Brothers and Cousins

Statistics of the animal research done in Britain during 2016 have now been published. They show a decrease of about 5% or 206,000 in the annual total of ‘procedures’ (down, but not very far down, to 3.94 million). The Home Office press release announcing the statistics was headed with that notable news – notable not so much because the achievement is very great (after all, the 2015 figure had been the highest number of ‘procedures’ ever recorded), but because it represents only the second time in about fifteen years that the numbers have not gone up. And the total in 2016 is still larger than it was in 1986, when the present Animals (Scientific Procedures) Act was introduced with the aim and expectation (for a time actually realised) of pushing the numbers steadily down.

Now is a good moment to recall that aim, because the European Union’s Directive 2010/63, which has been co-ordinating the laws on animal research in all 28 member states, is about to be revised. Although the U.K. will probably not belong to the Union by the time any revisions come into effect, its own practice will certainly be influenced by them. In fact, because science is an internationally collaborative business, published in international journals, the rules and standards established in the Union are certain to have some influence in all countries where animals are used in research.

Article 58 of the Directive requires the European Commission (the E.U.’s executive) to “review” its contents no later than 10 November 2017. In doing so, the Commission must take into account “advancements in the development of alternative methods not entailing the use of animals, in particular of non-human primates”. Specifying OU primateprimates in this way, the Directive’s authors no doubt had in mind a ‘declaration’ which the European Parliament had adopted back in 2007, urging the Commission “to establish a timetable for replacing the use of all primates in scientific experiments with alternatives”. Anyway, by way of limbering up for the review, the Commission asked one of its advisory committees, the Science Committee on Health, Environmental and Emerging Risks (SCHEER), to set up a Working Group to study and report on “the need for non-human primates in biomedical research, production and testing of products and devices”. Under this same title, with its ready-made implication that such a need really does exist, SCHEER accordingly published its conclusions (formally an ‘Opinion’) a few weeks ago. These conclusions, on such an especially controversial aspect of animal research, may be taken as indicative of what animals have to hope for from the coming review.

We’re deep inside the E.U. machine here: a working group reporting to a standing committee commissioned to advise the executive on the revision of a parliamentary directive setting the parameters for (and here we at last come out into the open) actual laws in the 28 member states. And the advice itself frequently does have a machine-generated feel to it, of truth made out of words rather than real things, and all the more conveniently incontrovertible for that. “It is indeed important to consider the limitations of the NHP when choosing which species to use in a drug-safety test: the use of an appropriate species or combination of species/models is essential to obtaining the most reliable and translatable information.”[p.63] Has anything been said here that isn’t necessarily true? Is anyone arguing, for instance, that an inappropriate species would produce more reliable information? This key word ‘appropriate’, with its built-in wisdom, is much used in the authors’ proposals: “appropriate training”“appropriate standards”, and of course “appropriate use of NHPs”.

Another such passe-partout word is ‘robust’: the authors variously recommend “robust scrutiny”, “robust peer review procedures”, “robust study design”, and so on. One wonders why scientists hadn’t thought of the great merits of robustness before. Anyway, everything will surely be better in this robust and appropriate new world.

But not very much better. Distinctly this is a technical account of the subject: how to make things as they are work properly (the machine again). There are some good suggestions to that end, certainly. For instance the authors recognize, as one of the barriers to progress in animal-free research, the weight of professional habit and institutionalized practice; they advise that training courses for animal researchers should include “non-animal technologies”, so that transition is easier and more acceptable [p.64]. Also I must concede that, for all the tautologies and self-evident truths, there’s a 12-page bibliography to back up what the committee says. But the rationale for all this attention, why it matters whether there’s a ‘need’ for NHPs in science or not – in short, the morality of it – is almost untouched. Two pages (out of 66 in the main text) make a hurried tour of the topic, though it is of course alluded to from time to time elsewhere. But then all members of the Working Group were scientists. Accordingly, the page headed ‘Minority Opinion’, which looks rather promising with the whole of page 23 to itself in the table of contents, proves, when one reaches it, to be blank, apart from the word “None”.

The committee recognises, as a political fact, that “polls of the European public repeatedly show low levels of acceptance of the use of NHPs in research” [p.24]. Approval for the use of NHPs in the U.K., for instance, was about 17% when last canvassed (see, in this blog, ‘Animal Pains and Human Attitudes: the new Ipsos Mori survey’, 26 September 2016). However, there is at least “greater acceptance of animal research where animal use and suffering are minimised in line with the 3Rs principle” [i.e. Replacement, Reduction, Refinement: p.25]. This is no doubt true, although it’s a somewhat disingenuous way of putting things: where acceptance has not been ‘great’ in the first place, it shouldn’t really be said to become “greater”. And I suspect that approval would actually have been even lower if the respondents had known, as this SCHEER report records, that nearly three quarters of ‘procedures’ conducted on NHPs in the E.U. are for “regulatory use and routine production” [p.15].

What these quotations illustrate is how the “3Rs principle” is seen by scientists as a sort of ethical machine labouring away to turn expediency into good conduct, rather as the “invisible hand” of the free market was supposed by Adam Smith to convert self-interested actions into social good. In this capacity, it’s expected to satisfy or at least placate opponents of animal research. That it does not do so, and that the whole managerial attitude to “ethical considerations” understates their seriousness, is evident in the consultation document which is published alongside the SCHEER report (but which came before it in time, of course).

I must say that this 234-page consultation document is conspicuous proof at least of the diligence and fair-mindedness of the committee, which here records in the left-hand column, and replies to in the right, hundreds of queries and comments. It wasn’t in the committee’s remit to deal with ethics except as a general premise, but at least the moral passion is now allowed printed expression in raw, ungentrified form: “cruel”, “inhuman”, “abhorrent”, “nearest cousins”, “brothers”, “freedom”. True, the committee makes little attempt to address this sort of complaint (there being plenty of other more strictly scientific representations). “Stop this insane abuse!!” says one contribution (well yes, two exclamation marks, but then, as the great Aneurin Bevan used to say, “In public life, those who would change things must shout to be heard”). To such, the committee can only reply with a slightly pompous set formula: “This is a personal opinion. The comment does not provide any suggestions for improvements of the scientific basis of the SCHEER preliminary Opinion and/or any scientific evidence.” Still, such remonstrations, earnest and unscientific, are at least recorded here. Thank you to those who did speak up with this authentic human indignation.

When it issued its previous ‘opinion’ on animal research, just prior to the making of the 2010 Directive, this same science committee was called SCHER. The second ‘E’, recently added, stands for ‘emerging’, and refers to novel or reappearing infectious diseases. It’s an ominous alteration for NHPs, because this is one of the areas of research in which the committee, so far from sketching out a diminution in their use, foresees an increase. NHPs, so SCHEER claims, “provide essential models for understanding and combatting (re)emerging infectious pathogens.” Thus, for recent research into whooping cough, “a new baboon model was developed” [p.47]. That rather euphemistic phrase actually means that research was conducted, for the first time, on juvenile baboons (from two to six months old): the opposite of the 3Rs, then. SCHEER justifies such retrogressions by speaking of “realistic dangers” [p.47]. Danger, which might properly be seen as a test and validation of our ethics, is evidently expected to frighten them away. And after all, even the great apes (gorillas, chimpanzees, orangutans, bonobos), whom the E.U. Directive in principle protects absolutely from scientific exploitation, may be used “in relation to an unexpected outbreak of a life-threatening or debilitating clinical condition in human beings” [Article 55.2].

So, shall a timetable be drawn up for ending the use of NHPs in European research, as the E.U. Parliament was dreaming ten years ago? SCHEER’s 12,000 word answer resembles the one being given in a famous Saul Steinberg cartoon from 1961. A well-fed manager of some sort, comfortably leaning back at his desk, addresses a petitioner with a mass of words, illegible but obviously full of patronizing civilities and bureaucratic reassurances. The words coalesce, above the petitioner’s head, into a giant ‘NO’.

 

Notes and references:

The 2016 statistics can be viewed here:

https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/627284/annual-statistics-scientific-procedures-living-animals-2016.pdf

These new statistics record about 3,600 procedures using NHPs. The SCHEER report uses the all-E.U. figure of 8898, which was the total in 2014. Note that the Home Office numbers don’t include Northern Ireland: i.e. they cover animal research in Great Britain rather than the U.K.

The 2007 Declaration of the European Parliament on primates in scientific experiments is published online at http://ec.europa.eu/environment/chemicals/lab_animals/pdf/fische_suite.pdf

The SCHEER report is at https://ec.europa.eu/health/sites/health/files/scientific_committees/scheer/docs/scheer_o_004.pdf

The results of the public consultation are published at https://ec.europa.eu/health/sites/health/files/scientific_committees/scheer/docs/followup_cons_primates_en.pdf

Aneurin Bevan is quoted in Michael Foot, Loyalists and Loners, Collins, 1987, p.36. Among other political achievements, Bevan was the Minister of Health from 1945 to 1951, therefore the man responsible for establishing the U.K.’s National Health Service.

The photograph is of a rhesus macaque monkey in Oxford University’s Biomedical Sciences Building, and is used here by permission of the University’s Public Affairs Office.

 

 

 

 

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Earth-born Companions

When Oxford University was first required to estimate its annual usage of animals in research and teaching – this was in 1875 – the tally was about 30 frogs and smaller unspecified numbers of fish, dogs, rabbits, insects. No mice were mentioned. In 2016, the University used 226 frogs but more than 200,000 mice.

I don’t know when mice overtook frogs as the leading victims of animal research. Now, in the U.K. at least and probably everywhere, they account for well over 60% of all experiments and a much higher proportion of the GM breeding programmes. A huge industry and international trade has come into being, devoted to the creation and exchange of genetically altered mice. Two of its primary sites are the Medical Research Council’s establishment at Harwell in the U.K., and the Jackson Laboratory in the U.S.A.

As well as its own research, MRC Harwell supplies mice to other laboratories round the world, either live or as frozen sperm or embryos (see web-site for prices). In more detail, its services include (just to give an idea of the sort of thing) “Production of blastocysts and pseudo-pregnant females [a blastocyst is a cluster of cells in the very early stage of embryo development]… Uterine transfer of injected blastocysts to pseudo-pregnant foster-mothers [the foster-mother is the female into whom the foetuses extracted from the first mother are inserted. Neither mother survives the process] … Oviduct transfer of injected embryos to pseudo-pregnant foster mothers … Harvest and preparation of F0 transgenic embryos …”, and so on. The gruesome gynaecology of all this, I won’t attempt to describe: a sample guide to one of the procedures, with illustrations, is referenced below. MRC Harwell bred over 213,000 mice in 2016, but this number would not include the mice archived or traded in unborn condition, or the wastage in mothers and unviable offspring.

The Jackson Laboratory, based in Bar Harbor, Maine, does things on an even larger scale. Like Harwell, it does its own research work. In addition, more than 3 million ‘Jax’ mice, from a selection of over 7000 genetically defined varieties, are sent out to other institutions.

A brief digression now on the likely experiences of these Jax mice at their destinations. Since the Jackson Laboratory receives state funding, it has to conform to national guidance as to the care of its own animals. The same does not apply to the privately funded or commercial laboratories in the U.S.A., well over 800 of them, to which Jax mice may be sent (still less, of course, to laboratories in other countries). These establishments are regulated only by the Animal Welfare Act, whose definition of ‘animal’ does not include mice (or rats or birds). This glaring anomaly is genially described as a “quirk” by the National Academy of Sciences, but actually it was a very deliberate omission, and one which was later emphatically fixed into law by the so-called ‘Helms Amendment’ of 2002. Senator Jesse Helms pointed out to his fellow-senators during the debate that a mouse was much better off in a laboratory than being eaten by a python in the wild, and evidently they accepted this as a useful bench-mark for mouse-welfare. Certainly the research industry did; indeed it had sponsored Helms’s intervention. This is just one instance of a consistent historical record. In spite of all the claims in their publicity to be making animal welfare their special concern, research institutions and their agencies have always resisted statutory controls. If they’d had their way, laboratory animals would even now be relying for their welfare wholly on the haphazard kindness of their vivisectors.

Back to the Jackson Laboratory, and the man who founded it in the 1920s, Clarence Little. In later years he declared that his institution “has done for the mouse in science what Disney has done for it in amusement.” In fact he hoped that Walt Disney’s version of the mouse might be employed to publicize medical research of the Jackson sort – rather Mickey_-_House_of_Mouseas comic pigs advertise bacon. And certainly Micky Mouse would very expressively have represented what has happened to the mouse since it got caught up in medical research. The Disney studio ruthlessly stylized Mickey Mouse, both to make repeat drawing easier, and to make him highly visible and recognisable (the strange white gloves and bulbous shoes, for instance): this is the mouse subdued to human idea and human use. So exactly is the Jax mouse, standardized as it is, and infinitely repeatable in its 7000 varieties. And just as Mickey Mouse became the iconic cartoon animal, so the Jax mouse established its species as the essential laboratory animal.

Both of these institutions, MRC Harwell and the Jackson Laboratory, belong to the International Mouse Phenotyping Consortium, an international collaboration whose aim is “to catalogue the functions of the roughly 20,000 genes that mice and humans share”. Last year the IMPC “released an analysis of the phenotypes of the first 1,751 new lines of unique “knockout mice” (mice in whom one gene has been deleted), with much more to come in the months ahead.” The National Institutes of Health, reporting this achievement, was especially interested in the genes which seem to have proven crucial to live birth in the mice. The heading to its announcement optimistically generalized the findings thus: ‘Of Mice and Men: Study Pinpoints Genes Essential for Life’.

Can mouse genetics really translate so usefully into knowledge about humans? In one of this month’s issues of the journal Science, there’s a report of research into “the nature of genetic predisposition to pain”, which is said to promise “new treatments of conditions affecting tens of millions of people worldwide”. Naturally the research used mice, designed and generated for the study (though using at least some Jax mice as starters). But other research in that same area of biology – incidentally an especially malignant one for laboratory animals, with its array of ingenious pain-supplying devices – has questioned the value of mice as models for humans, even where the same genes seem to be involved. An article about it in Yale Scientific said that “there was almost no correlation between human and murine reactions to any of the experimental conditions. For example, if humans were likely to activate a certain gene following trauma, mice were almost equally as likely to activate it or suppress it.” Acknowledging that “mice models are a cornerstone of biomedical research”, the Yale article suggests that this reported research “raises the question of how similar humans and mice really are. With such different genetic responses, perhaps the biology of mice is not an accurate representation of that of humans.”

Bad news in Bar Harbor and Harwell, then, but wait! A professor interviewed for the same article points out that the study only used the one mouse variety, C57BL/6, commonly called ‘Black 6’: “until other mouse strains are studied, the authors need to be cautious in their interpretations that use of mice is irrelevant to human responses.” Get out those order books, then, and let business resume.

The Yale article was headed ‘Of Mice and Men: The Mouse as a Model for Human Disease’. The upbeat NIH piece, you’ll recall, was headed ‘Of Mice and Men: Study Pinpoints Genes … etc.’ But it’s not much of a coincidence: that phrase, with its neat alliteration and reassuring link with a vaguely remembered literary classic, has also caught the imagination of many other science writers on this subject, or has at least appealed to them as likely to catch the imagination of their readers. After all, in a poll recently organised by an educational publisher, John Steinbeck’s fine novel Of Mice and Men has been ranked fourth in the “top 100 titles for the American literature classroom … chosen by American literature teachers across the country.” (But then The Great Gatsby came top!) And perhaps, although mice are only incidentally present in it, this story of two displaced and status-less labourers in forlorn search of a home is no bad fable for the modern animal.

But in fact the novel’s title is not the origin of the phrase. Steinbeck himself was borrowing it in his turn from the poem ‘To a mouse’ by Robert Burns, first published in 1786. And this certainly is an encounter of mouse and man to set beside and re-appraise the modern Disneyfied mass-mouse and the people who convert it into science.

The poem’s sub-title is ‘on turning her up in her nest with the plough’, for Burns was a farmer when he wrote the poem; he knew the situation. He was, besides, as the poem 220px-PG_1063Burns_Naysmithmakes poignantly clear, unhappy in his own ways, remorseful about the past and fearful as to the future. Accordingly there’s absolutely nothing suggestive of species-superiority in the way he speaks to the mouse, as he contemplates the ruin of her nest. He sees in detail and feels the catastrophe which the mouse has suffered, and he understands suffering as a universal burden, indifferent to species and size. Hence that phrase:

The best-laid schemes o’ mice an’ men
Gang aft agley,       

An’ lea’e us nought but grief an’ pain,
For promised joy!

The poem recognizes the encounter as an aspect of the power-relation whose characteristic modern manifestation we’ve been viewing in earlier paragraphs:

I’m truly sorry man’s dominion,
Has broken nature’s social union,
An’ justifies that ill opinion,
Which makes thee startle
At me, thy poor, earth-born companion
An’ fellow-mortal!

So the spoiling of the mouse’s nest is an incident in a much larger wreckage of that commonalty which Burns beautifully dignifies as “nature’s social union”. But in his poem he reasserts the union, at least between these two now present, pledging a true existential comradeship in those phrases “thy poor, earth-born companion / An’ fellow-mortal”.

And of course exactly this is “how similar humans and mice really are” (the phrase from the Yale article). They really are earth-born fellow-mortals, each in their own sphere liable to “grief an’ pain”. Unfortunately we’ve repudiated that fellowship for which Burns’s poem is a permanent model and recommendation, and have chosen instead to privilege human grief and pain, and to make of the mouse a multitudinous enslaved resource in our ruthless struggles to escape them.

 

 

Notes and references:

The numbers from 1875 were published by the Cardwell Commission in Report of the Royal Commission on the Practice of Subjecting Live Animals to Experiments for Scientific Purposes, HMSO, 1876, Appendix III.

Information and quotation about the work at Harwell appears on its web-site at https://www.har.mrc.ac.uk/

A clear, though highly technical, illustrated account of how a standard procedure works can be found in the article ‘Pronuclear Injection for the Production of Transgenic Mice’ at http://www.nature.com/nprot/journal/v2/n5/full/nprot.2007.145.html

About the welfare provisions in the U.S.A.: the “quirk” reference is from https://www.nap.edu/read/10733/chapter/11; the account of Helms’s amendment is from a contemporary news report in U.S.A. Today, readable at http://usatoday30.usatoday.com/news/nation/2002/05/07/animal-welfare.htm

What Clarence Little said about Mickey Mouse is quoted by Karen Rayder in Making Mice: Standardizing Animals for American Biomedical Research, 1900-1955, Princeton University Press, 2004, p.5

The announcement about the work of the IMPC is on a blog run by the National Institutes of Health at https://directorsblog.nih.gov/2016/09/20/of-mice-and-men-study-pinpoints-genes-essential-for-life/

The article in Science is from 16 June 2017, pp.1124-5 and 1168-71, quotations from pp.1124-5. The Yale Scientific article is from 5 April 2013, and can be read at http://www.yalescientific.org/2013/04/of-mice-and-men-the-mouse-as-a-model-for-human-disease/

The poll of American novels was organised by Perfection Learning, and is reported on their web-site at https://www.perfectionlearning.com/top-100-american-literature-titles.

The picture of Mickey Mouse is from the TV series Disney’s House of Mouse (2001-3). The portrait of Robert Burns in 1787 is by Alexander Naysmith, and is held in the collection of the Scottish National Portrait Gallery.

In the U.K., Animal Aid has recently started a campaign to raise awareness of the mouse, its qualities in nature, and its sufferings in laboratories: see https://www.animalaid.org.uk/animal-aid-new-campaign-mice-matter/