2016, 6:50 am
    M Paine

    The idea that the DVD's generate revenue, while being heavily subsidized just doesn't make sense.

    My reply from IiME;

    Thanks for your email and sorry for the delay in replying.
    We have occasionally been asked this before regarding DVDs.
    We have a lot of people who prefer to have the DVDs rather than them being online – and we try to make the conference available to these, and everyone else, if they cannot attend.
    We also want doctors to have easy access to the conference material if they do not attend as they can claim CPD points from this also – and we have heard that they find the DVDs easier.
    We also have groups (some in other countries) that play them in chunks for their members in meetings.
    And we have had quite a few comments from patients who find it difficult to view these on their computers – and a DVD set therefore allows some compromise for all.
    So we will continue to offer them in DVD form – and the latest conference will only be in DVD form at the moment.
    We introduced professionally authored recordings of our conferences from the beginning.
    And we also perform a lot of the editing of the DVDs ourselves and decide what is finally included – so it reduces costs and is easier to filter out unnecessary sounds, or pauses as well as avoid embargoed information from being given out.
    This is often better achieved after the conference events.
    The DVD is made into segments that allow each presentation to be seen at a pace that suits the viewer.
    We never make any profit from the production and sale of the DVDs (although if any profits were made then they would be ploughed back into the conference events or research).
    So we have been looking over recent years at other ways to distribute the content and will be looking at this again in the future when we get time.
    In the meantime we feel it is worthwhile to offer a professionally produced historical record of the conference on DVD, at a heavily subsidised and reasonable price for all to see as this satisfies the majority of our supporters and those interested in learning from the conference presentations.
    As we are moving to a new web site then we will likely make the older DVDs available via our website or linked medium in a way that is still to be decided – although we still get occasional orders for DVDs from previous years).
    We’ll give out details as and when that occurs.
    I hope that answers your question,
    Best regards
    Richard

    So, they have been asked about it before but at the moment they won't be offering it.

    Just looking on the DVD order page (http://www.investinme.eu/iimec11.shtml#dvd), they certainly keep the shipping costs as low as possible, in the UK the DVD costs £14, Europe is £15, and the rest of the world is £17.

  • Bob June 21, 2016, 9:51 am
    Kati

    Invest in ME's revenue relies on sales of DVD. SOmeone managed to post the videos online one year which did not please the conference organizers.

    There are costs associated with organizing an international conference. Room rental alone/catering the technical crew (A/V, filming) it's all a lot of money.

    Buy the DVD. Support the conference. Don't post the video content online (it's copyrighted) It's a win win situation.

    Everyone is grateful for the current arrangements. We were just wondering why they don't place the videos on, for example, Vimeo, for a fee. (Forgotten plague is available on Vimeo.) Streaming is very popular these days, and easily accessible. But it's not a big deal; it's just a question, which has now been answered above. I hope IiME do consider placing a copy of their DVDs onto Vimeo in the future, unless it would cause a disproportionate amount of extra work for them.

  • alex3619 June 21, 2016, 1:13 pm
    Simon

    These small molecules (usually 22 nucleotides long) were only discovered in 1993, and reseach on them only really got going since 2000.

    It was being debated in the biosciences faculties in 2000 at my university. People (lecturers) were talking about looking forward to conferences where findings were being presented.

  • msf June 21, 2016, 3:11 pm

    Prof. Edwards just mentioned in another thread that ´one of the European researchers) at the IiME conference had a slide showing no difference between patients and controls for several pathogens, including Borrelia, Bartonella, Herpes viruses and Coxsackie. Did anyone else see this or hear anything about it? There are only two European (rather than UK) researchers listed above, where there others there who only presented information without giving talks? I do not want to bring the Lyme, Herpes, or any other controversy to this thread, I will just say, ´uhuh, I see, interesting´ in response to whatever I am told.

  • msf June 22, 2016, 1:39 pm

    Bump.

  • MEMum June 22, 2016, 2:30 pm
    Bob

    I think so? But I've never owned one, so I'm not certain.

    My son's X-Box is the only way we can watch DVDs in our house. Two laptops have non-functioning DVD players.
    None of the computer stuff is very new….

  • MEMum June 22, 2016, 3:03 pm

    My notes did not include the names of other 'complex diseaeses', but I had written down 1990 American College of Rheumatology nearby. So I Googled something like microRNAs in diagnosis of rheumatoid arthritis and came up with this link to a Japanese paper, there are probably others too
    http://arthritis-research.biomedcentral.com/articles/10.1186/ar3013
    Professor Oltri mentioned Japan, but I thought this was re where the micro array machine they use, is from.

    Also @msf I cannot find ref to that slide in my notes re Borrelia etc. Prof Edwards may have seen it at the pre conference colloquium, or I may have missed it. However my daughter had a tick bite, with EM rash last summer and has now got IgM to Borrelia so I would prob have noticed it.

  • msf June 22, 2016, 3:16 pm

    Thanks for the reply, MEMum.

  • BurnA June 22, 2016, 4:14 pm
    M Paine

    The idea that the DVD's generate revenue, while being heavily subsidized just doesn't make sense.

    Subsidisation is used to cover part of costs generally, but not necessarily all costs. And revenue is just income, not necessarily profit. So its perfectly natural to charge for something that is being subsidised, in order to break even.

    My impression is iime are not the most up to date technology wise, but i am willing to overlook that, given that they are the most up to date, research wise.

  • msf June 22, 2016, 4:23 pm

    I mean, uhuh, I see, interesting…

  • Mark June 22, 2016, 4:30 pm
    Simon

    Hi Mark, great job! I'm still working my way through as I've not been too well and have lots of questions, but as you tagged me, here's a response for now:
    This study only had 43 mecfs patients and 36 heathy controls, which is very small. But that'st the total sample, the nationality groups are even smaller. I don't think you can read anything into this, especially as the biggest difference they found was between healthy Norwegians and equally healthy Belgians, which could be down to diet and mean nothing (though it's likely to be an unreliable finding given such a small sample).

    Maybe one day there will be enough data for someone to do a meta-analysis, combinging data from many small studies to look for an overall effect. Though of course nationality (and diet) will confound that, making it harder to do.

    Thanks Simon, and thanks for the brief analysis of the KDM study. I remember now that it was really no more than preliminary, because of sample size amongst other factors, but I did find the concept interesting at the time and thought it was good to see a start on this kind of analysis. In the context of the question I was originally asked, I suppose my response would be that actually this particular study has now been followed up by Hanson and others, with what look like more robust studies, but we're still in the early stages of this area of study, in general and not just in ME/CFS. And really it's not particularly a follow-up as such because a lot of people were interested in studying the microbiome anyway. Also it does seem to me that it's good news that Hanson's finding is consistent with what KDM's results showed, but time will tell whether the other results KDM reported then will be borne out or not – as Simon points out, with a small study like this there's just not enough data to answer that yet.

  • Mark June 22, 2016, 4:39 pm
    Simon

    Professor Elisa Oltra (Valencia), microRNAs
    Did she say which diseases? I did a quick google (yeah, flakey or what) and couldn't find anything specific on a disease, though lots of signs of activity trying to find biomarkers, including this published in January
    MicroRNA as Biomarkers and Diagnostics –

    Quite possibly she did mention diseases in which they have been useful as validated biomarkers, but I'm afraid there's nothing in my notes about that – sorry.

    Worth noting that FM/CFS study had only 11 patients vs 10 controls, but great that they are looking to validate the findings – that's the crtical step that's been left out in so many earlier biomarker studies.

    Fingers crossed for this one.

    Yes, this did seem very preliminary, very early stage, but hopefully attending IiME and networking with others will help Oltra to progress this research.

  • Mark June 22, 2016, 4:48 pm
    msf

    Prof. Edwards just mentioned in another thread that ´one of the European researchers) at the IiME conference had a slide showing no difference between patients and controls for several pathogens, including Borrelia, Bartonella, Herpes viruses and Coxsackie. Did anyone else see this or hear anything about it? There are only two European (rather than UK) researchers listed above, where there others there who only presented information without giving talks? I do not want to bring the Lyme, Herpes, or any other controversy to this thread, I will just say, ´uhuh, I see, interesting´ in response to whatever I am told.

    I'm not sure, but this sounds like it might have been a slide from Mady Hornig's presentation (not European, I know); it would seem to fit because I think that group did begin with a trawl for just those kind of pathogens. I can't think of anything else that fits the bill, but perhaps Jonathan was referring to something from the research collective meetings ahead of the conference.

  • msf June 22, 2016, 4:57 pm
    Mark

    Thanks Simon, and thanks for the brief analysis of the KDM study. I remember now that it was really no more than preliminary, because of sample size amongst other factors, but I did find the concept interesting at the time and thought it was good to see a start on this kind of analysis. In the context of the question I was originally asked, I suppose my response would be that actually this particular study has now been followed up by Hanson and others, with what look like more robust studies, but we're still in the early stages of this area of study, in general and not just in ME/CFS. And really it's not particularly a follow-up as such because a lot of people were interested in studying the microbiome anyway. Also it does seem to me that it's good news that Hanson's finding is consistent with what KDM's results showed, but time will tell whether the other results KDM reported then will be borne out or not – as Simon points out, with a small study like this there's just not enough data to answer that yet.

    The Hanson study is practically the same size as the KDM study, and although the KDM patients were split between Norway and Belgium, we don´t know whether say, the Hanson one recruited from both the East and West coast of America, or whether it included different ethnic groups, all of which might affect diet and therefore the microbiome.

  • duncan June 22, 2016, 5:07 pm
    Mark

    I'm not sure, but this sounds like it might have been a slide from Mady Hornig's presentation (not European, I know); it would seem to fit because I think that group did begin with a trawl for just those kind of pathogens. I can't think of anything else that fits the bill, but perhaps Jonathan was referring to something from the research collective meetings ahead of the conference.

    I, too, was interested in what @Jonathan Edwards had to say. I thought he wrote something to the effect that it was claimed at the conference that many viruses and bacteria (e.g., Bb, Herpes, coxsackie etc. ) were shown not to cause ME/CFS – but admittedly I may have that wrong – my memory is frequently in shambles.

    If anyone can clarify, that would be great.

  • Mark June 22, 2016, 5:17 pm
    msf

    Yes, it´s a small study, but then so are almost all of the studies done on ME so far. I don´t understand statistics, but doesn´t the fact that the same differences/trends were found between patients and controls in both the Belgian and Norwegian groups count for something? I think statisticians and medical types sometimes overlook what I would call circumstantial evidence.

    Also, going back to my original point, surely if it´s worth mentioning the findngs of the small Hanson study then its worth mentioning that it replicates the findings of an earlier small study?

    I think it's quite fair of you to point out that Hanson's study with the LPS findings had basically the same number of patients and controls as KDM's. When you halve that group, though, and compare Belgian and Norwegian groups and note the differences, I think it's getting way too small to conclude anything from that comparison, especially because it may just reflect different dietary factors. I think with all these things it depends on the detail of the findings as to how the sample size affects the results. If you have a clear and stated prior hypothesis about factor X and study 40/40 and find all the patients have X and none of the controls do, then that obviously means a lot more than a study trawling loads of different data points on 40/40 and simply reporting the results. In the small study that Hanson reported, there were several data points that fitted together to give stronger confirmation of the LPS findings, and they were looking at far fewer variables I think. So I think it's a bit stronger for that reason, but still very preliminary really.

    I do think Simon's right to urge caution in interpreting the results of small studies. Yes, an awful lot of ME/CFS research has been on small sample sizes, and that's a big part of the problem. Non-scientists interpreting results are liable to give them much more weight and read more into them than a scientist should. Small studies by one group suggest potentially interesting lines of inquiry, I would say, and not much more than that. Lots of small studies might add up to something, but even there, one would have to know about all the other small studies with null findings that were never reported in order to make an informed judgment overall. Because we don't have mandatory registration of trials before they begin, and mandatory publication of results, the whole situation regarding the quality and reliability of published science is highly unsatisfactory to say the least. The best one can really say about these small studies is that they are 'interesting' – and many things are 'interesting'…

  • Jonathan Edwards June 23, 2016, 1:17 am
    duncan

    I, too, was interested in what @Jonathan Edwards had to say. I thought he wrote something to the effect that it was claimed at the conference that many viruses and bacteria (e.g., Bb, Herpes, coxsackie etc. ) were shown not to cause ME/CFS – but admittedly I may have that wrong – my memory is frequently in shambles.

    If anyone can clarify, that would be great.

    Chinese whispers I fear.

    A presentation at the pre conference colloquium indicated that a large ME/CFS cohort had been compared to controls in terms of serological evidence of such infections and no differences were found. The data are several years old I think and were not published simply because it is frustrating trying to publish negative findings. This I think is a huge problem for ME research because there are lots of negative data lying around unpublished for this reason. And negative data are often the most powerful.

  • msf June 23, 2016, 1:29 am
    Mark

    I think it's quite fair of you to point out that Hanson's study with the LPS findings had basically the same number of patients and controls as KDM's. When you halve that group, though, and compare Belgian and Norwegian groups and note the differences, I think it's getting way too small to conclude anything from that comparison, especially because it may just reflect different dietary factors. I think with all these things it depends on the detail of the findings as to how the sample size affects the results. If you have a clear and stated prior hypothesis about factor X and study 40/40 and find all the patients have X and none of the controls do, then that obviously means a lot more than a study trawling loads of different data points on 40/40 and simply reporting the results. In the small study that Hanson reported, there were several data points that fitted together to give stronger confirmation of the LPS findings, and they were looking at far fewer variables I think. So I think it's a bit stronger for that reason, but still very preliminary really.

    I do think Simon's right to urge caution in interpreting the results of small studies. Yes, an awful lot of ME/CFS research has been on small sample sizes, and that's a big part of the problem. Non-scientists interpreting results are liable to give them much more weight and read more into them than a scientist should. Small studies by one group suggest potentially interesting lines of inquiry, I would say, and not much more than that. Lots of small studies might add up to something, but even there, one would have to know about all the other small studies with null findings that were never reported in order to make an informed judgment overall. Because we don't have mandatory registration of trials before they begin, and mandatory publication of results, the whole situation regarding the quality and reliability of published science is highly unsatisfactory to say the least. The best one can really say about these small studies is that they are 'interesting' – and many things are 'interesting'…

    Well, I´m not a statistician, but I will wait until the Hanson study is published before I compare it with the KDM study.

  • lansbergen June 23, 2016, 1:57 am
    Jonathan Edwards

    Chinese whispers I fear.

    A presentation at the pre conference colloquium indicated that a large ME/CFS cohort had been compared to controls in terms of serological evidence of such infections and no differences were found. The data are several years old I think and were not published simply because it is frustrating trying to publish negative findings. This I think is a huge problem for ME research because there are lots of negative data lying around unpublished for this reason. And negative data are often the most powerful.

    There should be a place where these data could be published.

  • duncan June 23, 2016, 5:42 am
    Jonathan Edwards

    Chinese whispers I fear.

    A presentation at the pre conference colloquium indicated that a large ME/CFS cohort had been compared to controls in terms of serological evidence of such infections and no differences were found. The data are several years old I think and were not published simply because it is frustrating trying to publish negative findings. This I think is a huge problem for ME research because there are lots of negative data lying around unpublished for this reason. And negative data are often the most powerful.

    Agreed.

    Negative studies can be essential. They can prove a connection. They can disprove it. Both of these effects can – once in a while – be evidenced inadvertently, in counterpoint to the conclusions reached or stated by the authors. Negative studies can sometimes reveal more about bias or intent, too. Just look at the notorious three RCTs for extended abx for Lyme as an example.

    I'm not saying that would have been the case here. Just bemoaning what I know is obvious to many.

  • Simon June 28, 2016, 12:42 pm

    Shorter version of @Mark's excellent piece – with links direct to each speaker's section

    I've written this for #MEAction but it might be a while before it's posted, so thought I'd put here too. Nb click on the title links to go direct to the relevant section of Mark's talk:

    The 2016 Invest in ME Conference – great write up on Phoenix Rising

    Phoenix Rising’s Mark Berry was at the recent Invest in ME conference and has written an excellent report: A New Decade of ME Research: The 11th Invest in ME International ME Conference 2016

    As the article is quite long, here are some tasters (my summaries, with quotes from Mark’s article) to whet your appetite for the feast, which concludes with Professor Ron Davis’s talk.You can click on the titles to go direct to the relevant section in Mark’s report.

    Dr Vicky Whittemore hails ‘new dawn’ at the NIH for ME/CFS

    Whittemore acknowledged historical problems at the NIH, such as the “shocking and disappointing” funding levels and outlined the NIH’s emerging agenda for the illness including the ‘deep dive’ intramural study.

    ‘She said that her “hope and vision” was to return to IiME in the next two years and present a graph showing levels of government funding for ME/CFS research “off the charts.”’

    Clinical Diagnosis of Myalgic Encephalomyelitis

    Professor Olli Polo talked about how he diagnoses ME/CFS, and said that symptoms affect the whole of the sympathetic trunk, making ME/CFS a whole-body condition that doesn’t fit well with the prevailing model of medicine. He also said that many of his patients had signs of connective tissue disorders.

    Autoantibodies to neurotramsimtter receptors in CFS/ME – Professor Carmen Scheibenbogen

    Scheibenbogen reviewed the evidence for autoantibodies playing a role in ME/CFS, and discussed her recent finding that patients had more autoantibodies than controls against two types of neurotransmitter receptors: beta-adrenergic and muscarinic acetylcholine receptors. She noted that stimulation of these receptors could cause familiar ME/CFS symptoms.

    Her research also found that responders to rituximab in the Fluge and Mella trials had reduced levels of these antibodies after treatment, while this wasn’t seen in non-responders.

    Immune regulation in patients with ME – Dr Jo Cambridge

    Cambridge worked with Professor Jonathan Edwards to develop rituximab as a treatment for rheumatoid arthritis, and got involved in ME/CFS research following those promising rituximab pilot studies in Norway.

    She discussed how rituximab works in various autoimmune diseases. It kills most B cells and may work in ME/CFS either because it stops B cells turning into the antibody-producing factories called plasma cells (cutting off supplies of autoantibodies), or through stopping the interaction between B cells and T cells, which are another key type of immune cell.

    PhD student Fane Manseh, who works with Cambridge, presented his work studying ME/CFS patient B cells in the lab, looking at what controls their development and antibody production, and how they interact with T cells.

    Gut Virome in ME – Professor Tom Wileman

    You’ve heard of the gut microbiome, and the gut virome is part of this: it’s all the viruses that infect the bacteria in the gut (“Every flea has a flea that lives on a flea”). Interactions between the gut microbiome and the body can affect inflammation, and the ‘Virome hypothesis’ says that the gut virome can play an important part in triggering this inflammation leading to disease.

    Wileman has studies the virome in IBS, and found that reduced diversity in the virome (fewer different types of virus than normal) is linked to IBS. The virome may provide a biomarker in diseases, including ME/CFS.

    Invest in ME-sponsored PhD student Daniel Vipond is currently exploring the gut virome in ME/CFS patients.

    Receptors and intracellular signalling – Professor Don Staines

    Staines, of Griffith University, discussed the team’s recent work on receptors that play an important role in cell signalling. Their previous research had identified an association between a genetic variant of the ion channel receptor, TRPM3, and ME/CFS. When the TRPM 3 receptor is activated, it briefly lets calcium into the cell, which is a common way the body uses to send a signal.

    Recently work from the group showed patients had reduced levels of the TRPM3 receptor in B cells and natural killer cells, which together with the genetic variant may affect cell functioning: they found reduction in calcium levels within cells. Staines said his group believe that ion channel receptor function, and calcium signalling problems, could be causing ME/CFS.

    Staines said they have many more papers on this subject to follow.

    New European research networks launched

    Professor Simon Carding introduced EMERG, the European ME Research Group that was launched last autumn. It’s a network of research groups which aims to jointly define a co-ordinated research strategy. EMERG is already working to improve research with expert groups looking at clinical diagnosis and stratification, biomarkers and standardising how different research groups prepare samples.

    A separate network, EUROMENE – for individual researchers rather than research groups – was launched in Easter this year and has secured 6 million Euros in funding. EMERG and EUROMENE have already met up and will work in complementary ways.

    Early feasibility projects are looking at infectious origins (environmental and microbiome alterations), and clinical trials and supporting research (e.g.,rituximab).

    Pathogen Discovery in ME – Dr Mady Hornig

    Hornig explained how the group at Columbia University are working to identify pathogens and triggers for ME/CFS.

    “Much of her wide-ranging and complex presentation aimed to explain why her group’s model of ME is an immune-mediated brain disorder, with a significant connection to the gut. When the microbiota (gut microbes) are disordered, disorders of brain function are among the many consequences.”

    Changes in the gut microbiota could trigger autoimmunity, she said, and also have an effect on the brain, for example by affecting the levels of tryptophan, a molecule that’s needed to make some neurotransmitters (infections can affect tryptophan levels too). In short: it’s complicated.

    The Search for Biomarkers for Myalgic Encephalomyelitis – Professor Maureen Hanson

    Hanson talked about her study with Susan Levine using 49 ME/CFS patients to search for biomarkers in the gut microbiome. They’ve made two interesting findings. The first is a big increase in blood lipopolysaccharide, LPS, which could be due to bacteria or bacterial breakdown products from the gut crossing into the blood. The second finding is a shift in microbiome profile, with more bacterial species reported to be pro-inflammatory, and fewer bacteria reported to be anti-inflammatory. There was also a “loss of species richness” i.e. fewer different types of bacteria in patients. The microbiome profile has potential as a biomarker, she said, and her group will do more work to develop its potential.

    Hanson commented it was hard to square these findings with a psychosocial model of ME/CFS.

    Molecular Biomarkers of Myalgic Encephalomyelitis

    Professor Elisa Oltra is looking for biomarkers among microRNAs, small RNA molecules that play a key role in regulating gene expression that have been established as proven biomarkers of other diseases, she said. Her group have already found microRNAs with biomarker potential in a small study of Fibromyalgia patients who also had ME/CFS, and they are working on a replication in a larger sample of patients.

    Exercise Testing and Orthostatic Tachycardia – Professor James Baraniuk

    Baraniuk reviewed the changes in diagnostic criteria for ME/CFS, fibromyalgia and Gulf War Illness. He noted that fibromyalgia criteria had ‘drifted’ from the original versions, as had ME/CFS, but he praised Carruther’s focus on the key ME/CFS symptom of post exertional malaise in later criteria. Baranuik shocked the audience when he said that Gulf War Illness – a major focus of his research – affects 25-32% of those deployed. Many had been exposed to chemicals.

    Baraniuk’s current ME/CFS study uses an MRI brain scan before and after a submaximal exercise test and early results from this unfinished study show changes in brain blood flow, especially after a cognitive test. Patients also show greater activation of the sympathetic ‘flight or fight’ nervous system than controls, and half of patients had postural tachycardia – a racing heart when they stand up, which may be linked to reduced blood flow.

    Big Data Approach: Severely Ill ME Patient Cohort – Professor Ron Davis

    Invest in ME had saved the best til last: “Davis delivered a mind-blowing presentation that drew the day’s longest round of applause by far.”

    Most people know that Davis is motivated by finding effective treatment for his son who’s very severely-affected. Davis was part of the IOM panel reviewing 9,000 publications and he said he found little useful biomarker data so decided to collect his own, teaming up with the Open Medicine Foundation to raise funds for a small but intense study. The study costs $70,000 a patient, even with many companies providing their services at greatly reduced because of the esteem in which they hold Davis (several are run by former students).

    While the study is small, with only 25 patients, Davis said focusing on the severely-affected who have a ‘larger molecular signal’, together with looking at many potential biomarkers simultaneously, increases the odds of finding biomarkers. Any promising biomarkers will be validated in larger groups of patients.

    Davis has some results in already, and the early findings are dramatic: they are….

    … well, you’ll just have to read Mark’s account to find out. It’s well worth it.

    Mark wrapped up his excellent account with personal reflections on the conference: he’s excited that things seem to be coming together at last in ME/CFS research.

    There are shorter, but less detailed write-ups from Dr Charles Shepherd of the ME Association, and Dr Rosamund Vallings for Invest in ME itself. Buy the Invest in ME conference DVD.

  • Mark July 10, 2016, 9:50 am

    Thanks for setting that up Simon. I've now added an index ('conference agenda') to the top of the article; hopefully that will make it easier for people to navigate.

  • Gingergrrl July 10, 2016, 4:02 pm

    Thank you @Mark for the great summary and am especially interested in the work being done at the Charite with trying to reduce autoantibodies with plasmapheresis, IVIG and RTX. I wish something like this experiment was being done in the US!

  • Jill July 10, 2016, 4:26 pm

    Thank you Mark for a great write up. I can only imagine how difficult it is to summarise technical stuff on such wide topics . You do it brilliantly, with an ME brain it must be so so hard. Thank you again. I love your reports.

  • Groggy Doggy July 10, 2016, 6:27 pm
    Gingergrrl

    Thank you @Mark for the great summary and am especially interested in the work being done at the Charite with trying to reduce autoantibodies with plasmapheresis, IVIG and RTX.!

    Did you see Staines?
    "Staines said his group believe that ion channel receptor function, and calcium signalling problems, could be causing ME/CFS"

  • Gingergrrl July 10, 2016, 7:30 pm
    Groggy Doggy

    Did you see Staines?
    "Staines said his group believe that ion channel receptor function, and calcium signalling problems, could be causing ME/CFS"

    Hi GD, I am not certain if I'd read that exact link by Staines but it is possible b/c everyone on PR has been incredible with sending me links on this topic (and you've sent me some really amazing stuff- thank you so much! :hug:) I just bookmarked the post and also sent the link to myself.

    I truly believe that this is my core issue (calcium channelopathy) and if this turns out to be one of the sub-types of ME/CFS, then I am certain that this is the illness that I have. I wish I could fast-forward the science by about 10-20 years b/c at present many docs still feel that even with a positive ANA titer, calcium channel auto-antibodies, abnormal EMG, etc, that everything is "normal" or a "technical error" or other BS since I do not fit into the "lupus" box (or that of any other known autoimmune disease) in 2016 as if having POTS, MCAS and all these other issues are just random.

    But thank God my main doc, MCAS doc and new neuro all "think outside of the box" and got me approved for IVIG which I will start as soon as we can get it arranged. I am going to try to follow as closely as I can to the treatments in Dr. Scheibenbogen's study on my own and hoping it will give me some improvements.

    Will of course post about in the appropriate thread (and will not take this one off topic :D) but hoping everyone reads the portions of Mark's phenomenal summary that include the work being done at the Charite and the link you included to Staines's group. This stuff all makes me really hopeful that at least there is something that I can try with a fairly decent chance of being in the right sub-group for it.

    Thanks @Groggy Doggy

  • Simon July 19, 2016, 3:21 am

    I've already posted a summary of @Mark's long piece in an earlier post, and it's now on #MEAction:

    2016 Invest in ME Conference write-up on PR | #MEAction

    There are links in my summary piece that go direct to the releant section of Mark's full article, eg Ron Davis's talk.
    Big Data Approach: Severely Ill ME Patient Cohort

    Feel free to share the #MEAction article if you think it will help take the IiME conference to a wider audience :)

    [btw, Mark has also added an index at the start of his article so that you can again go direct to the different speaker's talks]

  • Sasha July 19, 2016, 4:16 am
    IiME on FB

    Having previewed the presentations and continuing the editing we can say this is the best quality conference DVD that we have had.

    An excellent job being performed by our DVD authoring company partner David Meachen. Excellent and fascinating presentations. We hope to be able to begin distribution this month.

    https://www.facebook.com/groups/580…0153802382167507&comment_tracking={"tn":"R0"}

    Can't wait! Next couple of weeks, then…

  • Sasha August 4, 2016, 8:55 am

    IiME just posted on FB that deliveries of the DVD will start at the end of the week. :woot:

  • wastwater September 13, 2016, 4:09 am

    Must get this years dvd,I'm usually in for the early bird a bit late for that.
    Interested in the microRNA whatever that is.
    Interested in CLL region at 13q14 which is where I tracked down my genetic focus to with riegers

    Buy it and make notes its very good,lasts about 8 hours in total.(works on a playstation 3)
    Mentions B cells the gut,calcium and metabolic pathways.
    Was interested to see serotonin and dopamine mentioned as you would expect as a way of shutting down function,these pathways seem very resistant to restarting
    Hsa-miR223-3p and hsa-miRNA-145-5p are they tumour suppressors

  • wastwater September 19, 2016, 8:27 pm

    Are professor oltra potential bio markers involved in tumour surpression?yes

  • wastwater October 24, 2016, 9:04 pm

    Having an oncovirus like EBV and missing tumour surpressor pathways sounds like bad synergy to me,maybe rituximab helps knock back any advancement of cancer formation
    Found something on 13q14 and B cells in leukemia https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778015/
    It mentions nematode worms too