Lower organisms can be particularly useful as high discrimination models in fundamental research, but cannot offer the high fidelity required when specific questions are asked about humans in health and disease, and about their responses to drugs and other chemicals.
In The Principles of Humane Experimental Technique,1 Russell and Burch discussed comparative substitution as a form of replacement by organisms which were not of humanitarian concern. This included non-sentient material, such as higher plants, micro-organisms, and the more degenerate metazoan endoparasites, “in which nervous and sensory systems are almost atrophied”.
They accepted that “a more difficult question arises when we consider the free-living metazoan invertebrates”, but they “arbitrarily excluded them from consideration as objects of humanitarian concern”. They commented that “to shed obsessional tears over the fate of these organisms would bring the whole concept of humanity into contempt by Samuel Butler’s famous reductio ad absurdum” (disproof of a proposition by showing that it leads to absurd or untenable conclusions), and his satirical piece about the fictional country where a professor of botany contended that “vegetables are only animals under another name”, and that, if it is “sinful to kill and eat animals”, it is no less sinful to eat “vegetables or their seeds”!
Russell and Burch made frequent references to studies with fish, amphibians and birds, particularly those concerned with animal behaviour, including flight and fight responses. However, they also drew particular attention to “the trivial use of lower vertebrates, which make up less than 5% of the total” number of animals used. They saw this as “yet another expression of the high-fidelity fallacy”, and argued that “all the arguments we adduced for the use of discriminative models apply with no less force to the choice of [lower] vertebrate species than to that of absolute replacement” (i.e. the use of nonsentient organisms, tissue culture and non-living physical and chemical systems). An understanding of the application of the Three Rs principles to higher organisms (i.e. mammals) and lower organisms (i.e. non-mammals) is heavily dependent on an appreciation of Russell and Burch’s distinction between fidelity and discrimination.2
Fidelity models have a high general similarity to what is being modelled (e.g. old world monkeys and humans), whereas discrimination models involve a high specific similarity to what is being modelled, while lacking many other similarities. The problem, which they call the high-fidelity fallacy, arises when a fidelity model is used in attempts to predict precisely what will happen in what is being modelled, such as when rats, mice, dogs or macaques are used to predict whether candidate drugs will work in humans, without unacceptable side-effects. The use of discrimination models is less demanding and less likely to be fallacious, since the questions asked are better targeted (e.g. will this treatment damage cell membranes or DNA, or inhibit DNA, RNA or protein synthesis, or mitochondrial functions). Another way of expressing the distinction is to draw the contrast between fundamental and applied research.
It cannot be denied that many types of organism undoubtedly have value as discrimination models at the fundamental research level, including plants such as onion (Allium cepa) and garlic (Allium sativum), bacteria such as Escherichia coli, fungi such as yeasts (Saccharomyces cerevisiae), slime moulds such as Dictyostelium discoideum, coelenterates such as hydra (Hydra magnipapillata), nematode roundworms such as Caenorhabditis elegans, insects such as Drosophila melanogaster, and lower vertebrates, including fish such as the zebrafish (Danio rerio) and amphibians such as the South African clawed toad (Xenopus laevis). These organisms are being extensively used in fundamental research on cell and molecular biology, cell death, ageing, developmental biology, immunobiology and neurobiology. However, they cannot tell us precisely what happens in humans, in health or disease, or after exposure to drugs and other chemicals. Hence, although some pharmacotoxicological test systems involving lower organisms and aimed at predicting effects in humans have been proposed, they are unlikely to provide solutions to the problems currently facing the pharmaceutical industry (lack of efficacy or unacceptable side-effects, discovered late in drug development), because the differences between these organisms and humans are too great for tackling other than certain highly specific questions which may apply to many different kinds of organisms. That is why so much effort is currently being invested in the search for relevant and reliable, more-directly human-oriented systems, which will combine high fidelity and high discrimination.
Russell and Burch’s Principles was, of course, primarily focused on “the intimate relationship between humanity and efficiency in [animal] experimentation”, and they were rightly concerned about how their concept of inhumanity and its diminution or removal applied to lower animals, as well as to mammals. By chance, as I was thinking about this, I received a copy of a new book by Robert Hubrecht, a zoologist who is CEO and Scientific Director of the Universities Federation for Animal Welfare, the organisation which employed Russell and Burch to do the research which led to The Principles. Entitled The Welfare of Animals Used in Research,3 the book provides a highly-detailed, wide-ranging, thoughtful, thought-provoking and up-to-date analysis of the kinds of issues raised by the principles and application of the Three Rs, based on his own long experience.
Hubrecht discusses the reasons for using animals in research, legislative and other controls, and the moral imperative — the need to reduce any animal harm to a minimum. In a chapter on species choice and animal welfare, he discusses consciousness/sentience, and the relationship between neurological complexity and the capacity to suffer, with reference to invertebrates and lower vertebrates, as well as mammals. Later on, he argues that, “rather than attempting to develop some scale of suffering so that an animal lower on the scale is always used in preference to one higher up, a much more rigorous approach is to evaluate the impact of the proposed study on the candidate species”. He describes this as an “evolutionary approach, which requires a deep understanding of the needs and adaptations of each species. Here, as in many other parts of the book, Hubrecht’s training as a zoologist shines through, and I am convinced that another zoologist, Bill Russell, would have been very supportive of what he has to say.
As for me, while I haven’t yet had time to read the book in detail, and I doubt whether I will agree with absolutely everything it says, I am content to endorse the remark of Paul Flecknell on the back cover, that: “This book should be read by all those involved in the use of animals in research and by anyone who has interests or concerns as to how this type of research is conducted”.
1 Russell, W.M.S. & Burch, R.L. (1959). The Principles of Humane Experimental Technique, xiv + 238pp. London, UK: Methuen.
2 Balls, M. (2013). The wisdom of Russell and Burch. 3. Fidelity and discrimination. ATLA 41, P12–P13.
3 Hubrecht, R.C. (2014). The Welfare of Animals Used in Research, vii + 271pp. Chichester, West Sussex, UK: Wiley Blackwell.