When doing research, doesn’t help your cause


As part of our remit of working with beasties, it is important for us to discuss animal work.

Working on EAE is becoming a dying art….I have recently met a few colleagues who have said their ethical boards have stopped them working on EAE. The Home Orifice in the UK, who control animal experiments in the UK has EAE within its sights and so we are living on borrowed time.

Indeed in Europe you now have to integrate the 3Rs (reading, righting and rithmatic) of animal use into animal work, you have to read about the problems and as some bright spark thinks that doing pain studies in EAE creates a new avenue for research when (a) they are wasting their time as the pain (e.g. enhanced sensitivity before disease develops) they think they are looking at, has very little to do with the neuropathic pain that occurs in MS and (b) making alarm bells for the ethical review panels because now they not only think that EAE stops animals moving, they now think it is painful and so (c) more determined to stop people doing EAE studies. (d) It makes it impossible to get money to do animal work in the UK and the work goes east or westwards where they don’t care as much about the furry beasties…..The horror stories that I reject from publication come from the Far East. (e) Doesn’t it make you happy that GSK (UK based pharma) moved their neuroscience research from UK to China. It was cheaper and less regulated.

Now you have to rite loads of proposals to get anywhere as people aren’t interested in animal work. You have to do the rithmatic to determine whether it is worth doing it or not.

Yep I know the 3Rs (Reduction, refinement, replacement) mean something else it is all about stopping animal use or refining what is done. Some will argue that doing chemical demyelinating studies is more refined and less stressful to the animals than EAE. So just as the do-gooders have got it in for EAE, the chemical demylination brigade is being sent a nail for its coffin. Now they are having to worry about the heart problems they are causing and never knew about. You often only know if there is a problem if you look for the problem. So in this study the cardiac risk that we were not thinking about now becomes an animal issue and the severity of the procedure may now increase.

A novel role of cardiac inwardly rectifying potassium channels explaining autonomic cardiovascular dysfunctions in a cuprizone-induced mouse model of multiple sclerosis. Akyuz E, Villa C.Auton Neurosci. 2020;225:102647

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS), believed to have an autoimmune etiology. MS patients showed an increased cardiovascular (CV) risk probably related to an impairment in the autonomic control of CV functions, but the underlying molecular mechanisms are not completely elucidated. Inwardly-rectifying potassium (Kir) channels play a key role in cardiac excitability by contributing to the repolarization phase of action potential and were recently identified as target of the autoantibody response in MS patients. Therefore, we investigated the role of cardiac Kir channels in the CV dysfunctions occurring in MS. Cardiac functions were evaluated by electrocardiographic recordings (ECG) in cuprizone-fed C57BL/6 mice, a classic demyelination animal model. Gene expression profiling of cardiac Kir2.2, Kir4.1 and Kir6.2 channels was performed using real-time PCR in mice. Cuprizone-induced mouse model was confirmed by immunohistochemistry analysis showing demyelination in the corpus callosum. ECG recordings from mice showed an increase of the heart rate in cuprizone-treated mice as compared with the controls. Significant increased relative expression levels of Kcnj11 and Kcnj12, encoding for Kir6.2 and Kir2.2 channels respectively, were observed in mouse heart tissue, whereas no differences were found in mRNA levels of Kir4.1 channel as compared with controls. For the first time, these findings provided valuable insights into the potential role of Kir channels in cardiac problems associated with MS.

Now cuprizone cause heart problems, and problems for remyelination researchers.

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  • “Working on EAE is becoming a dying art….I have recently met a few colleagues who have said their ethical boards have stopped them working on EAE.”

    I am so pleased to hear this. As MS unravels it now looks as if something in the CNS (probably EBV) is causing damage and the immune system then gets involved causing more damage. The researchers using EAE focussed on the latter and treatments have come to market over the last 25 years. But we are now finding out that this is not the real MS – it’s smouldering MS that is the real MS. So progressive MS is there from the start and wins eventually regardless of the treatments which seek to address the immune response (which causes focal lesions).

    EAE does not model in any way the real MS. EAE does not address how EBV causes damage to the CNS. EAE does not provide a proper model for researching progressive MS / smouldering MS.

    If I were Prof G I’d say thanks Mouse Doctors for all your efforts, enjoy your retirements. Team G needs to be focusing on EBV, smouldering MS / progressive MS, neuroprotection and remyelination. EAE has held back real breakthroughs as it was, and could never be, the real MS. EAE should have been put to bed 15 years ago – if it had been, we would be way nearer to addressing the real MS / progression. Perhaps in the future we will find out that EAE was sponsored by the pharma companies behind the DMTs and by the manufacturers of mobility aids!

    • Aw, thanks for the praise. You are obviously unaware that the smouldering MS/neuroprotection concept is a direct result of the EAE immune tolerance studies we did 15 years ago in addition to the parallel cannabinoid studies but were ignored by the wider MS research community and pharma. If we had been listened to sooner, we’d be further along.
      Still, keep those positive comments coming, 😉

      • I could do fakery, but I don’t.

        I’m not here to give praise where there has been no progress. It’s Prof G that is questioning the real benefit of DMTs and saying that the real MS is smouldering MS not focal inflammation.

        Lots of mice have gone to see their maker. Until I see real results – treatments to shut down smouldering MS, neuroprotectants and remyelination therapies, I can’t say thanks. Lots of published papers is not a metric I value. It looks like advances have been stifled by the slowness and conservatism of the MS research industry.

        • “Curt”, believe me, lots of published papers at this particular time (REF) is most certainly a metric value 😉
          Now you can throw as much manure as you like at the thousands of crappy unreralistic EAE studies that have been done and I will be the first to agree but if I may be immodest, if you’re trying to dump it on the MDs then you’ve got the wrong target and we are hugely proud of our contributions to MS research, which we humbly suggest are benchmarks for the fourth R, which is Realistic.

        • Curt a lot of our add-on molecules have been tested in EAE and CPEAE (chronic progressive EAR) and SPEAE (Secondary progressive EAE) and have provided important data for getting drugs into trials.

          • As a PWMS I want my privacy protected. With data protection issues I don’t see the point in giving him my real name. The points I make are what is important. They are based on my long experience of living with MS and my assessment of the progress being made. If you are after praise then you’ve come to the wrong person. I’ll certainly be singing your praises if you come up with something to tackle progression / smouldering MS.

          • We can always address any privacy issues you have by directing your screeds straight to the spam bin 😉
            BTW you’ll be singing your heart out before long.

    • We developed a model of an GFP-luciferase transduced EBV-positive LCL that, when injected in a vein, goes straight to the brain. We think it might be a better model of MS. We’re still working on publishing it, but it’s difficult to continue work on it without any funding. We’re battling the EAE and T-cell-centric crowd of reviewers.

      • I know the feeling of the dreaded reviewer…..You may be interested to know that Nature have decided to go open and document reports of the reviewers now it will be possible to see just how much they are being prima donnas.

        By the way what is an LCL ……..lateral collateral ligament and why would anything injected do straight to the brain…is there a targetting mechanism of doe sit go everywhere including the brain

        P.S. I have an idea for the new name for Curt/Gavla…

          • Yes, Lymphoblastoid Cell Line (LCL). Basically, a B-cell immortalized with EBV. We’re trying to figure out what makes these cells accumulate in the brain.

          • A human B cell in a mouse, is this a NOG mouse? We had a dabble when interested in human specific reagents. Does it have cells besides the EBV cell and is there a phenotype?. Anyway probably too much secret info requested. Way back when it was suggested that any activated cell can get into the brain this work I think was Bill Hickey, if not try Wekerle (it was ovalbumin specific T cells in the 1980s). Is there any specificity?

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