Day 2 Report

Presenter: Dr Brett Lidbury

Brett: Good afternoon everyone.  My presentation of day two won’t be quite as whizz-bang as Daniel and Amber’s, we’ll see how we go. Now the speakers from day two, feel free to jump in.

I basically took copious notes yesterday and decided this morning I can’t present everything because it was too a bit much so I decided to take stuff out but then I decided not to do that because I might miss something, so what done is I’ve highlight stuff in red and green and other pretty colours to hopefully draw attention to it.

So the day two report. Really, the focus has been on innovation, big data, various omics, methods, computers, and in big red letters, collaboration. Don said this morning and I agree, the answer’s actually here in the room, whether it’s for biomarkers, diagnostics, and of course candidate pathways for treatments, it’s all here, the knowledge is here, it’s how we capture that, so collaborate please.

Before I do that, some of you are aware, under the Medical Research Futures Fund there is a call to look at health economics in relation to ME/CFS in Australia. The ANU wants to put a proposal in as I know other universities do and we wish to establish an advisory committee. If you’re keen please see me or if contact me later, just go to the ANU website, put my name into staff and you’ll find me quite easily, send me an email. The advisory committee can be clinicians of course, researchers, patients, people particularly like Emerge, representative advocacy groups.

Just to remind you too, as one of the two editors with Professor Paul Fisher, there’s a special edition of Diagnostics coming out devoted to this conference and we’ve also accepted papers by others who want to contribute by unsolicited paper submissions to this journal, and we’ve had a couple accepted already. This is going to be a bumper volume I hope and I said to Paul last night at dinner, it’s like planting a flag, particularly for the biomedical thinking around ME/CFS and progress from this point onwards. So I can’t force you but particularly to the speakers, I’d love to hear from you. As with Paul of course we’re waiting like a wicketkeeper in cricket to catch those wonderful nuggets of wisdom, so please get involved with that if you have time. By early May would be good. If you want to know more, just go to your search engine, put in ‘Diagnostics special issue’ and you can see more information about what’s involved and how to submit, which Paul and I will then assess. For the academics, you need to publish or perish, unless it’s really awful, nudge-nudge wink-wink, there’s a pretty good chance it will get in, so sharpen the pencils.

So session one yesterday, we were very privileged of course, thanks Ron for travelling as far as you have. It was interesting to hear Ron’s comment which reflected what Mark said this morning about GET, graded exercise therapy is – I think the word was barbaric, we heard the word malpractice, we heard some fairly strong language around that. The other thing that really resonated because it agrees with what I said to colleagues is, when you give funding, we fund the people that know what they’re doing. There’s always a risk through national research bodies – they say, great, we need to solve this, let’s put out a general call, and all these people come in and take all the money and often people who have been in the field for a long time miss out because we don’t have gilded CVs and amazing track records. So fantastic, we need that, for people to trust us and say, here’s some money, get on with it. Scientists want to do science.

Now for the speakers. DNA viruses are being looked at, a range of DNA viruses, with nothing detected in Ron and his colleagues’ system, no new pathogens necessarily. We heard about the risk of post viral syndromes and other types of infections and pathogens. What I just want to flag here – the stuff in black just read at your leisure, I’ll make the notes available – but it’s the red stuff that caught my eye [slide 1]. The multiplex cytokines, T-cell expansion, and this has come up with my work that I presented two days ago: you get these nice patterns but when you add more samples to the study you no longer find the effect. This is an issue that’s been discussed a lot in Australia at a discovery level, so at a fundamental science level we have some really excellent work that gets in to good journals but we need to scale up. We need many, many more research participants, we need to do more work at validating our discoveries and bringing together all the knowledge in this room into something useable in the clinic.

We had also in session one Dr Xiao talking about a severe ME/CFS cohort and I had to highlight this name here, Dr Neil McGregor, director of our nascent and emerging ME/CFS Research Discovery Network, and we’re keen to collaborate as Neil’s already doing with Stanford, with other colleagues around Australia and overseas [slide 2]. This was interesting Dr Xiao, there’s been a lot discussed in Australia about Lyme and Bruce commented on it this morning. I don’t want to weigh into this because people either love you or throw bricks at you but it has been an issue about whether this is the cause and it’s interesting to see from that talk that no difference was found between ME and controls. This sort of thing rings my bell as a lapsed immunologist. The cytokine panels do show changes, 21 out of 61 changed significantly and the metabolites, 63 out of 592, for example lysine, and we heard a bit more about lysine in Neil McGregor’s talk. So we’ve got these interesting things going on – there are changes and if you look at a healthy research participant versus someone who fulfils whichever criteria and is diagnosed ME/CFS there are differences, there’s something going on at the metabolic and the immune level.

The reason I’m rushing and I had this issue the other day, I was the last speaker before the wine tour and today I’m the last speaker before lunch.  How to become really unpopular at a conference is cut into lunch or wine!

It was a great honour last night to hand out awards to my friend and colleague Paul Fisher but also to Dr Phair who is an electrical engineer by trade and I often say that biologists in particular need to think more like engineers and that is, rather than spinning around in circles, actually solve problems, actually move it like it’s an engineering project. So it’s great, thank you for injecting that can-do problem-solving approach.

I didn’t know about the Northfield Hospital in Adelaide and the ME/CFS epidemic there. Most of us know about the 1955 Royal Free disease in London but I had no idea that we had such a history in this country [slide 4].  But what really, again in red, rang my bell, because other people from Ron Davis’s network and elsewhere commented on this. IDO2, and there’s five common missense mutations. There’s some focus in this talk about the missense mutations being quite common, and this kynurenine pathway and the implications of these pathways, which of course link immune system, gut function and brain, which are all implicated in ME/CFS. This bistability input versus output, I didn’t quite follow that but please talk to Robert later if you want to know more. But what I did pick up was the seratonin pathways. We talk about brain fog and various other cognitive functions being impaired so there’s something very interesting there about the precursors, the phenylalanine, the tyrosines that Chris talked about as well, and dopamines and seratonins through these various indoleacetic acids and 5-HT, hydroxytryptophan.

Now this one, this is a deadset ripper as we say here [slide 5]. A mean of 1.8 damaging IDO2 mutations in this IDO trap, I’d love to hear more about that so I hope you submit a paper Robert. The day two presentations from several of our overseas visitors seemed to have common theme about this IDO gene, and the kynurenine and actual pathway which was found to be decreased in ME/CFS. It seems quite compelling.

Now on to our friend who is from Melbourne and has moved elsewhere for the moment. Chris Armstrong, thanks for your presentation mate. The B-cell studies with the UCL team that was reported from day one, again in red, increase in CD38 [slide 6]. Now for those uninitiated I left immunology when we were up around CD100 and now we’re up to about CD250. They used to just call them things like TNF receptor 1 and 2 and I could handle that. Look, I don’t know what it does but it’s going up on B-cells and increased in ME/CFS. Again, please talk to the experts and we’ve got plenty of them here.

I have some involvement with the project at La Trobe with Paul, Sara [Annesley], Daniel and colleagues, on the greater utilisation of glucose and the media. There’s something metabolically very different about the cells that are extracted and grown in culture ex vivo from people with ME/CFS. They exhibit different things and as we saw Paul’s talk, it has a lot to do with the mitochondrial function and various complexes not operating as well as they should.

I just touched on the whole thing about serotonin and the 5-hydroxytryptophans, we’ve got this thing going on with phylalanines which you must take in through your diet. You’ve probably all heard of PKU, it’s something you take in, and the production of dopamine, so again we’re looking at a neurological issue. That was another study that Chris is involved in, in the metabolomics realm.

Now Ruud Raijmakers is a colleague from the Netherlands and he mentioned CBT and there was a lot of discussion after Ruud’s presentation. Ruud actually did some work here with the animal health laboratory in Geelong, he might be visiting them today so it was just perfect that we invited him to Geelong. It’s not something that’s nice to talk about but there was a massive outbreak in the southern Netherlands of Q fever and the Q fever fatigue syndrome emanated in one to five per cent of patient who were diagnosed with Q fever, caused by coxiella burnetii named after Macfarlane Burnet, a great immunologist from Australia. The Expert Centre in chronic fatigue and QFS, it’s been going for 30 years, 40 thousands cases, my goodness, I’d love to get hold of that data set.  But the focus was on QFS and from my reading it’s a fatigue syndrome but it’s quite a bit different too what we see. There’s no persistent infection detected and there was of course the mention of CBT, which did have some impact for the people soon after diagnosis but then they relapsed.

It was good that there was a mention of Professor Marmion who is no longer with us and his cytokine studies way back when, and the whole link with QFS and the Australian contribution to that. Again as a lapsed immunologist, with the immune responses the pattern differences were quite compelling, you’re looking at many, many cytokines and other immune markers at once, and you can see through heat maps the different patterns and how they shift. So there are differences at that level. There is an immune response but it’s different to what we see with chronic fatigue syndrome, ME.

So what’s also interesting as a former virologist is that C. burnetti does replicate inside of monocytes and I assume phages, and I’ve highlighted here the link with mitochondrial function because of the downregulated genes, the MT-RNR 1 and 2 genes were found to be downregulated in their QFS sample. It’s very interesting too that there’s mitochondrial proteins somehow affected in this case of fatigue syndrome post coxiella burnetti or Q fever. Another interesting difference between chronic fatigue and the Q fever fatigue, we’ve talked a lot about the possibility of autoimmunity and part of the evidence being the ratio of 3:1 or 4:1 females to males, but they were finding male to female was 50/50 with the manifestation of symptoms for Q fever fatigue syndrome. So I think we could almost safely say, and of course more validation is needed. but they’re different diseases. Maybe that’s helpful.

Now back to Neil McGregor who I mentioned before, who’s got access to data from elsewhere [slide 8]. Neil is the most devoted biochemist. The sort of things he talks about takes me back to the late 1980s when I studied biochemistry and actually enjoyed it, unlike 98 per cent of students who study biochem, so I have fond memories but even so I find it difficult. There’s lots of really good stuff going on – the work done at Bio21 with our colleagues Neil, Paul Gooley and Chris and Henry Butt and others. Of course they’ve been working this field for quite some time with Don Lewis at CFS Discovery. But Neil reported on getting 777 cases, and having that many cases to work with, on hypoglycaemia and actually stratifying the responses based on the GTT, depending on whether you had a flat response or you had different sort of kinetics in the insulin and glucose responses. And then looking at those relationships with antinuclear antibodies, serum creatinine which again rang my interest because of what I reported the other day about the creatinine excretion rate over 24 hours for the patients in our study and the difference. We could actually separate them based on how much creatinine, in fact the creatinine answered the question. It was significantly lower in the urine in our study so there is something going on with the nitrogenous waste pathways and there’s some implications for urea as well, Neil talked quite a bit about what you see in hyper-exercise or athletes, and the extension I assume being of what parallels there are with people with ME/CFS who are in an exhausted state [slide 9]. We do see electrolyte loss in our studies as well but it’s very labile in terms of significance. The creatinine clearance through the urine is quite consistent but the potassium and sodium rates of excretion in our data sets vary, sometimes significant sometimes not.

As a lapsed molecular biologist, learning about the eukaryotic initiation factors was a very fascinating observation as well, in terms of protein translation and maybe the disruption to that. That’s normally impacted by viruses, which is another story.

Dr Moreau, thank you very much [slide10]. The big thing here was on post external malaise and the microRNAs that were differentially expressed in the studies, and there’s the list [slide 10]. There is a range of microRNAs that have been found and of course once you find these markers, whether it’s a microRNA or t’s a protein or it’s a gene, you can then use the literature to understand what other scientists have found about their function and what they’re involved with. So it’s a good way to go because you can learn a lot form these experiments just by consulting the literature. So there’s a few there but there is no magic bullet. When I was learning science in the ‘80s and ‘90s we very obsessed with magic bullets but no, it’s about many things. So congratulations on that work. There is a number of candidates there that, when you look at the various functions associated with these microRNAs, do resonate in the context of CFS.

Dr Bergquist, all the way from Sweden. Neuroimmunology: again, we’re seeing regular reports about low-grade inflammation, flu-like symptoms, but I just want to highlight the common themes, the mitochondrial involvement and looking also at brain function [slide 11]. I’ve put arrows here pointing up or down just indicating whether, say, synaptic plasticity was increasing or axon repair decreasing. And the pregnenolone story was quite fascinating, that drew some attention and comments. I just thought it was a hormone and didn’t think much more about it particularly in terms of mitochondrial function and production, so there were amazing insights there.

We had Suzanne MacDonald speak about n=1 research [slide 12]. Means misleading, and I just put a little note here that we do actually have a project running with my colleague Alice Richardson with Don Lewis from CFS Discovery, and one of the things we are finding of course is looking at people with these differential pulse pressures, you’ve got such variation that if you just do your standard means and standard deviation, the variation or the critical functions are being missed despite be lapped up by the variation and by finding the central tendency. So one patient statistically aggregated, and there can be interventions involved in these types of research strategies. There was a paper published in 2011 or ‘12, we discussed it yesterday, of what’s called personal omics where you just take lots of data off the one individual over time. The question Paul Fisher had was, how is that different from longitudinal studies or is that the same thing, so I’ll let you two work it out over lunch.

We’re very lucky to have some computer scientists here talking human-computer interfaces and the way I’d link all of this together is that there’s been a lot of talk just in the last couple of days about measuring people when they have good and bad days, and wouldn’t it be great if we had some sort of app, or computer interface with a monitor for those people who consent to that sort of research, where we could track and see the variation in fatigue levels or some other measure [slide 13]. The computer scientists are looking at this and as they admit, there’s been little done in this space in their discipline of computer science. But of course with the technology these days, with people carrying Fitbits and all sorts of technology on their wrist, wouldn’t it be great if we could maybe combine that with Suzanne’s n=1 research and gets lots of data on individuals, and then come to the markers that we’ve been talking about and look at them as well. Which might be a bit more challenging given that it’s harder to collect blood away from the clinical environment.

Just finally, the Euromene endeavour, which is part of the COST Action initiative through the EU [slide 14]. Eliana spoke deliberately not about the science but about putting together a network which we’re very keen to do in this part of Australia through the MDRN and we’d love to hear from people who are interested, particularly people who can help with recruitment of research volunteers and participants. What was interesting was how they’ve divided themselves into working groups with this wide coverage. We tend to think in science, well I’m a molecular biologist, I look over here, I’m a neuroscientist, I’ll look over here. But this brings those working groups together towards a common goal, which isn’t easy. It’s also interesting and alarming that in some parts of Europe ME/CFS just isn’t considered, or you might have one practitioner in countries like Serbia or Croatia.

I’ve done is a final slide to say, collaborate. It’s all here, we now need to put our arms out, grab it all and bring it in to something meaningful that we can translate, the sooner the better. I’m a fundamental scientist and it used to be you discover things and you publish them. I’ve moved out of that, now it’s about discovering stuff and using it. We need to think about the next steps. Discovery is great but it’s now talking to other people and moving it towards something.

The themes for me were, the IDO seemed quite fascinating in terms of its consistency as we heard from Robert and from Ron and Xiao as well. The glucose tolerance, I found that a fascinating study Neil, and how this fits in with amino acids, and kreb cycle and all the things we tried to avoid as students as university because it was so hard to learn, but it’s important, it’s how we produce energy. The B-cells, they keep coming around, we’ve had quite a B-cell focus both through the La Trobe work and but also from what we’ve heard from UCL and colleagues there. And collecting the data through the human-computer interface. Data and more data and good statisticians, that’s something that we really need. We need to handle data better and analyse it more deeply and efficiently. With Euromene, we’d love to be an associate, our MDRN here in Victoria and the ACT and elsewhere. And I just have to highlight some work we did at the ANU looking at using factor analysis to look at the diagnostic criteria under the Canada Consensus Criteria and what’s most important. If you’re interested in that at a deeper level let me know because again, I think there’s so much going on, it would be good to pull it back to something useable. Thanks for your attention.

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