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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 }

  • Sea June 14, 2016, 5:42 pm

    Thank you Mark. Far too much for me to read in one sitting. I appreciate the effort that has gone into this and will wade through it slowly.

  • *GG* June 14, 2016, 6:55 pm

    Only read the articles with American research, did I miss anything?

    GG

  • Sean June 14, 2016, 9:06 pm

    Thanks for the excellent write up, Mark. This is soooooo encouraging. Not just for any particular results (such as from Baraniuk on brain MRI before and after a submaximal exercise test *), but as much because the big guns are clearly starting to turn their sights onto the problem in rapidly increasing numbers.

    We have won the scientific and ethical arguments, and now are starting to win the political one as well.

    * …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.

  • aimossy June 14, 2016, 11:50 pm

    Thank you so much for these reports Mark. They are always one of the biggest highlights of the year for me!

  • justy June 15, 2016, 1:23 am

    Thanks Mark for such a comprehensive overview of the conference. Exciting times indeed.

  • Mark June 15, 2016, 2:14 am
    *GG*

    Only read the articles with American research, did I miss anything?

    GG

    Scheinbenbogen and Cambridge's work is very important IMO, the details of why Rituximab works and how it works are really important, although there wasn't much there that was new in terms of results. Scheibenbogen's study has already been published but there's a bit of news (to me) on what's happening next and I got a better understanding of the findings (which I tried to communicate in those sections). Cambridge's presentation was background but I think there were some interesting snippets of preliminary news on the work Fane Mensah is doing in her team. There will be more detailed articles on those two soon.

    I also thought Tom Wileman's presentation was important; again it was background theory mostly, and very preliminary as far as ME/CFS research is concerned, but I think that field of research is going to become very important.

    Olli Polo's presentation was one of those that became a lot more interesting to me when I came to write it up and had to do a bit of research to figure out what he was talking about…an interesting theory that makes quite a lot of sense to me, probably relevant to a subset.

    Davis and Whittemore were the biggest stars of the show though, for sure.

    There's very rarely any actual new science at IiME because people need to hold things for publication in order to get the best public profile for publication. But I did pick up two snippets of good news which unfortunately I can't share; one a new finding which will hopefully be published soon which could be an exciting continuation of existing research, and one more of a political development which I think is positive. Sorry I can't share that info but I'm confident that both will be public knowledge in the next few months.

  • Mark June 15, 2016, 2:15 am
    aimossy

    Thank you so much for these reports Mark. They are always one of the biggest highlights of the year for me!

    Aw, thanks aimossy, that's so nice to hear. :)

  • MEMum June 15, 2016, 7:33 am

    Great article Mark.

  • Bob June 15, 2016, 2:29 pm

    Thanks soooo much, Mark. Very interesting. I've no idea how you manage such a comprehensive outline of events from on-the-hoof notes! I'm in awe!

  • Mark June 15, 2016, 3:38 pm
    Sea

    Thank you Mark. Far too much for me to read in one sitting. I appreciate the effort that has gone into this and will wade through it slowly.

    Yes, once again it ended up as an enormous article. I really tried not to do that this time, I had a different plan but it didn't work out. Hopefully I've learned and I already have a new idea on how to do it next time. The rest of the articles are going to be much more of a sensible length, I promise: I've already written one and almost finished another, but we won't publish them for a week for maybe a week or so to give folks time to digest this one.

  • Mark June 15, 2016, 3:41 pm
    Sean

    Thanks for the excellent write up, Mark. This is soooooo encouraging. Not just for any particular results (such as from Baraniuk on brain MRI before and after a submaximal exercise test *), but as much because the big guns are clearly starting to turn their sights onto the problem in rapidly increasing numbers.

    Thanks Sean. I think that's a very good summary of the big message from this conference. Bigger and bigger names each year, but this year Ron Davis and Vicky Whittemore were the big story I reckon…one on the research side, one on the political side. The other thing I'd add to flesh out that theme is international co-operation amongst researchers, and the game-changing work that Invest in ME has been doing to make that happen.

  • Mark June 15, 2016, 3:45 pm
    MEMum

    Great article Mark.

    Thanks MEMum. Did I have a very quick chat with you at the conference by the way? If not, do come over and say hello if you're there again. Always great to meet PR members at IiME. :)

  • Mark June 15, 2016, 3:50 pm
    Bob

    Thanks soooo much, Mark. Very interesting. I've no idea how you manage such a comprehensive outline of events from on-the-hoof notes! I'm in awe!

    Thanks Bob. Basically I sit there typing away furiously the whole time, taking my own kind of shorthand notes – it helps that I'm a pretty fast typist. Then I come back and flesh out what I typed; as I write each section I look it all up on the web, and read the tweets, to try to figure out what it all meant! I got some vital help up front, as usual, preparing the skeleton of the article (I don't know if my helper wants to be named – but thanks!)

  • duncan June 15, 2016, 3:52 pm

    @Mark , did Professor Hornig repeatedly refer to ME/CFS as a brain "disorder"? Was that the word she used?

  • Sea June 15, 2016, 3:58 pm
    Mark

    Yes, once again it ended up as an enormous article. I really tried not to do that this time, I had a different plan but it didn't work out. Hopefully I've learned and I already have a new idea on how to do it next time. The rest of the articles are going to be much more of a sensible length, I promise: I've already written one and almost finished another, but we won't publish them for a week for maybe a week or so to give folks time to digest this one.

    No no no… Don't change anything, it wasn't meant to be a criticism. I really appreciate all the info, it will just take me a while.

  • Mark June 15, 2016, 3:59 pm

    I just want to mention, in the interests of full disclosure, that this year for the first time Kina and I both claimed our expenses for attending the conference (conference fees, train tickets, and one night's accommodation) and we claimed for last year's expenses at the same time (which I'd recorded last year but never got round to processing). I just felt it was getting too expensive for us and neither of us are loaded with cash. It's the first time that anyone currently involved with Phoenix Rising has claimed any expenses (and none of us have ever been paid anything, though we've paid a few writers for articles, as folk probably know), and I've mentioned a few times that none of us have ever been paid anything including expenses, so I thought I'd better mention it in the interests of transparency.

  • Mark June 15, 2016, 4:09 pm
    duncan

    @Mark , did Professor Hornig repeatedly refer to ME/CFS as a brain "disorder"? Was that the word she used?

    I'm pretty sure she did Duncan, yes. I tend to write things down verbatim but I don't write up all the text that way. I only put things in quotes if I'm pretty sure I've got all the exact words correct; anything else may be me paraphrasing it. I can't guarantee it's all accurate, but I think "disorder" was her word. I did find it notable that a few times she seemed to primarily categorise ME/CFS as a brain disorder; she's clearly presenting that an interaction with the gut, the immune system, and more is fundamental to the disease, which I think is an emerging consensus, and I don't believe at all that she sees this as originating in the brain (I get a strong impression that she sees it as originating in the gut, actually) but the characterisation of all of that as fundamentally a "brain disorder" (as opposed to, say, a neuro-endocrine-immune-gut-microbiome-metabolome disorder) seemed striking to me. She does see a whole range of diseases as having the same dynamic, and I think calls them all "brain disorders"…that was the impression I got but I could be wrong. Those with a better understanding than me of Hornig's research could probably illuminate this further.

  • Mark June 15, 2016, 4:12 pm
    Sea

    No no no… Don't change anything, it wasn't meant to be a criticism. I really appreciate all the info, it will just take me a while.

    I know it wasn't meant as a criticism, but I am going to have to change it this way. I don't think I can keep on doing this to myself, not in quite the same way at least. It would be preferable to put out one sensible-length summary soon after the conference, and then a series of sensible-length explorations of selected presentations in more detail over the following weeks. For my own sanity, I think I have to do that in future, sorry!

  • rosie26 June 15, 2016, 4:58 pm

    Fantastic write-up @Mark . I'm really excited about all the areas of research especially genetics and I loved reading Dr Mady Hornigs (Dr Lipkin team) work and the questions she is asking, one being about the different areas of the body where microbiota changes could cause dysregulation and the affect on the brain, really love that they are looking deep here. Also great LPS is being looked at, and of course the mitochondria. We have waited so long for this day. It's wonderful.

  • Bob June 16, 2016, 10:26 am
    Mark

    neuro-endocrine-immune-gut-microbiome-metabolome disorder

    Ha! That could be a great catchy new name for ME! Or NEIGMMD for short!

  • Bob June 16, 2016, 10:37 am

    I thought this year's line-up of speakers was exceptionally interesting, perhaps because of the 'biomarker' theme of the conference. Perhaps partly because I rarely read about her work, I found Professor Carmen Scheibenbogen's work particularly interesting. I think Professor Elisa Oltra is someone who we should keep an eye on; I like the theme of her research. Also interested to read some more about Dr. Jo Cambridge's thoughts. But the whole line-up was fascinating to read about.

  • alex3619 June 16, 2016, 12:11 pm

    The notion of an impact from bacteriophages in ME and CFS has been around for about two decades or more. Its nice someone is finally working on it.

  • Daisymay June 16, 2016, 3:21 pm

    Thank you very much indeed for this write up, very interesting and encouraging. And absolutely right you both take your expenses, you are there on behalf of all of us who can't get there. Looking forward to seeing the dvds of the conference.

  • Mark June 16, 2016, 4:05 pm
    rosie26

    Fantastic write-up @Mark . I'm really excited about all the areas of research especially genetics and I loved reading Dr Mady Hornigs (Dr Lipkin team) work and the questions she is asking, one being about the different areas of the body where microbiota changes could cause dysregulation and the affect on the brain, really love that they are looking deep here. Also great LPS is being looked at, and of course the mitochondria. We have waited so long for this day. It's wonderful.

    Thanks Rosie. :) The LPS did seem particularly important, and a lot of people are pointing at the mitochondria now, it will be exciting if that's all confirmed because the idea goes back quite a long way and makes quite a lot of intuitive sense. For a lot of scientists, I get the impression they are saying that mitochondrial dysfunction would be so serious that it doesn't make sense for ME, partly because they don't get how serious ME can be, but I suppose also because the known mito problems actually do cause quite different and more visibly blatant kinds of effects (though I don't know any detail about that). Anyway, it'll all be very exciting to watch it unfold, if all goes well…

    It's great to have you on the forums by the way, thanks so much for all your recent posts. My heart goes out to you with what you're coping with, with poor Whitney's illness.

  • Mark June 16, 2016, 4:06 pm
    Bob

    I thought this year's line-up of speakers was exceptionally interesting, perhaps because of the 'biomarker' theme of the conference. Perhaps partly because I rarely read about her work, I found Professor Carmen Scheibenbogen's work particularly interesting. I think Professor Elisa Oltra is someone who we should keep an eye on; I like the theme of her research. Also interested to read some more about Dr. Jo Cambridge's thoughts. But the whole line-up was fascinating to read about.

    Yes, Oltra may be one for the future I think…early days with her ME/CFS research, but promising…

  • Mark June 16, 2016, 4:07 pm
    alex3619

    The notion of an impact from bacteriophages in ME and CFS has been around for about two decades or more. Its nice someone is finally working on it.

    From what I understood, it's only really been possible to get really useful data very recently…maybe that's why…it did seem really exciting to me.

  • Mark June 16, 2016, 4:08 pm
    Daisymay

    Thank you very much indeed for this write up, very interesting and encouraging. And absolutely right you both take your expenses, you are there on behalf of all of us who can't get there. Looking forward to seeing the dvds of the conference.

    Thanks dasiymay. And I'm glad to hear you're buying the DVD – everybody who can, should, I always make a point of recommending that.

  • rosie26 June 16, 2016, 6:58 pm
    Mark

    Thanks Rosie. :) The LPS did seem particularly important, and a lot of people are pointing at the mitochondria now, it will be exciting if that's all confirmed because the idea goes back quite a long way and makes quite a lot of intuitive sense. For a lot of scientists, I get the impression they are saying that mitochondrial dysfunction would be so serious that it doesn't make sense for ME, partly because they don't get how serious ME can be, but I suppose also because the known mito problems actually do cause quite different and more visibly blatant kinds of effects (though I don't know any detail about that). Anyway, it'll all be very exciting to watch it unfold, if all goes well…

    It's great to have you on the forums by the way, thanks so much for all your recent posts. My heart goes out to you with what you're coping with, with poor Whitney's illness.

    Yes, I can imagine that some may not realize how bad this illness really is. It can be very hard for a well person to grasp. I hope the scientists are expecting something big to show up because this illness is seriously 'out there' in hell territory.

    Btw. Mark, I think you thought I was Rose49. It is great to have Rose49 here and I wish the very best for Whitney and so glad he has such wonderful parents caring for him.

  • alex3619 June 16, 2016, 8:03 pm
    Mark

    From what I understood, it's only really been possible to get really useful data very recently…maybe that's why…it did seem really exciting to me.

    Most of the big breakthroughs occur when the technology is available, or because someone deliberately creates new technology.

  • Kati June 16, 2016, 9:34 pm
    Mark

    There's very rarely any actual new science at IiME because people need to hold things for publication in order to get the best public profile for publication. But I did pick up two snippets of good news which unfortunately I can't share; one a new finding which will hopefully be published soon which could be an exciting continuation of existing research, and one more of a political development which I think is positive. Sorry I can't share that info but I'm confident that both will be public knowledge in the next few months.

    That's exciting!

    Thank you @Mark and @Kina and your expenses are approved and you also get my vote for next year's expenses. :thumbsup::thumbsup::thumbsup:

  • Janice Hargreaves June 17, 2016, 2:53 am

    to hear all this progress makes my heart sing with happiness. After having this for a while it's lovely to hear the science is getting there. Thank you so much Mark for all your efforts. Yes I've already ordered the DVD . This will be my sixth one. They have all always been the highlight of my year giving me hope. Many , many thanks again. Plus of course you should be able to claim expenses!

  • MEMum June 17, 2016, 4:12 am
    Mark

    Thanks MEMum. Did I have a very quick chat with you at the conference by the way? If not, do come over and say hello if you're there again. Always great to meet PR members at IiME. :)

    Hi Mark
    Yes I did say Hi. I wasn't really v organised pre conference this year. Maybe we could all take/wear something or have an agreed meeting place. I thought I'd recognised someone from PR, but it wasn,t them. Had a good chat anyway.

  • Mark June 17, 2016, 4:51 pm
    rosie26

    Yes, I can imagine that some may not realize how bad this illness really is. It can be very hard for a well person to grasp. I hope the scientists are expecting something big to show up because this illness is seriously 'out there' in hell territory.

    Btw. Mark, I think you thought I was Rose49. It is great to have Rose49 here and I wish the very best for Whitney and so glad he has such wonderful parents caring for him.

    Sorry Rosie26! :redface::rolleyes: I think I'll remember both of your numbers from now on! 😀

  • Mark June 17, 2016, 4:53 pm
    Janice Hargreaves

    to hear all this progress makes my heart sing with happiness. After having this for a while it's lovely to hear the science is getting there. Thank you so much Mark for all your efforts. Yes I've already ordered the DVD . This will be my sixth one. They have all always been the highlight of my year giving me hope. Many , many thanks again. Plus of course you should be able to claim expenses!

    Thanks Janice. :) Enjoy the DVD! :)

  • Mark June 17, 2016, 5:05 pm
    MEMum

    Hi Mark
    Yes I did say Hi. I wasn't really v organised pre conference this year. Maybe we could all take/wear something or have an agreed meeting place. I thought I'd recognised someone from PR, but it wasn,t them. Had a good chat anyway.

    Aha, I thought so! :) I'll contact you privately because I wanted to continue our chat but we got interrupted, my fault I think, I can't remember why. I've wanted to arrange some PR merchandise for ages, t-shirts, mugs, that sort of thing, I just never had the time; it would be handy at IiME for identifying each other. Maybe we should come up with something else while we're waiting for me (or someone) to get that sorted..

  • msf June 18, 2016, 4:10 am

    It might be helpful to point out that Hanson has replicated some of KDM´s findings.

  • Mark June 18, 2016, 4:12 am
    msf

    It might be helpful to point out that Hanson has replicated some of KDM´s findings.

    Do you have any reference for that msf? Ideally a publication, but doesn't have to be. I'm not sure what findings you're referring to.

  • Bob June 18, 2016, 7:48 am
    Mark

    it would be handy at IiME for identifying each other.

    Perhaps some sticky paper badges might do the trick, if you don't get anything else organised?

  • msf June 18, 2016, 2:02 pm
    Mark

    Do you have any reference for that msf? Ideally a publication, but doesn't have to be. I'm not sure what findings you're referring to.

    Here is the paper that shows a significant decrease in Ruminoccus in Norwegian patients. It does not seem to mention a decrease in Bifidobacteria or in overall diversity, but I believe these are both fairly common findings in his patients (when I was tested, I had almost no Bifidobacteria).

    http://www.sciencedirect.com/science/article/pii/S1075996413000929

    I do not believe he has published the findings about LPS anywhere, but he mentions it in this video at 6.00:

    According to KDM, the level of LPS in the plasma correlates with the severity of the disease, so it will be interesting to see if Hanson confirms this finding. KDM also says that the severely ill patients had higher levels of LPS than did AIDS patients in a 2006 study.

    The good news is, he may have found one of the causes of this, described in a meeting abstract that was recently posted in the ME – current research forum.

    I really think we would be a lot further ahead by now if there had been a group (preferably with more money than KDM) that had just dedicated itself to confirming KDM´s findings, along with those of Maes.

    Oh, and in the same video KDM coins a new name for the disease: Gut-Immune-Neurotoxic Disease, which isn´t a million miles away from your description above.

    NB. In the video, he actually mentions an increase in Bifidobacteria in patients, along with a decrease in the gram-negative to gram-positive ratio, but this was based on culture tests, not on the 16S rRNA tests he now uses, which I believe show the opposite in both these cases.

  • Sushi June 18, 2016, 2:29 pm
    msf

    Oh, and in the same video KDM coins a new name for the disease: Gut-Immune-Neurotoxic Disease, which isn´t a million miles away from your description above.

    That is more or less the diagnosis he gave me a few years ago. I was also high in LPS.

  • Mark June 18, 2016, 6:05 pm
    msf

    Here is the paper that shows a significant decrease in Ruminoccus in Norwegian patients. It does not seem to mention a decrease in Bifidobacteria or in overall diversity, but I believe these are both fairly common findings in his patients (when I was tested, I had almost no Bifidobacteria).

    http://www.sciencedirect.com/science/article/pii/S1075996413000929

    Ah yes, I remember that now! I rather liked that paper at the time, and it still looks good to me now. They seemed very preliminary findings, but interesting; this is a new and very fashionable field (independently of ME/CFS) that's moving forward rapidly just now, it seems. I don't know how solid the methodology is, perhaps @Simon could comment?

    The paper does mention ruminococcus, but mentions lots of other things as well in those results; one would have to look at all the detail to determine to what extent the rest of his findings are consistent with what Hanson found.

    I do not believe he has published the findings about LPS anywhere, but he mentions it in this video at 6.00:

    It's been observed a few times before that it's a shame that KDM doesn't seem to publish papers regarding a lot of the things he talks about. If he did, that would be the way to get more people following up on what he says. But no doubt funding is a major issue there.

    According to KDM, the level of LPS in the plasma correlates with the severity of the disease, so it will be interesting to see if Hanson confirms this finding.

    It certainly will! At IiME it did seem like they were very interested in LPS; if one of these candidates could be shown to be correlated with severity or specific symptoms or subsets, I think that would be very significant.

    KDM also says that the severely ill patients had higher levels of LPS than did AIDS patients in a 2006 study.

    A reference for that study would be helpful too.

    The good news is, he may have found one of the causes of this, described in a meeting abstract that was recently posted in the ME – current research forum.

    Another reference you might like to track down… 😀

    I really think we would be a lot further ahead by now if there had been a group (preferably with more money than KDM) that had just dedicated itself to confirming KDM´s findings, along with those of Maes.

    Hindsight is a wonderful thing. There have been so many promising leads and so many dead ends; so much that should have been properly followed up, and would have been followed up if the proper funding had been there. I've felt for a long time that when the answers finally come, we will look back and see that some of the key features were actually found 20 years ago or more and not followed up. Further on from that, when it's all well understood, we'll be able to see a simple test or piece of research that could have resolved things decades ago if only we'd known exactly what to do. But I think that's all hindsight really. It's always easier to work out the answer when you already know what the answer is! The problem is sifting through all the findings and figuring out which ones are true, which aren't, and which are significant and why. Having weak evidence of something is one thing; having proof is quite another – and all the necessary studies cost money. And a lot of what has been published will turn out to be flat out wrong – likely that will be the case for much or most of the published biomedical research on ME/CFS too – perhaps also for much or most of what KDM himself has published or claimed. Still, I do agree that all these things should have been properly followed up.

    Oh, and in the same video KDM coins a new name for the disease: Gut-Immune-Neurotoxic Disease, which isn´t a million miles away from your description above.

    Yes, that's very similar, but that aspect isn't surprising. I think this model of causality is fairly well established now in a number of diseases; perhaps a quarter or half of the IiME presenters over the last few years have been talking along similar lines, and talking about that as an established model for other diseases as they've done so…at least, if I've understood things correctly…

    NB. In the video, he actually mentions an increase in Bifidobacteria in patients, along with a decrease in the gram-negative to gram-positive ratio, but this was based on culture tests, not on the 16S rRNA tests he now uses, which I believe show the opposite in both these cases.

    As I say. :rolleyes: Another confounder is the mechanisms mentioned (by Scheibenbogen) whereby different pairs of antibodies (that either up-regulate or down-regulate their targets) could cause opposite symptoms in individuals who have one or the other, or both opposing sets of symptoms in patients that have both! There are lots of bits and pieces here, but it's fairly likely the picture will get even more complex in the next few years…

  • msf June 19, 2016, 2:38 am
    Mark

    Ah yes, I remember that now! I rather liked that paper at the time, and it still looks good to me now. They seemed very preliminary findings, but interesting; this is a new and very fashionable field (independently of ME/CFS) that's moving forward rapidly just now, it seems. I don't know how solid the methodology is, perhaps @Simon could comment?

    The paper does mention ruminococcus, but mentions lots of other things as well in those results; one would have to look at all the detail to determine to what extent the rest of his findings are consistent with what Hanson found.

    It's been observed a few times before that it's a shame that KDM doesn't seem to publish papers regarding a lot of the things he talks about. If he did, that would be the way to get more people following up on what he says. But no doubt funding is a major issue there.

    It certainly will! At IiME it did seem like they were very interested in LPS; if one of these candidates could be shown to be correlated with severity or specific symptoms or subsets, I think that would be very significant.

    A reference for that study would be helpful too.

    Another reference you might like to track down… 😀

    Hindsight is a wonderful thing. There have been so many promising leads and so many dead ends; so much that should have been properly followed up, and would have been followed up if the proper funding had been there. I've felt for a long time that when the answers finally come, we will look back and see that some of the key features were actually found 20 years ago or more and not followed up. Further on from that, when it's all well understood, we'll be able to see a simple test or piece of research that could have resolved things decades ago if only we'd known exactly what to do. But I think that's all hindsight really. It's always easier to work out the answer when you already know what the answer is! The problem is sifting through all the findings and figuring out which ones are true, which aren't, and which are significant and why. Having weak evidence of something is one thing; having proof is quite another – and all the necessary studies cost money. And a lot of what has been published will turn out to be flat out wrong – likely that will be the case for much or most of the published biomedical research on ME/CFS too – perhaps also for much or most of what KDM himself has published or claimed. Still, I do agree that all these things should have been properly followed up.

    Yes, that's very similar, but that aspect isn't surprising. I think this model of causality is fairly well established now in a number of diseases; perhaps a quarter or half of the IiME presenters over the last few years have been talking along similar lines, and talking about that as an established model for other diseases as they've done so…at least, if I've understood things correctly…

    As I say. :rolleyes: Another confounder is the mechanisms mentioned (by Scheibenbogen) whereby different pairs of antibodies (that either up-regulate or down-regulate their targets) could cause opposite symptoms in individuals who have one or the other, or both opposing sets of symptoms in patients that have both! There are lots of bits and pieces here, but it's fairly likely the picture will get even more complex in the next few years…

    Sorry , there are no endnotes in a video!

    This is the recent KDM meeting abstract: http://forums.phoenixrising.me/index.php?threads/dr-de-meirlier-april-and-baff-iga-study.44919/

    I think the surprising thing is that the video is six years old – I am not aware of anyone else describing the disease in those terms in 2010 (except perhaps Maes). I agree that it would have been better if KDM had published more, but like you said, money was probably a limiting factor.

    http://forums.phoenixrising.me/index.php?threads/dr-de-meirlier-april-and-baff-iga-study.44919/

    I do not believe that ´much of what KDM has claimed may turn out to be false´, but it may not be the whole picture. In my view the disease is at least partially driven by the gut issues, but it may also be driven by autoimmunity in some patients – or perhaps there is some autoimmunity going on that affects the gut? I think the key to it all is working out why Ritux works for some, but I guess that isn´t all that easy to do…

  • Sasha June 19, 2016, 2:59 am

    This is an excellent artice, @Mark! Thanks so much to you and @Kina to attending the conference on behalf of all of us who can't go. I know what an immense amount of work it must have been to have produced something this comprehensive in so short a space of time and it's hugely appreciated – the suspense is terrible for those of us waiting for the DVD!

    Especially exciting to hear in some detail about Ron Davis's work. If you're planning more detailed versions of each presentation, I hope you might start with his! :)

    Really terrific job. :thumbsup::thumbsup::thumbsup:

  • Mark June 19, 2016, 5:04 am
    Sasha

    This is an excellent artice, @Mark! Thanks so much to you and @Kina to attending the conference on behalf of all of us who can't go. I know what an immense amount of work it must have been to have produced something this comprehensive in so short a space of time and it's hugely appreciated – the suspense is terrible for those of us waiting for the DVD!

    Especially exciting to hear in some detail about Ron Davis's work. If you're planning more detailed versions of each presentation, I hope you might start with his! :)

    Really terrific job. :thumbsup::thumbsup::thumbsup:

    Thanks Sasha. :) Yes it's a lot of work, but I do enjoy it and it helps me get a lot more out of the conference and understand it better.

    MEAction did a great article about Ron Davis' talk, and I wrote an extended section on that presentation including everything in my notes that wasn't covered in their piece. So I'm not planning on adding anything further about that one – sorry. I'll have another look but I think it's pretty much been covered now.

  • M Paine June 19, 2016, 7:31 pm

    Thank you for your write up. I was wondering if there is any way to purchase a downloadable version of the DVD's?

  • Bob June 20, 2016, 3:41 am
    M Paine

    I was wondering if there is any way to purchase a downloadable version of the DVD's?

    Invest in ME make the videos available on DVDs only, so there's no way to download them, or watch them online.

  • msf June 20, 2016, 5:52 am

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

  • Simon June 20, 2016, 6:38 am

    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:

    Mark

    >Here is the paper that shows a significant decrease in Ruminoccus in Norwegian patients. It does not seem to mention a decrease in Bifidobacteria or in overall diversity, but I believe these are both fairly common findings in his patients (when I was tested, I had almost no Bifidobacteria).

    http://www.sciencedirect.com/science/article/pii/S1075996413000929

    Ah yes, I remember that now! I rather liked that paper at the time, and it still looks good to me now. They seemed very preliminary findings, but interesting; this is a new and very fashionable field (independently of ME/CFS) that's moving forward rapidly just now, it seems. I don't know how solid the methodology is, perhaps @Simon could comment?

    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.

  • Simon June 20, 2016, 8:25 am

    Great to see Vicky Whittemore shares patients views of the dire levels of NIH funding in the past.

    Mark

    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.”

    Think all patients would share that hope, nice to hear it coming from the NIH

    Euro collaboration

    Mark

    Following [EMERG's] 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).

    Dull, dull, dull – but also so important: it's great to see stuff like this happen.

    Mark

    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.

    I suspect I'm not the only one a bit confused by this – it seems odd for one group to establish a European research agenda that the other is presumably expected to buy in to. Hopefully stuff like this will work itself out in time

    UCL: Jo Cambridge and Fane Mensah

    Mark

    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.

    Cool! That seem to be upping the game in the sophistication of looking at immune cell function. (I think the NIH intramural study will do this too, one of those study leader Nath mentions is an expert at studying immune cell interactions, eg the B/T cell interaction that Mensah is studying)

    Also, this seems a good place to park the official IiME abstract ofJo Cambridge's talk, where she gives what I thought was a really helpful explanation of how and why rituximab works in general.

    Dr Jo Cambridge (UCL, London) and Fane Mensah (PhD student) discussed B cell biology and rituximab treatment in patients with ME/CFS.

    … B cells are produced in the bone marrow, pass into the tissues, recognise antigens, following which they can interact with T cells, develop into plasma cells which then secrete antibodies.

    B cells are killed by rituximab, which binds the CD20 molecule on B cells. It is used immunotherapeutically in rheumatoid arthritis, lupus and lymphoma, all of which are affected by B cell function. Rituximab does not affect pre-B cells or plasma cells.

    In the clinic, rituximab (2 x 1 gm) is given intravenously 1-2 weeks apart. B cells are quickly killed in the blood, but decline slowly in the tissues. A blood test is performed at one month to see if the B cells are decreased, but there may be residual memory cells left in the lymphoid organs. B cells start to resume exit from the bone marrow at approximately 6 months.

    Rituximab works best in autoimmune diseases where auto-antibodies are part of the disease process. It removes the “parent” B cells of the rapidly turning over (short-lived) plasmablasts which make the auto-antibodies, and therefore stops the supply of auto-antibodies to tissues or from making part of pro-inflammatory immune complexes (such as in lupus and rheumatoid arthritis).

    Because of some positive outcomes in ME/CFS, does this imply that auto-antibodies are part of the disease process?

    The clinical response to rituximab can take months, and the time varies between diseases and patients. Tests need to be done at baseline, depletion stage, repopulation stage and during relapse. The B cells return once the rituximab is cleared from the bone marrow. Relapse is not always associated with B cell return. In rheumatoid arthritis, 70% respond to rituximab and, B cells are back in approximately 6 months. Some B cells can trigger a relapse when they come back but this is not always the case.

    In ME/CFS, rituximab may therefore stop the B cells differentiating into plasma cells, and stops the B cells interacting with other cells (such as T cells). Treatment protocols should thus be fitted to how the B cells are involved, by looking at the changes in the B cells. Interventions should be modelled specifically in the immune system changes in ME/CFS in order to target the patients most likely to respond.

  • msf June 20, 2016, 12:31 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.

    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?