Mark Berry presents the first in a series of articles on the 11th Invest in ME International ME Conference in London …
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.
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
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, USADr. Vicky Whittemore
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, FinlandProfessor 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.
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
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, UKDr. 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
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, AustraliaProfessor Don Staines
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, UKProfessor 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
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, USAProfessor 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”, SpainProfessor 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.
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, USAProfessor 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.
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, USAProfessor 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 …