Why do we think of MS as if it were a mouse?

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Are they? aren’t they?….For years we had the issue about differences between rodent and human immune systems The mousers won and we think of MS as if it were a mouse. What about myelinating cells? Are humans the same or different? Because if they are different, we are throwing a lot of money and hope on studying rodents.

Having watched the EAE debate role on and on to see how people bend their data and ideas to make human MS look like a mouse. For example we are told how MS is a problem of neutrophils….because the people doing the mouse work don’t realise that neutrophils are a quirk of mouse biology, not present in rats or guinea pigs and dare I say it humans either. However, I can pull out quite a few papers where neutrophils are made to be important in MS.

Base your treatment ideas on stopping neutrophils into the brain and you have I suspect a failed trial on your hands. We become desperate to show that our mouse studies are relevant. However, in doing so, people may show that they are not. Don’t believe me. This paper surfaced this week

“T cell delivery of nanonparticple-bound anti-CD20 monoclonal antibody”. Successful depletion in the spinal cord during experimenatl autoimmune encephalomyelitis. 2020 Jun 9″. Best not give them an altmetric by inserting a link, I have got my head bitten off by a few irrate researchers. Needless to say I can’t go to Saudi Arabia on fear of being beheaded. OK a =bit of an exaggeration but you get the point:-). As Jack Nicholson said “Can you handle the truth?:-)”

The study shows that T cells delivery of anti-CD20 inhibits disease (blue). Great you say. However, they show that their delivery system is better than the antibody, but in doing so they show that the anti-CD20 antibody does not work (red)! We know anti-CD20 works in humans…….Therefore, the model is not translational, as such, the model and hence the work has no predictive value….so sorry to say the rest of the study all crumbles. If you want to be harsh the blue shows a small reduction from mint green so they get diease, but not quite as severe. In a human trial half a relapse is still a relapse and so this would be seen as a failure:-(.

I am fine with this answer, we showed that anti-CD20 didn’t work in mice years ago and so gave up studying B cells in mice and moved to humans.

Depletion of CD20 B cells fails to inhibit relapsing mouse experimental autoimmune encephalomyelitis.Sefia E, Pryce G, Meier UC, Giovannoni G, Baker D.Mult Scler Relat Disord. 2017;14:46-50.

However, quite a few didn’t and have continued to produce toilet paper:-), which has been very helpful when I couldn’t get any during the early COVID madness times, when we were stripping shelves like locusts.

Anyway back to the story. Now we have the remyelination machine and this is firmly based in the land of the rat and more recently human. All is well and dandy, you have nice paper after nice paper and grant after grant…but then you had the H-bomb that said humans don’t myelinate like rodents….Bang!.

So what happens? Do you address this head-on our do you simply rubbish the claim. It seems like the latter has been one common approach. I have seen the mousers claim that the humans tissues weren’t actually remyelination. So they suggest the long-held view that the shadow plaque is not remyelination. When the same issue was leveled at a very senior pathologist at ECTRIMS 2019, their defence I have to say was really rather lame. But the evidence mounts as seen this week.

Functional Heterogeneity of Mouse and Human Brain OPCs: Relevance for Preclinical Studies in Multiple Sclerosis.Bribián A, Medina-Rodríguez EM, Josa-Prado F, García-Álvarez I, Machín-Díaz I, Esteban PF, Murcia-Belmonte V, Vega-Zelaya L, Pastor J, Garrido L, de Castro F.

ABSTRACT Besides giving rise to oligodendrocytes (the only myelin-forming cell in the Central Nervous System (CNS) in physiological conditions), Oligodendrocyte Precursor Cells (OPCs) are responsible for spontaneous remyelination after a demyelinating lesion. They are present along the mouse and human CNS, both during development and in adulthood, yet how OPC physiological behavior is modified throughout life is not fully understood. The activity of adult human OPCs is still particularly unexplored. Significantly, most of the molecules involved in OPC-mediated remyelination are also involved in their development, a phenomenon that may be clinically relevant. In the present article, we have compared the intrinsic properties of OPCs isolated from the cerebral cortex of neonatal, postnatal and adult mice, as well as those recovered from neurosurgical adult human cerebral cortex tissue. By analyzing intact OPCs with 1H High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (1H HR-MAS NMR) spectroscopy, we show that these cells behave distinctly and that they have different metabolic patterns in function for their stage of maturity. Moreover, their response to Fibroblast Growth Gactor-2 (FGF-2) and anosmin-1 (two molecules that have known effects on OPC biology during development and that are overexpressed in individuals with Multiple Sclerosis (MS)) differs in relation to their developmental stage and in the function of the species. Our data reveal that the behavior of adult human and mouse OPCs differs in a very dynamic way that should be very relevant when testing drugs and for the proper design of effective pharmacological and/or cell therapies for MS.

The rodent remyelination gurus have hit back and don’t say that the Swedish technology was wrong, they suggest that the pathologists have got it all wrong and that they can’t spot remyelination! So the Swedish reasearchers weren’t looking at remyelination. Are shadow plaques remyelination? Maybe time to rip up the pathological text books. The challenge has been thrown down. Do you ask the pathologists to prove themselves or ask the remyelinators to prove that the pathologists are rubbish, because if they are wrong what else do we have to rip up? This really important. However, the implication is that there is remyelination that we don’t see. We base this on the width of the myelin and the nerve. Is this wrong too? This needs to be sorted.

The guantlet has been laid down (Challenge)

Problems and Pitfalls of Identifying Remyelination in Multiple Sclerosis

Bjoern Neumann 1Sarah Foerster 1Chao Zhao 1Benedetta Bodini 2Daniel S Reich 3Dwight E Bergles 4Ragnhildur Thóra Káradóttir 1Catherine Lubetzki 2Luke L Lairson 5Bernard Zalc 2Bruno Stankoff 2Robin J M FranklinCell Stem Cell. 2020 May 7;26(5):617-619. doi: 10.1016/j.stem.2020.03.017. Regenerative medicines that promote remyelination in multiple sclerosis (MS) are making the transition from laboratory to clinical trials. While animal models provide the experimental flexibility to analyze mechanisms of remyelination, here we discuss the challenges in understanding where and how remyelination occurs in MS.

(Sadly such an important paper is behind a pay wall)..Oops it has fallen into my Drop Box ! https://www.dropbox.com/s/59dow0adda6al8v/Cell%20reports%20Neumann.pdf?dl=0

We should have the Next ECTRIMS Burning Debate. But this is too important to have the Usual Love-In (were the opponnents as Kissy-Kissy. We need the gloves to come off and have a fight. Maybe we can have two fights

Pathologists do not know what remyelination is!

Wolfganng Bruck/Cristine stadelmann versus Robin Franklin/Catherine Lubetzki

or

Use human cells to study Remyelination not Rodents! Anna williams vs Catherine Lubetzki

What do you think?. It seems to me to be centrally important question. Too important not to get an answer! As you have trials lined up and done based on this rodent data.

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MouseDoctor

3 comments

  • Well

    If it look ,smell, and walk like a mouse , Maybe its not human… 🙂

    “Oops it has fallen into my Drop Box ”

    Loll

  • I believe it’s known for a while now that EAE models do not translate that well (at all) into humans especially for progressive ms trying to modify the disease course. Robert Fox, MD, a Staff Neurologist at the Mellen Center for Multiple Sclerosis at Cleveland Clinic presented that fact in an online presentation a few weeks ago.
    Could Human Brain organoids and/or brain slice cultures be an alternative and/or additional research option in time or is that too early to tell at the moment?

    • That is not true we….have translated stuff from models into progressive MS…and therefore shows that Dr Fox has blinkers. Could human brain organoids…maybe, it is interesting we could not get any interest in developing the human brain slices. Maybe we should try again, but after two years of going round in circles we put it on the back burner

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