The 4Rs of animal research.

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Non-human Primate Research has it had its day or is it the way forward?

We have heard of the 3Rs of animal research, but as this article says we need the 4Rs. I agree.

The fourth R is R for Relevance

With this extra R as a central driver of research, we could lose alot of esoteric animal research and importantly large amounts of futile in vitro cell-cuture studies that take thousands of animals lives, but are not reported because they are not working with living animals.

If people using animal cell cultures had to get ethical approval and licences like the animal researchers using animals. Many studies would not be approved due to relevance e.g. a 10 micromolar dose has no relevance to human biology when the dose occuring in the human is 1 nano molar (10,000 times less). People use animal cells because they are easy to grow but you can make human cell type from a stem cell.

The Centre of the NC3Rs should bend the ears of the Home Office animal inspectorate as it would be an easy win in the real reduction of animal work, but the Home Orifice would be too frightened as they then may have to get statistical accounts of how many animals are really used in scientific research. The numbers would shoot up.

At present you don’t have to report animals if they are normal and killed for the use of obtaining cells. The Home Office made a mistake becuase they included breeding transgenics and knockouts in the reporting as an experimental procedure…hence thousands of extra animals. They are trying to fudge this by say the severity is below importance, because these are in effect normal animals and they are desparate to get the numbers down. You now have to report animals with transgenic or natural adverse mutations. However, the nonsense here is that it is only an adverse event when you look for it. The standard lab mouse has all sorts of of issues if you look for them, many mice are blind (CBA, SJL) others are deaf (BALB/c), so no wonder they don’t listen when I talk to them, some prefer to drink alcohol over water (British Mouse actually C57BL/6) .

This has just appeared on pubmed

Experimental autoimmune encephalomyelitis in the common marmoset: a translationally relevant model for the cause and course of multiple sclerosis. ‘t Hart BA. Primate Biol. 2019;6(1):17-58 (click)

Non-human primate research is emotive. They are rat sized new world monkies. There are moves to stop EAE research because of its severity. Doing EAE in mouse raises ethical issues, but when we consider non-human primate work this is taken to another level.

Aging Western societies are facing an increasing prevalence of chronic autoimmune-mediated inflammatory disorders (AIMIDs) for which treatments that are safe and effective are scarce. One of the main reasons for this situation is the lack of animal models, which accurately replicate clinical and pathological aspects of the human diseases. One important AIMID is the neuroinflammatory disease multiple sclerosis (MS), for which the mouse experimental autoimmune encephalomyelitis (EAE) model has been frequently used in preclinical research. Despite some successes, there is a long list of experimental treatments that have failed to reproduce promising effects observed in murine EAE models when they were tested in the clinic. This frustrating situation indicates a wide validity gap between mouse EAE and MS. This monography describes the development of an EAE model in nonhuman primates, which may help to bridge the gap.

So do we keep the monkies….and scrap the neurologist, after all there is a long list of therapies that weren’t that great in rodents, that were then used in humans and failed…..OK. I am sort of joking we should keep the neurologist. However, in defence of the humble mouse and rat, it is not their fault the way that humans interpret the data.

Here’s an example…I use for teaching and the Smt’s about how you look at the data. Yes sure there are issues with rodents…a good example here is that B cells form a minor component in the development of EAE as it is a T cell driven issue. You say that this shows that anti-integrin 4 does not work in rodents…maybe but guinea pigs was used for the drug development. So you pick you modle for the question you ask.

It is logical that the immune system of a primate is going to be more like a human, but the point is we don’t really need primates to suggest what may work in humans they are surely there to try say what is may not safe. As Scotty from Startrek says “Captain we do nee have the power” and monkey experiments are generally too small to tell us enough.

There are also failures in marmosets too and there are agents used in marmosets that made humans worse, so it is not perfect. However, the pressing question to my mind is not about immunologicals, as they are not the main unmet need, progressive disease is. What are we learning from our furry friends that human research is not suggesting about progression?

It is easy to make a story up when you know the reallity. The key is to predict the reality before the answer is known.

Also whilst on the subject of 4Rs there should also be Fifth R of animal research should be Reproduction. This does not reduce numbers but it is essential for the translational process. Time and time agian we see stuff that never reproduces and this is difficult with non-human primate work.

This article is published in Primate Biology and is preaching to the converted, but does that quell the nutter with the carbomb? I used to work with someone who worked on malaria and cancer and EBV in Marmos and every day they had to check under the car for bombs…. Working with non-human primates is an emotive subject.

Have a read interested. I’m all for the 4Rs

What do you think? The author sometimes reads the blog, Have your say.

About the author

MouseDoctor

4 comments

  • Mice Doctors,

    We have lots of anti-inflammatory drugs, lots of remyelination therapies are in trial and there are trials of neuroprotectants. There are also trials of potential therapies that promote repair. Humans with MS are happy to be guinea pigs for promising therapies and technology can now be used to identify promising therapies and track their impact on humans.

    The age of the mouse model of MS is dead. Mickey and his friends do not need to be injected with battery acid to see if their neurological function is affected.

    The four Rs are Rubbish, Rank, Risible and Redundancy (for you and MD2). EAE has held back real breakthroughs in MS by focusing on the low hanging fruit (inflammation). It did not address smouldering MS or the viral cause (EBV). Keeping EAE alive is desperation.

    MD1 and 2 have had a good innings. MD1 can retire to Barnsley to listen to his Kiss albums, drink real ale and join the local brass band. MD2 can head of to Ggffdwg (or some other village in Wales) to listen to his Max Boyce CDs and count sheep. Mice around the world can celebrate knowing that their offspring won’t be slaughtered in order for researchers to be kept off the dole. Please don’t list out the great things which EAE and mice killing has delivered – I don’t believe it.

    • HaHa from the tone it must be the “The Chameleon from Siddcup” our sparring partner. Yesterday Uranus, Bazil today and Faulty as usual:-)…

      1. Humans with MS are happy to be guinea pigs……maybe but when it goes tits-up, humans are also the people who are happy to contact lawyers to litigate.

      2. How do you decide what neuroprotective, remyelinating agent to use in humans…Shoot in the dark….that is what gave us thirty years of failed immunosuppressive studies and threw away countless agents that would no doubt be of some value. Likewise, you can argue if the data from Cambridge is correct, you are throwing your remyelinating agents away too.

      3. In some countires the age of the mouse is alive and kicking….shame its not the UK

      4. “Mickey and his friends do not need to be injected with battery acid to see if their neurological function” is affected……so that is a good example of how you got minocycline in humans. It has a small impact on MS following oral injection, in mice it had major impact when injected into the abdomen and was used to justify the human trials….Not surprising it works in EAE as the acidity of minocylcine is about ph 1-2 (neutral is Ph 7, vinegar is ph4. So it was like injecting hydrochloric (battery) acid, burning the insides and stressing the animals to not get EAE. Eating it, it goes into the stomach which is acid.

      5. Kiss …..really, I mean really…now you are insulting me……Actually I did go to Stafford Bingley Hall in about 1980 to see the first UK full stage show…Once was enough. Great show, shame about the music.:-(. Plus never been to Barnsley, although I am sure it very nice.

      6. In chameleon it seems R is for “ranting” and “rudeness”.

      • Can we still be friends? Take my rants with a pinch of salt.

        “Likewise, you can argue if the data from Cambridge is correct, you are throwing your remyelinating agents away too.” What you mean by this?

        Enjoy the first day of meteorological spring. A bunch of doffs for Mrs Mouse wouldn’t go a miss!

        • Bexley is near Siddcup?

          The data from Cambridge indicates that metformin is a switch factor to make old macrophages, young. The importance of this is that young macrophages clear debris and allow repair to occur. Old macrophages don’t do this and repair fails. Most animal studies use young mice and so they repair…therefore trials are done and they dont work that well because they are done in old humans. Therefore as, most current therapies are monotherapies it suggests that they won’t work or won’t work well…making the likelihood of the Bexarotene trial to fail or not do well. In old animals these therapies are not that great a shown by the Cambridge group. Using their logic you need metformin + bexarotene to work, but a failure is a black mark..trial fails and drug is dead as it is one strike and you are out. I suspect we won’t hear from Bexarotene again after the trial reports…but happy to be proved wrong.

          Therefore fear the worse with regard to that study.

          P.S. Yesterday two bunches of tulips (Daffs are in the Garden) and some White Roses as ever..none of the Red Rose stuff.

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