Day 1 Report

Co-presenters: Daniel Missailidis, La Trobe University, and Amber Jaa-Kwee, Victoria University 

Daniel Missailidis: Hello everyone, it’s not only my absolute pleasure but my genuine privilege to address you all today with what we’ve spoken about in the last couple of days. I think it’s really valuable that we have this kind of connection to the real stakeholders here, which is the ME/CFS community at large and the people on the ground trying to find the answers for you.  

So I’m just going to take you through the first few sessions that were covered on day one, the first one is mitochondrial function and signalling. 

So the first talk that was given was by my supervisor on work that I had undertaken by coincidence, it’s also the first one that I’m going through today.   

So as Bruce [Wauchope] already mentioned to you, the mitochondria have this machinery that generates our energy currency called the electron transport chain and as Bruce said it’s a really interesting and glorious thing but in ME/CFS we think that there’s a problem. So in the work that I’ve undertaken it seems that there’s some manner of inefficiency, it may be and it likely to be in Complex 5 [slide 1]. Complex 5 is the part of the machinery that directly generates ATP, which is the energy currency of our cells. So this inefficient energy generation is accompanied by an elevation of supporting catabolic pathways and respiratory complexes. This could be compensatory effect but don’t know which is the cause and which is the effect as yet so we’re pursuing these angles but it’s very clear that in the cell type we’re looking at from ME/CFS patient blood, there is some manner of mitochondrial inefficiency that’s accompanied by stress sensing elevation, which is in response to an energy stress. 

There’s been some other work done in the UK by Cara Thomas. She’s found that mitochondrial respiration was reduced in ME/CFS PBMCs [slide 2]which are cells taken straight out of the blood of ME/CFS patients and the difference in the patterns that Cara sees from what we’ve reported are likely due to difference in cell type. The cells that we use actively metabolise and are happy in a culture environment. These cells are challenged by an environment outside of the body so it’s kind of two different suites of information though they are compatible with each other and give us parts of a broader picture.  This figure here is a typical read out of the technique that both of us use and Cara focussed on for her work, it’s called sea horse barometry and the thing I want you to take away is that this Y axis here is the oxygen consumption by respirationit tells you how much respiration is taking place. The top line are the controls and the bottom is CFS, so the CFS have reduced respiration and Cara’s also found in subsequent follow up work that the respiratory complexes are functionally normal so it’s not necessarily a defect inlets say, complexes 1 to 4, it’s some manner of effect on the cells perhaps by the environment or some more global defect. 

So the second session was on immunology, which I’ll move to now. The group in Queensland at Griffith University specialise in looking at natural killer cells, which are one of the most commonly affected immune types in ME/CFS, and looking at calcium signalling in these cells [slide 3]. Over the course of many studies and many years they’ve pursued looking at calcium signalling in these NK cells and how they may be dysregulated, and what they’ve come up with is that a family of calcium transport channels called the TRPM family channels had genetic changed detected and reduced expression, responsiveness and function of these channels which move calcium into and out of the cells which is key for their proper effective function in the immune system. Reduced parameters of these channels are associated with diminished flux, which is represented by some data they’ve reported. This is the response of these calcium ion channels to stimulus in healthy controls, and this is in individuals with ME/CFS You can see it’s a flat line, there’s no response. So this seems to be some kind of pathological calcium signalling dysregulation in this important immune cell type. 

So Travis Craddock and his team are looking at ways of using computational modelling to assess the alternative resting states that chronic conditions may be perpetuated by [slide 4]. So if, if we look at ME/CFS as an alternative state nudged by some kind of say chemical exposure or initial infection or high stress, if that resting steady state of let’s say metabolism, immune regulation, homeostatic regulation, if that state is nudged into an alternative rut from which it can’t spill back into normal function, you get perpetuation of a chronic disease state. And what Travis’s team does is, they model pathways that may be affected or that are of interest which is over here, just some examples. You don’t need to know what the specifics are, it’s just a visual representation of how they do things. They define limits on pathways of interest and then use computational modelling to interrogate which alternative homeostatic resting states may be possible within that defined pathway network. Then they can look at, from these alternatives steady states, which parts of the pathway may be targets for therapeutic interventions and then can use that as a screen to look for future therapeutic options targeted at candidates in these pathways. They’ve identified several targets relevant to CFS that they are pursuing.   

group up in London, work undertaken by Dr Fane Mensah and supervised by Dr Jo Cambridge who presented this work, is looking at both immune cell function and metabolism and looking at the relationship between these two things. CD24 is a cell surface marker, which is involved early in immune B cell development and these markers are elevated as a percentage in ME/CFS patients which suggests that these early immune B cells make up a larger percentage of the B cell population in ME/CFS. But what’s very interesting is that CD24 presentation and the prevalence of these cells are associated with an unresponsiveness to immune stimulation, elevated cell death and changes to metabolism in this cell type, which may have some relevance with the previous reports of mitochondrial dysregulation as well. Specifically as done by metabolomics work undertaken by Dr Chris Armstrong, glycolysis seems to trend downwards with the presentation of the early stage cell surface markers, which suggests that as the cells mature, glycolysis is less preferentially relied on. 

Amber Jaa-Kwee:  Hi everyone. Before I start with the summaries of session three and four I would really like to thank Daniel for calming my nerves and also putting these slides together. We had about a 24-hour turnaround to put all of this together into 20 minutes. It’s more difficult than you think. 

So the first session was on neuroimaging which focussed on two presentations about the brain and MRI results or magnetic resonance imaging. The first one was Brain Stem Myelination and MRI changes in CFS/ME, and this was presented by Dr Leighton Barnden from Griffith University in Queensland [slide 6]. In ME/CFS the brain stem is not functioning and connecting with the rest of the body as it should. Correlation of clinical measures with the MRI results revealed abnormalities in ME/CFS patients compared to healthy controls, and it focussed on the myelin which is a part of the nerve structure which acts like a highway for signal transmission for the nervous system.  In the nutshell their study found that in ME/CFS the impairment of myelination and nerve conduction within the brain stem can be seen as a compensatory response from the breakdown in the communication and contributing to the presence of symptoms.  

The second presentation in this session was from Dr Elisha Josev at the Murdoch Children’s Research Institute at the Royal Children’s Hospital Melbourne, and their research was about mapping fatigue in the brain in paediatric ME/CFS [slide 7]. Their study focussed on children and adolescents at the time of diagnosis and again at a two-year follow up. They used MRI studies and questionnaires before and after a period of cognitive exertion. Their results showed that there was affected cognitive performance and higher fatigue in this paediatric ME/CFS group compared to the healthy controls. It’s great research but it’s also a highlight of the research specific to ME/CFS, as it is important because it has implications for the young patients as well as anyone who is involved their care and management. 

The last session of day one was about biobanking and clinical data, and there were two presentations in this session. The first was infrastructure and translational research in ME/CFS, the experience of CureME and the UK ME/CFS biobank and this was presented by Dr Luis Nacul from the London School of Hygiene and Tropical Medicine in the UK [slide 8]. He addressed the need for a biobank, which is a repository of biological samples and associated data. I think of it as a huge library of everything put together in a safe spot. This rich resource allows for opportunity for international collaboration and efficiency with conducting quality research. At the end of the day it all supports the translation of research discoveries to clinical application and practice, so that’s the journey from the benches in the laboratories to the bedside of the patient. 

The last presentation of the day was from Associate Professor Brett Lidbury at Australian National University in Canberra, and their study was about rethinking diagnostic reference intervals for ME/CFS by machine learning and utility of Activin B to assess symptoms severity. Machine learning is an application of artificial intelligence used to make sense of the data and I can tell you there are no aliens involved in this. This technique or tool can be used to analyse a range of pathology test results of ME/CFS patients. By using machine learning, their study has identified serum Activin B concentrations are significantly different between CFS patients and healthy controls. From the study, apart from the findings, but also this approach can provide effective screening tools for clinicians when they interpret test results. 

That was last presentation of day one. It was a fantastic day overall and I think we can all agree that all the presentations have been fantastic. Definitely the research space is heading in the right direction for ME/CFS. 


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Clinical Q&A

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