Mark Berry reports on the 10th Invest in ME International ME Conference in London.
The 10th Invest in ME International ME Conference (IIMEC10) was held, as usual, in the Lecture Theatre at 1 Birdcage Walk in Westminster on May 29th, 2015.
Also, the pre-conference issue of the Journal of IiME, which gives details of the speakers, and abstracts of the talks, is available as a PDF document here. Invest in ME (IiME) have posted a conference report by Rosamund Vallings, and Phoenix Rising tweeted the conference live.
Quotes of the Day
“This is an exciting event every year, but it gets better and better… The commitment and enthusiasm of the people who present…is second to none…We’re on an up, and I think this conference is going to demonstrate that.” Dr Ian Gibson
“2015 seems to be the year, in which we’re seeing so much coming together, and so much synergy, across the globe really.” Professor Mady Hornig
“The pieces of this jigsaw are really coming together…I think we’re getting there…but…we’re not quite there yet.” Dr Luis Nacul
“It’s a good thing for doctors to listen to patients, because what they tell us is the truth…what they tell us is in fact what is happening to them, so it’s up to us to find a cause…” Professor Olav Mella
- Fluge and Mella news: Impeccably designed ‘RituxME’ rituximab Phase III trial to be unblinded summer 2017. Rituximab Phase III sub-study pre-trial tests are already seeing clear, measurable confirmation of endothelial dysfunction in ME/CFS, seemingly correlated with level of disability. Phase II cyclophosphamide ‘CycloME’ trial under way, follow-up with severe/very severe patients planned next if successful.
- Dr Jo Cambridge reports distinctive differences in maturation markers of B-cell subsets, potentially of use for subgrouping patients in a rituximab trial.
- Professor Jonas Bergquist reports promising proteomics results in study awaiting publication.
- Dr Claire Hutchinson reports experimental confirmation of multiple patient-reported visual symptoms.
- Professor Mady Hornig’s team now analysing metabolomics study results: masses of data, but strong signals, will take some time to interpret.
- Professor Sonya Marshall-Gradisnik and Dr Don Staines review single-nucleotide polymorphism (SNP) differences in ME/CFS patients they’ve reported, showing how they fit neatly with known symptomatology of ME/CFS.
- Dr Amolak Bansal describes common symptoms absent from most case definitions: hypersensitivity to medications, alcohol intolerance, cold peripheries, altered pupil reflexes.
- Dr Neil Harrison explains his field of immune-brain and inflammation-behaviour research, and says he now has some money to explore immune-brain interactions in ME.
- Conference-goers get up on their feet and follow along with Professor Betsy Keller’s demonstration of “Activity guidelines to avoid symptom flares”.
Welcome and introduction to IIMEC10
Richard Simpson got Invest in ME’s 10th International ME Conference under way, reminding attendees to register for their copies of the conference DVD (which I strongly encourage you to purchase), summarising Invest in ME’s research projects, and celebrating the continued impressive growth of the Research Colloquium.
The previous two days had been attended by 60 researchers from 13 countries, the largest colloquium yet. He also welcomed representatives of member organisations of the European ME Alliance (EMEA) to the conference.
Simpson then praised the rest of the surprisingly small group of people who put the conference together each year, and emphasised how essential togetherness is to making it all happen: “We are a small charity but it’s the way we work together that really matters”.
He finished by setting the scene for Dr Gibson to open proceedings, quoting an audience member from last year’s conference — a quote that he said “summed up the efforts and ethos of supporters and IiME over last 10 years”:
“Things really don’t have to be the way they are – we can change things, and we are.”
Dr Ian Gibson — Former Dean of Biological Sciences, UEA
Dr Gibson, the conference’s long-time master of ceremonies, anticipated the conference eagerly: “This is an exciting event every year, but it gets better and better…”.
He revealed that he’s currently researching a book focusing on the question of what delays progress in research. He first praised the researchers: “The commitment and enthusiasm of the people who present…is second to none”, and then the conference organisers: “The work they do, you would pay £150,000 to get it all done…they do it because of love and determination to make it happen”.
Keen to get the packed programme under way, Gibson summed up the optimistic mood: “We’re on an up, and I think this conference is going to demonstrate that.” And with his head spinning as he contemplated what might lie ahead for ME/CFS in the future, he said he would simply note that he wanted Ewan McGregor to play him in the film.
Gibson explained that the first session had been re-ordered to allow the early speakers to catch their flights, so Professor Ian Charles’s keynote speech would come after Professor Mady Hornig and Professor Jonas Bergquist’s presentations.
‘Markers of Immunity and Metabolism in ME/CFS’
Professor Mady Hornig — Associate Professor, Center for Infection and Immunity (CII), Columbia University Mailman School of Public Health, New York, USA
Professor Hornig echoed Dr Gibson’s optimism about the progress now being made in ME/CFS research: “2015 seems to be the year, in which we’re seeing so much coming together, and so much synergy, across the globe really”.
Her own work, of course, has produced one of the most promising insights of what’s already shaping up to be a vintage year for ME/CFS research, with the discovery of a distinct change in the immune profile of patients after about 3 years of illness…and there’s still lots more to come from Hornig and the Center for Infection and Immunity (CII)…
She began by quickly summarising the “three strikes” model that they work to at the CII – genes, environment, timing — and explained that diseases experienced in early life, factors during pregnancy, exposures over one’s lifetime (including when in the womb) and even the mother’s microbiome (the bacterial population of the gut) all affect an individual’s immune profile later in life.
Listing the many ME/CFS studies taking place at the CII, she highlighted a new 200-patient, 200-control follow-up microbiome study that they are planning in association with the Chronic Fatigue Initiative (CFI).
Hornig then reviewed the major findings from her recently published studies of immune markers in the peripheral blood of ME/CFS patients, which found a host of significant differences between the immune profiles of short duration (less than three years) and long-duration patients, with a range of in pro-inflammatory cytokines elevated in one group and lowered in the other.
In particular she noted the differences in IL-1b, IL-6, IL2p40, IL-17a and IFN-gamma (they had found IFN-gamma at very high levels in short-duration patients) and said they were now wondering whether existing treatments that dampen these cytokines might be appropriate — but she cautioned that these ideas are still in the very early stages and that nobody should be rushing to experiment with such treatments just yet.
Hornig said that she and her team are also examining how individual cytokine profiles change over time, in a study of 50 patients. They are exploring the regulatory networks — the complex patterns of linkage between the many immune markers — and they are again finding clearly visible differences (as she demonstrated with a slide) between these regulatory networks in short-duration and long-duration patients.
They seem to be less tightly regulated in short-duration patients, and in long-term patients the patterns are quite different to controls. They’re still working to understand what these differences mean.
Turning to their study of cerebrospinal fluid (CSF), Hornig explained that here the cohort of patients they are studying are a long-duration group, and they are finding in this group the same pattern of reductions in pro-inflammatory cytokines that they found in the peripheral blood.
In the comparison between ME, MS and controls, they found some similarities between ME and MS, but the controls were very different to both. Dr Peterson’s biobank is key to their continuing follow-up on this work, she said.
The remainder of Mady Hornig’s talk concerned their metabolomics study, which has yielded a mass of interesting data which they’re currently analysing. Hornig did share some preliminary findings from this study, which appear to be very significant, but further analysis will be needed before publishing these findings.
The audience were asked not to share this preliminary information too widely at this stage, so I’m afraid you’ll have to wait for the research to be published — or buy the conference DVD — to get more details about this exciting work.
‘Proteomics in ME/CFS’
Professor Jonas Bergquist — Full Chair Professor in Analytical Chemistry and Neurochemistry, Department of Chemistry, Uppsala University, Sweden
Professor Bergquist said he would present a “tutorial” on the work his team at Uppsala in Sweden are doing, and on what proteomics is. But he began by quoting Lord Kelvin: “To measure is to know”, and “If you cannot measure it, you cannot improve it”.
This idea, he said, is the foundation of his field of analytical chemistry — a field that began at Uppsala with Torbern Olaf Bergman (1735-1784), the first analytical chemist and the discoverer (amongst many other things) of a method of making carbonated water — making him responsible for the existence of Coca-Cola, Bergquist joked.
In Bergquist’s lab, he explained, they study the brain and central nervous system, but their work is “holistic biology”: they also study the respiratory system, the reproductive system, and many more systems of the human body, using mass spectrometry.
The objective of proteomics, he said, is the large-scale analysis of all proteins, asking what’s there, where, how, when, and why?
Humans only have about 26,000 genes, yet there are over a million proteins in the human body. Bergquist said that part of the explanation for this is the Golgi apparatus (present in most cells), which applies post-translational modifications (PTMs) to proteins. About 450 of these PTMs are currently known to occur in humans, and they can be measured using 2D gel electrophoresis, but this doesn’t provide a simple picture.
Bergquist explained the shotgun proteomics workflow, which his team uses: complex protein mixtures are digested by protease and the resulting peptide mixture is separated using high-performance liquid chromatography. High-resolution tandem mass-spectrometry is then used to identify the peptides, and by searching a database for the distinctive “fingerprint” signatures of each peptide’s fragmentation mass spectrum, it’s possible to determine the protein from which the peptide derives.
Some of the proteins that they are looking for are present at extremely low levels, requiring extremely sensitive equipment. To illustrate the low levels of concentrations involved, Bergquist invited the audience to imagine placing a sugar cube into a cup of coffee, pouring the coffee into a swimming pool, then taking one cup of water from the pool and putting that into another swimming pool…and then taking another cup of water from the second pool and putting it into a third.
Looking in that last pool for traces of the sugar is analogous to what Bergquist’s group are trying to measure, down to the femtomolar level of concentration. And to add to the difficulty, as Bergquist cautioned (raising a laugh), swimming pools do not usually contain only pure water…
The cerebrospinal fluid (CSF), said Bergquist, has a total volume of about 150 ml, and it offers an opportunity to look at the chemistry of the central nervous system. When studying CSF, strict protocols for sample-handling, biobanks and transport are super-important, he added. In 2010 his group’s research established the proteome of normal human CSF, finding between 3,000 and 4,000 proteins which they detailed in a 776-page long research paper — a “blueprint of what’s normal and healthy”.
He followed this up in 2011 with a study comparing CSF in ME/CFS and post-treatment Lyme disease, in a paper that has now been downloaded over 29,000 times — some kind of record, Bergquist said, for him at least. That research found evidence of low-grade inflammatory reactions in both post-treatment Lyme and in ME/CFS, with clear differences between the healthy, ME/CFS, and post-treatment Lyme patients. He found dysfunction in axonal guidance, and the CDK5 signalling pathway was significantly enriched — as it is in Parkinson’s disease.
Bergquist now has further findings to report from his proteomics work with the CSF of ME/CFS patients, but as this work is awaiting publication I’m afraid you’ll have to wait for publication — or for the conference DVD — to get the details.
Keynote Speech: ‘Solving ME: What a Research Park Has to Offer in Resolving a Chronic Disease’
Professor Ian Charles — Director, Institute of Food Research, Norwich, UK
Professor Charles began his (slightly delayed) keynote speech by revealing that he’d only been in the UK for just over 3 weeks, after returning from Australia where he’s lived for many years. What could have induced him to leave the sunshine and barbies? His wife, he joked, also wanted to know that!
The answer is that it’s his excitement about the work he’ll be doing: he’s looking forward to taking an “interdisciplinary approach” to studying the gut, which researchers are interested in because of what it harbours: the microbiome.
What Charles is so interested in is the vast community of organisms living in our guts and on our skin. When studying the microbiome, as compared with the study of the genome, the complexity is a magnitude greater, with such colossal potential for interactions that the study of this subject will affect the way we understand complexity itself, he predicted.
Offering a simple but deep insight into how we should perhaps be thinking about this field of study, Charles said that he doesn’t think in terms of “good and bad bacteria” but of “a community, and signalling”.
Turning to ME, Charles highlighted some key questions: in ME patients, are there alterations in the microbiota and are there alterations in the integrity of the intestinal barrier? And is there evidence, in ME patients, of exposure of the immune system to, and (auto)reactivity to, commensal microbes?
Charles then introduced the Norwich Research Park, one of Europe’s largest single-site concentrations of research in food and health, and environment sciences. Within the Park is the UK’s only public research institute on food and health: the Institute of Food Research (IFR), which Charles has just joined to lead the programme to develop the UK’s new Centre for Food and Health — a major investment which will bring a wide variety of disciplines into a single building.
He pointed out, on an aerial photograph, the close proximity of the IFR to the Sainsbury Laboratory, the Genome Analysis Centre, the John Innes Centre, the University of East Anglia, and the Norfolk and Norwich University Hospital, and he highlighted how having these facilities in such close proximity can (if communication is good) enable the inter-disciplinary model that so excites him.
Charles spoke of the global challenges that this area of science will need to address, and of how co-located facilities for gut biology, sequencing, pathology and much, much more, as well as the intersection of the Hospital, the University and the Institute of Food Research, can enable a critical mass to be reached in gut health research.
Professor Charles emphasised that the Centre for Food and Health is taking a new approach: holistic, systematic, and integrated. He described the shift from a reductionist model of breaking things down into components to a holistic model of the merging of large data sets, and also the shift from basic research to applied research — all delivered through a single-site centre of excellence. The Centre, he said, is set to play a pivotal role.
In terms of scientific focus, the Centre for Food and Health will investigate areas including foodborne bacterial pathogens and where they come from; how food interacts with the gut, and how to manipulate bacteria in the gut; new varieties of cereal for health; and personalised nutrition.
Regarding ME, Charles recognised the huge challenge — and the huge personal and societal cost, with an estimated 1 million sufferers in the US alone, and a cost to the economy of $18-$24 billion per annum.
Professor Charles faced some pointed questions from the audience on some of the political issues around the work he’s engaged in. Asked how he would cope with “butting up” against powerful vested interests, he replied that one must go into this situation with eyes open, and yes, of course there would be vested interests — “Industry is very Darwinian” and you need to be prepared.
Dr Gibson noted that there is “some experience” of such issues in that part of the world, around GM foods and climate change.
Another questioner asked of Charles how traces of the Roundup herbicide in our food are affecting the microbiome. Charles’s answer was that we simply don’t know, which he said is a “fair and honest position for any scientist”. “We are prepared to look at it”, he said, “but it depends on funding…we just don’t know what Roundup does”. Some audience members clearly disagreed.
Malcolm Hooper was clear that he didn’t want to buy bread with endocrine disruptors in it — he said that there was a big sorting-out needed regarding chemicals in the environment. Charles pointed out that we all take antibiotics and we do know they will have a massive effect on our microbiome — just as (without going into detail) they had done for him that morning! In that context, Charles agreed, yes, these things will all have a big effect on the microbiome.
Dr Gibson continued the political theme by mentioning court cases in process at the moment, regarding organophosphates and aerotoxic syndrome, where the court’s view on scientific evidence will be decisive. Another audience member continued the line of questioning about pesticides, mentioning work on the correlation between glyphosate and disturbances of the microbiome, noting that rates of juvenile Crohn’s disease have gone up “astronomically”, and arguing that there must be effects on the microbiome in play here.
Charles remained noncommittal: as responsible scientists, he said, we have to be clear regarding correlation and causation; there’s vast complexity involved here, and we need to be certain, when making statements, that we know the facts.
Coming up in Part 2…
Dr Amolak Bansal reviews some issues around ME/CFS diagnostics, rooted in his experience as Consultant in Clinical Immunology and Immunopathology for the last 18 years at Epsom and St Helier University Hospitals — and suggests some interesting new angles that may be worth exploring.
Dr Luis Nacul explains how epidemic epidemiology can help us get to where we want to be — and how bad epidemic epidemiology may have prevented us from getting there so far.
Professor Sonya Marshall-Gradisnik and Dr Don Staines review the findings from their investigations of single nucleotide polymorphisms (SNPs) in biological receptors in ME/CFS patients, and show how the likely biological implications of these SNPs seem to fit well with the symptoms of ME/CFS.
Daniel Vipond, Bharat Harbham, Fane Mensah and Navena Navaneetharaja — representing the “Next Generation” of ME research — boldly go where no student researcher has gone before, and present themselves for Q&A with the conference audience.