The cause of MS

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When I posted the link to our EBV and MS meta-analysis on social media yesterday I was taken to task because of the slow progress we have made in MS prevention. 

Can I remind you that science moves steadily and slowly and the biggest problem we have is the slow adoption, or rejection, of innovations or new ideas. 

“The human mind treats a new idea the same way the body treats a strange protein; it rejects it.”
Peter Medawar, Nobel prize laureate, in Physiology or Medicine, 1960.

I was convinced by the evidence already back in 1999 that EBV was the likely cause of MS. I have been working on EBV ever since and the progress has been very slow. The main reason I left the Institute of Neurology (Queen Square) was to move to a multi-disciplinary institute, that would allow me space and time to work on EBV. However, it takes more than just moving to a new research environment to build momentum around a new research hypothesis. 

I have had more grant applications rejected around the viral hypothesis of MS than I care to count. It is very depressing. Despite this, we are pushing on slowly with our plans to create a trial-ready cohort of people at high risk of MS for exploratory MS prevention studies. Dr Ruth Dobson is doing quite an amazing job at getting this off the ground. We are also pushing forward with our ideas around treating MS with antivirals that target EBV. To say that the funding for doing these trials has been difficult is an understatement, but I am hoping if we can get pilot data we can convince the sceptics to fund definitive trials. 

We are also not the only team working on the EBV hypothesis of MS. Michael Pender in Brisbane, Australia, is doing great things and Atara Bio has taken up the baton in industry. I have recently posted on their preliminary results that were presented at ECTRIMS.

I spend most of my waking day doing MS and a large part of that is thinking about EBV and MS prevention. The main strand of MS prevention is an EBV vaccination study. The vaccine is not in our hands, but the capable hands of Jeff Cohen at the NIH, and hopefully a deep-pocketed Pharma company to commercialise it. Even if we get an effective EBV vaccine developed and launched we will still have to overcome the public resistance to vaccination and to convince public health officials that this is a worthy idea. 

The battles ahead are numerous, but we will get there in the end. We have to. We don’t want the next generation of MSers asking us why we haven’t done anything to prevent MS given the current state of knowledge.

EBV is almost certainly the cause of MS. What are we doing about it?  

Jacobs et al. Systematic review and meta-analysis of the association between Epstein-Barr virus, Multiple Sclerosis, and other risk factors. https://doi.org/10.1101/19007450

Background: EBV infection is thought to play a central role in the development of Multiple Sclerosis (MS). If causal, it represents a target for interventions to reduce MS risk. 

Objective: To examine the evidence for interaction between EBV and other risk factors, and explore mechanisms via which EBV infection may influence MS risk. 

Methods: Pubmed was searched using the terms multiple sclerosis AND Epstein Barr virus, multiple sclerosis AND EBV, clinically isolated syndrome AND Epstein Barr virus and clinically isolated syndrome AND EBV. All abstracts were reviewed for possible inclusion. 

Results: 262 full-text papers were reviewed. There was evidence of interaction on the additive scale between anti-EBV antibody titre and HLA genotype (AP 0.48, p<1×10-4; RERI 3.84, p<5×10-3; S 1.68, p=0.06). Previous IM was associated with increased OR of MS in HLA-DRB1*1501 positive but not HLA-DRB1*1501 negative persons. Smoking was associated with a greater risk of MS in those with high anti-EBV antibodies (OR 2.76) but not low anti-EBV antibodies (OR 1.16). No interaction between EBV and risk factors was found on a multiplicative scale. 

Conclusions: EBV appears to interact with at least some established MS risk factors. The mechanism via which EBV influences MS risk remains unknown.

CoI: multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

59 comments

  • “New scientific truth does not triumph by convincing its opponents and making them see the light, but rather because it’s opponents eventually die” – Max Planck.

      • Creeping determinism is a cancer inflicting MS research. The quotation was lifted from a book I’m reading titled ‘everything is obvious once you know the answer’. Interesting read. Highly recommended

    • “All truth passes through three stages. First, it is ridiculed. Second, it is violently opposed. Third, it is accepted as being self-evident”, Arthur Schopenhauer.

        • MS researchers are cockroaches… no leaches, sucking the blood from the animal known as innovation, feeding on the carcass of the animal known as hope. They thrive in the dingy darkness of London pubs spending the money they have earned from the beasts which pedal ineffective drugs to the weak and vulnerable.

          Horacio Opzechenstein. 2019

          • Oh dear. That’s a rather bleak quotation and one that should be viewed in context. Let’s not overlooked the improvements in disability progression associated with DMTs. Any improvement is better than no improvement. MS outcomes are not what they were 20 years ago. What I am concerned by is the second, third and fourth generation of me too drugs. This isn’t research. This is profit ahead of innovation. This will change as the voice of the MS community becomes unified.

  • “Can I remind you that science moves steadily and slowly”

    Science didn’t move slowly when they invented an atomic bomb with the aim of ending WW2. Science didn’t move slowly when, under pressure from the great and the good, they ended the death sentence which was AIDS and turned HIV infection into a manageable condition……

    Given the computer power available today to analyse our genes, scan our brains… the ability for research papers to be exchanged across the globe in second… we should be light years ahead in MS research and treatments, but neuros are still prescribing drugs licensed 25 years ago.

    Science moves slowly because scientists won’t bite the hand that feeds it (have a look at the COI lists at the front of every PowerPoint presentation given at ECTRIMS 2019 – interestingly the amount of money received is never disclosed).

    If MS is shown to be caused by a virus (EBV) it would be (1) the biggest scandal in medical research given that the connection was known about 30+ years ago, but no one had the nerve to do the proper research to prove it and (2) knock billions off the market value of all the pharma companies who sell MS drugs.

    My challenge to you Prof G is this – you’ve got your Profship, you’ve made enough money, you’ve done enough conferences and international tours… dedicate the next 5 years to MS and EBV. Prove it as the cause and work with those currently looking at drugs to address EBV. This will be your legacy.

    • RE: “Science didn’t move slowly when they invented an atomic bomb…”

      The invention of the atomic bomb was built on centuries of theoretical physics, maths, engineering, chemistry, material science, etc. I just seems like it happened quickly.

      • It did happen quickly. From Fermi’s first Chicago pile to the atomic bomb was years not decades. My point being that with focus and adequate funding the most difficult of scientific issues can be overcome. MS research needs clear direction and funding. Money spent on biome studies detracts from money spent in areas that show promise…like EBV and remylination.

        • It only happened quickly at the end because they knew how it worked, without the preceding theory and experiments it would not have happened . Once we know how MS works the same thing will happen.

          MS is at the stage of looking for a black cat in a room with no light. Drugs are being found by accident. They work because they accidentally affect what is causing MS not because we know what they are doing, and they come from treating other diseases. The actual cellular mechanism is the light switch.

          It would help to give up looking at mice as mice don’t get MS.

    • Re: “Science didn’t move slowly on HIV/AIDS..”

      Imagine if the virus causing CD4 depletion was not found and researchers were frantically trying different drugs to prevent such loss. Once the target was identified research could speed forward. Although we have drugs for MS that slow the disease course the disease will not be halted until the source is found. I agree, if there is a MS/EBV connection analogous to AIDS/HIV only then will there be true progress.

  • If I remember well, AIDS antivirals have controlled MS in a handful of cases?
    If so, how is is that not a single MSer has taken antivirals since 1999 specifically
    Or is the hypothesis that once infected, the damage is done if MS chain reaction is triggered and therefore irreversible with antiviral treatment?

    • Last I heard is that our index case is still alive and well on HAART with no evidence of MS disease activity. How many swallows does it take to make a summer?

      Maruszak H, Brew BJ, Giovannoni G, Gold J. Could antiretroviral drugs be effective in multiple sclerosis? A case report. Eur J Neurol. 2011 Sep;18(9):e110-1. doi: 10.1111/j.1468-1331.2011.03430.x.

      • As I understand it, the cost of antiretrovirals for HIV are now very low (genetics available). Why not take 30 patients with active RRMS and not on treatment, and treat them with Antiretrovirals for 5 years? Cost of drugs for trial c. £20k for 5 years. Cost of annual MRIs for 5 years – £75k. Blood test costs for 5 years – £5k. Researchers to give time for free. Trial costs £100k. No need for double blind distraction or placebo (created by researchers to make more work). Question to answer is do antiretrovirals suppress MS. 30 swallows should make a Summer. Start thinking creatively rather than being mired in the academic bog that scientists and researchers have created. If a drug works ie total suppression of a disease, you don’t need a placebo to show it works. Placebo effect is minimal as interferon beats it and we now know that interferon is pretty hopeless. If two people were on fire and you had a hose, you would squirt water on both. You wouldn’t only squirt water on one and let the other be the placebo to show that water puts out the fire and reduces damage!

        • The set-up, governance and running costs of a 5-year study like this would be closer to £2.5M and possibly more. If it was Pharma doing it times that by 10, i.e. £25M. The gravy train we call research is wide and long.

          • Amen to that. I work for a CRO that bloats cost and adds little value. Guilty as charged. Looking to get out and work for an organisation where my skills directly benefit people.

  • What is the potential benefit of treating established MS with antiviral therapy? Including progressive disease?

    Surely if a benefit can be shown, prevention with the same would naturally follow on.

  • What if EBV was an important co-factor in the development of a fully functioning immune system and MS is an unfortunate side-effect in a minority?

    • In which case eradicating EBV could cause a worse situation than we are currently in with ms. But I have ms with impaired thinking (and I am a bit thick anyway) and can’t tell if you are joking.

    • The small percentage who do not catch Epstein Barr do not seem to have problems, they still seem to have fully functioning immune systems. I got to 45 before catching it an had no immune problems and allergies. All my problems started after I caught it. I doubt it has any benefit to the host only the virus.

    • Nice said

      You forgot Ra and Lupus

      It look like Ebv is implicated also

      Ohh wait those are autoimmnne diseases…

      Sorry

      • The EBV hypothesis is not incompatible with autoimmunity. EBV may be driving autoimmunity by lowering the threshold at which T and B lymphocytes react to antigenic stimuli.

      • Yes, there are many autoimmune disease linked to EBV. This is not a problem. An analogy is the many autoimmune diseases linked to streptococcal bacterial infection. We now know that streptococci stimulate the T-cells via superantigens, i.e. the superantigen lowers the threshold for T-cell activation.

  • I don’t know how many times I have posted questions about the HIV antivirals working for someone who had both AIDS and Ms but they have been in the monthly random question section and never answered.

    If antivirals are cheap and are not dangerous to take why not allow people with MS to take them anyway even if they self fund?

    • Re: “If antivirals are cheap and are not dangerous to take why not allow people with MS to take them anyway even if they self fund?”

      But that wouldn’t be scientific. There a method to science that needs to be followed. Evidence-based medicine has proven to the correct way of doing things.

      • The main problem is that PWMS must convince someone else (researchers in academia or pharma) to put together a plan to address a specific question, eg specific EBV reactive antiviral nucleoside analogs may treat MS. We do not write the grants, since it is always about money to fund the clinical visits and record keeping. Since no one else wants to write a grant, we remain outside the gate with no control over the future while we watch other possible treatments which likely have no evidence based bearing on disease outcomes source millions in funding (biome studies).

        MS has a large enough base population in the US to create a straightfoward matched outcome of DMTs +/- antiviral. It shouldn’t be this difficult. ECTRIMS should have one funded clinical trial PER YEAR which is voted on solely by PWMS to determine what to test. Antivirals? Sure that is year one. Clemastine or Ibudilast? Sure that is year two. Vaccination against EBV for children of PWMS or deep sequencing of parents/siblings/children where there exists familial MS? Yes year three please. All can be done as add on therapies to existing DMTs.

        The breadth of the dismissal of suffering because MS doesn’t kill you outright is appalling sometimes as patients are continually treated to “wait until next grant cycle” for something really important to be done. Hope you can still walk by then.

        • Surely people with MS can convince the MS Societies…The Canadian MS Society spent $10 million doing CCSVI studies, the academic community were not fans of that one.

    • The use of anti virals assumes the effect is directly from the virus and not from a change made to a subset of cells in the body. So if the virus infects and mutates B cells so they cause something that causes MS, then killing the free virus will have no effect, as you are not killing the mutated B cells. So the anti viral has no effect and you assume the virus is not causing MS. It is, but in an indirect way, possibly many years before.

      As I have said many times before look at the B symptoms of Hodgkin’s Lymphoma, significant immune effects occur nowhere near the lymphoma. Hodgkins is a B cell lymphoma often caused by EBV.

        • As we do not know how those antivirals affect MS, assuming they do, we do not know if they are acting on the virus or something else. They have side effects so they are doing other things in the body. If we got lucky and they work then they should be used. That does not mean they work by affecting the virus.

  • Conclusions: EBV appears to interact with at least some established MS risk factors. The mechanism via which EBV influences MS risk remains unknown.

    Ok,….so for sure for sure sure Ebv Is the bad guy

    All we need is to say it manny manny times and eventually come true

    Ps: can we research another virus ,bacteria etc
    and see ?
    Who knows another 10 meta analysiss and we will get there

  • I think that Jeff Cohen is a superb scientist doing some incredible work. But I worry that you will never be able to achieve sterilizing immunity with an EBV vaccine. There is evidence that people exposed to EBV (and presumably developed an immune response) can be superinfected with other strains of the virus. https://jvi.asm.org/content/77/11/6546 EBV is a cunning virus and has adapted to evade the immune system over eons.

    We have taken a different pharmacological approach that is different than all the nucleoside inhibitors that are (somewhat) active against lytic virus. We have targeted EBNA1, which is expressed in all EBV infected cells. EBNA1 is a EBV-expressed specific DNA binding protein critical for the replication and maintenance of LATENT EBV. After about ~7 years of work and making about 2500 compounds during the hit-to-lead and lead optimization campaign, we identified a clinical candidate. (Someone asked why research takes so long. Sometimes it takes a long time to convince yourself that something is real! It also took more than $10 million in Wellcome Trust funding to get to that point as well.). Part of the work was published in Science Translational Medicine: https://stm.sciencemag.org/content/11/482/eaau5612.

    We decided to do a first clinical trial in patients with advanced EBV-positive nasopharyngeal carcinoma because the regulatory hurdle was lower than for people whose MS disease can be (somewhat) managed. It’s still early days in the clinical trial, but the safety profile is looking good, the exposure (pharmacokinetics) is looking excellent, and we have some interesting preliminary effects with our pharmacodynamic biomarker (cell free EBV plasma levels).

    We also have developed an interesting preclinical mouse model where we observe EBV-positive B cells that are neuroinvasive. But we also are struggling to get funding to pursue this research more and to optimize the molecule for brain-penetrance. The peer reviews are blistering–the kind that make you just want to curl up in the fetal position for even having the audacity to think you had a good idea.

    What is it about the MS community that make them so resistant to take a chance on high-risk, high reward research?!?

    • Wow, well done! As much as I want things to move faster, I totally get how difficult it is to develop a small molecule NCE, and 2500 compounds in 7 years in impressive!
      Hang in there with the reviewers… remember Helicobacter pylori! Some times a real change to accepted knowledge takes time (unfortunately). I don’t think it is just the MS community, I think it is the established researchers in every field (see H. Pylori example above), they really hate challenges to the status quo. But keep it up.

    • Very impressive, Troy. I’m afraid, as you are experiencing and those who have been working in the MS field for decades can testify, that, perhaps uniquely, arrogance, closed minds, unthinking dogmatism, and jealously guarded reputations, in some cases established on shaky evidence, is distressingly common. This may not be unique to MS but it is a problem we have a lot of sympathy with.

  • Playing Devil’s advocate. If EBV was the cause of MS like u say. And they infect B cells which become rogue and manifest in a autoimmine disorder of some kind, diabetes, arthritis, MS, etc. This implies b cell therapies should be the most effective. So does Alemtuzumab and HSCT therapies are the most effective?

    • EBV doesn’t only infect B cells. EBV also infects T-cells, which is why HSCT and Alemtuzumab have the edge over anti-CD20 therapies.

      • Thanks Prof G. Hope u are right. But Pharma is not going to slit the throat of their cash cow. Also its reported in MS News there’s initial activation T cells that’s drives b cell inflammation. I think MS people have waited long enough. As soon as a effective antivirals becomes available against Hepres and EBV they should self medicate. It may not be scientific. But if MS disappears. Who cares!

        • We found 32 seronegative in over 1,000 CIS cases. When we screened these with more sensitive assay 31 were positive and one borderline. We categorised that one as being negative. The problem is the fact that the current MS diagnostic criteria are not 100 sensitive. Approximately 4-5% of people diagnosed as having MS in life don’t have MS at post-mortem.

          • Fascinating. Does the same apply to lupus, etc…

            And what is the framework backing the idea that cleansing an infected CISer will modify the course of their disease?

  • I’ve read that EBV infection can be spread for up to 18 months after contracting it; beyond this, the virus stays dormant. Does this seem correct? thanks.

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