Animal research for ME

[EndME]

You said "clearly ME Research UK and Action for ME does fund research that involves the use of animals". That directly contradicts their policy.
If you are saying that their policies are not as they say they are, then that is a curious state of affairs.

I'm not able to understand how the repeated example of lab reagents generated in animals is not self-explanatory of the situation.

This overview puts the number of lab mice at between 10 million and 100 million. A couple of hundred mice would be 1/50,000th to 1/500,000th of that figure.

That overview has no relevance to what I said. The problem is not the lack of the existence of lab mice, no one has ever suggested that. Such an experiment would not be "garguantuan" due to there being a lack of lab mice or because some people have ethical considerations that others don't have or because there's a rarity of experiments with mice. Different studies require different set-ups one cannot simply equate everything.

A quick google has thrown this up: https://www.ox.ac.uk/news-and-events/animal-research/research-case-studies
I am sure there are more examples if you care to search for them.

None of those links tell me anything how this is research that has lead to hypotheses that has led to breakthroughs that would be applicable in the field of ME/CFS or LC, rather than being research that yields results, that yields further grants. Perhaps I'll be more precise: Do you have knowledge of such studies when it comes to IgG transfer and establishing a till then unknown pathology or where viral persistence was uncovered due to a hypothesis that was generated in mice or something similar? No one is saying that mice have have no use in medical research, they obviously have. The question is the relevance to ME/CFS. Is there a historical precedent that would have relevance to ME/CFS?

 

[PeterW]

I'm not able to understand how the repeated example of lab reagents generated in animals is not self-explanatory of the situation.

There is a very clear, highly restrictive policy in two cases against use of animals in testing. Even if reagents conflict with that policy (which calls into question their capability as research leaders), it is still highly restrictive in a field which does not need any additional hurdles.

That overview has no relevance to what I said. The problem is not the lack of the existence of lab mice, no one has ever suggested that. Such an experiment would not be "garguantuan" due to there being a lack of lab mice or because some people have ethical considerations that others don't have or because there's a rarity of experiments with mice. Different studies require different set-ups one cannot simply equate everything.

So why would a study involving 200 mice be so guargantuan then? 10 - 100 million is the number of mice used annually.

None of those links tell me anything how this is research that has lead to hypotheses that has led to breakthroughs that would be applicable in the field of ME/CFS or LC, rather than being research that yields results, that yields further grants. Perhaps I'll be more precise: Do you have knowledge of such studies when it comes to IgG transfer and establishing a till then unknown pathology or where viral persistence was uncovered due to a hypothesis that was generated in mice or something similar? No one is saying that mice have have no use in medical research, they obviously have. The question is the relevance to ME/CFS. Is there a historical precedent that would have relevance to ME/CFS?

To ask whether mouse research has been useful in past ME/CFS research in order to justify its future use is not a reasonable hurdle to set.
Frankly there has been so little research up to now that past ME/CFS research cannot be used as a benchmark of what good looks like.

The dismissive attitude to some of the trials cited previously in this thread is unjustified. The reality is that a number of leading academics have found these studies useful.

 

[EndME]

There is a very clear, highly restrictive policy in two cases against use of animals in testing. Even if reagents conflict with that policy (which calls into question their capability as research leaders), it is still highly restrictive in a field which does not need any additional hurdles.

I'm not so sure. To me it shows the discussion is more nuanced and that one should be informed about these nuances before one makes conclusions or even accusations. Here is one of plenty examples of a project that was partially funded by ME Research UK in which mice were involved https://www.sciencedirect.com/science/article/pii/S2666354620300120, here's another https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024602 and here's another . I don't think this has to be explicitly mentioned by anyone because anybody involved in research or carefully reading the studies is probably extremely well aware of all these things.

So why would a study involving 200 mice be so guargantuan then? 10 - 100 million is the number of mice used annually.

Because this would be a far more extensive and longer setup than in most other experiments in which mice are used annually. I'm not sure 200 mice would be sufficient. Probably more than 1000 (i.e. several hundred), but that is an extremely crude estimate if we accept the assumptions initially made, maybe it would be far less or even more, who knows. An experiment where you give mice some cosmetics and see whether there is a short term reaction is a much easier set up than the one proposed, where you have to infect mice and inject a control solution in your controls, run behavioural tests on all of them for an extened period of time, longer than most mouse studies even take, maintain them under specific pathogen-free conditions in well ventilated cages with equally distributed and continuous access to food and water in a temperature and humidity controlled room with specified day and night cycles making sure control mice are kept under the exact same conditions, in the same cage, whilst making sure there is no infectious spread between controls and infected mice as you co-house them 1 to 1, making sure they are acclimatised to their surroundings when performing each test, making sure all experiments are always performed at the same time and following the same pattern over several months if not years etc. There's an extreme amount of potential noise in mouse studies which means you have to have to be extremely careful and have multiple levels of controls making the task extremely laborious. Iwasaki’s study took larger efforts, so did the one by den Dunnen, why is this the case if they just used a handful of mice and a few patient samples they anyways already had access to? Why did Iwasaki only perform her mouse experiments with 4 patients and 4 controls if this is all so quickly done? Running all the necessary tests on one mice takes alone takes multiple days of work, just image having to do that repetitively for a long-term mouse study (which neither den Dunnen, nor Iwasaki nor the study you had cited did) and that for hundreds of mice.

If you're studying something "rare" (for instance ME/CFS or long-lasting LC phenotypes) that happens following a common event (for instance Covid-infection or EBV) you will always need massive sample sizes if you don't start your study with those that are ill (thousands is a low example Ascherio needed more than 10 million in his EBV-MS study and even at that sample size it yields completely unreliable rates, in the above setup you'd probably be able to get away with a much smaller sample size if you can indeed control the number of genuinely uninfected controls).

To ask whether mouse research has been useful in past ME/CFS research in order to justify its future use is not a reasonable hurdle to set.
Frankly there has been so little research up to now that past ME/CFS research cannot be used as a benchmark of what good looks like.

At no time point did I ask about past mouse research in ME/CFS, which obviously would never be a good benchmark for any research in ME/CFS. I’m asking whether you had any examples of past mouse research leading to breakthroughs that would be applicable to ME/CFS, rather than general examples of mouse research in medicine, which is something you have not been able to supply. One would have to ask someone that is actually knowledgable on the subject, but it seems Myasthenia Gravis could be such an example.

 

[Jonathan Edwards]

OK, but surely the point of these studies is not to give definitive answers... Their objective in these studies is to generate hypotheses. These are ideas which can go on to be investigated further in increasingly appropriate (but perhaps less accessible) systems such as cadavres, organ bank samples or biopsies. But at least they can go to those resources with a few ideas about where to look.

That appears to be non sequitur to my quoted comment, Peter, which was that most of these studies turn out to be artefact. They are not for generating hypotheses, they are for testing them. The idea that post-infective disease is due to autoantibody is sixty years old and has failed to show any evidence of being valid. Why flog dead horses?

Surely the theme of most research endeavors is that it's an endless stream of failure with occasional moments of success.

It may be, but why keep repeating a failure over half a century.

This appears to support the value of animal models, surely?

In relation to lupus and myasthenia, no. The experiments added nothing useful to what we knew and told us nothing about mechanisms of human disease which are about disordered regulation. Adoptive transfer cannot model disordered regulation. The ability of antibodies to cause pathology was known from the newborn cases.

In a world of few hypotheses, we should be wary of blocking off early stage ideas. I (used to) teach entrpreneurship, and that exact statement can be said about many of today's largest and most successful companies.

Please read what I write, Peter. My point was that these are not early stage hypotheses. They are hypotheses that have failed to show any validity over decades. It is just that the great majority of immunologists follow memes of dogma that never died. To be honest I have no faith that the people doing these studies have any real grasp of immunology. They make so many basic mistakes.

 

[PeterW]

To be honest I have no faith that the people doing these studies have any real grasp of immunology. They make so many basic mistakes.

One of the authors we are talking about is Akiko Iwasaki, Sterling Professor of Immunobiology and Molecular, Cellular and Developmental Biology, elected to the US National Academy of Sciences, and is currently elected president of the American Association of Immunologists. She has had 2 papers published in Nature, and one in Science - all 3 on immunology.

While past achievement does not mean that all future achievement will be to the same standard, is it really reasonable to doubt that Akiko Iwasaki has a real grasp of immunology?


Coming back to the original point of this thread, I understand that issues of ethics and efficacy may be controversial, and that people have different views on their use, but we should at least recognise that there are highly competent people who see some value in these studies.

 

[PeterW]

Another study relevant to LongCovid which used mice.

While the details are over my head, it is published in Nature - generally a strong indicator of quality:

https://www.nature.com/articles/s41586-024-07873-4

 

[forestglip]

Up to now, I've mostly tried to avoid reading or posting research that involves animals, because I find the practice often is abhorrent, and I don't want to support more of it happening.

Making mice fear for their life in a swimming test, injecting animals with chemicals that we would never inject in a human first because of the risk of unknown consequences, entirely removing genes to see what horrific disfigurements or mental disorders an animal is born with..many of these animals must be going through far more suffering than that of the suffering humans who are using the animals to find a treatment.

I can't imagine myself directly giving money to such research or advocating for more of it (without a lot of assurance that much more concern is paid to animal welfare than there is now).

But reading, posting, and discussing the research is more of a grey area. In a sense, the research has already been done. If we ignore it, we may be setting back the discovery of treatments when the necessary knowledge may already exist. On the other hand, reading, sharing, and discussing such research is implicitly supporting that this research is fine and there should be more of it. It increases demand through view counts of journal articles and encouraging others to also be interested in the articles.

If the signs we're seeing that ME/CFS includes brain pathology are correct, then I imagine a large amount of the path forward will include data based on animal research. While animal models of ME/CFS may or may not ever be useful, I think there's little doubt that animal research has a lot of history and potential of greatly accelerating understanding of fundamental biology, like what specific genes in a neuron do.

I just feel deeply uncomfortable reading these papers. Uncomfortable reading the parts of papers outlining the myriad negative effects of knocking out various genes, as if a mouse is just lab equipment and not a living being that all this pain is happening to. Uncomfortable with the feeling that even if it can lead to a cure, the path there may not be worth it.