Tag Archives: russell & burch

Comparative Substitution

Michael Balls

The scientifically-justifiable choice of species is a crucial issue in animal
experimentation, which should not be based on ignorance and habit,
or 
on slavish compliance with political expectations
and regulatory requirements

 

 

The Principles of Humane Experimental Technique1 was published a year after it was written, and Russell and Burch added an Addendum, because they felt that year had “seen much activity in several parts of the field”.

One point they made in the Addendum was that “the comparative substitution of lower for higher animals raises difficult issues”, but, “where great severity is concerned … we must be glad to see lower forms substituted for mammals”. Unfortunately, they said nothing more about the “difficult issues” to which they referred, and I wish I had asked them about it, while I had the chance to do so.

The discussion on comparative substitution in the chapter on Replacement in the main part of the book focuses on the use of non-sentient material (plants, micro-organisms), degenerate metazoan endoparasites and free-living metazoan invertebrates. They regarded such use as a “limited gain”, and considered that “to shed obsessional tears over the fate of these organisms would bring the whole concept of humanity into contempt”. They preferred to concentrate on “the wholly desirable progress and prospects of replacement proper”, i.e. the use of any scientific methods which “replace methods which use conscious living vertebrates”.

Russell and Burch considered that not enough was being done with lower vertebrates, and saw the predominant use of mammals as “yet another expression of the high-fidelity fallacy”.2 Here, Russell’s experiences as a zoology student at Oxford came to the fore, since “our ignorance of the behaviour of common laboratory mammals is offset by a wealth of knowledge about that of numerous lower vertebrate species”. He had worked on mating behaviour in Xenopus laevis, the South African clawed toad, alongside the Nobel-prizewinning work of Tinbergen and his colleagues on the behaviour of birds and fish. In a section on The Choice of Species, Russell and Burch argued that, in terms of humanity, the “subtle matching of procedure to species, and species to objectives, is more significant that it appears at first sight”. They said that “a formal or informal training in zoology has again and again proved its value in the progress of medical research”, and lamented attempts to “correct the mistaken choice of a wrong species by forcing it to conform to the requirements of the investigation”.

They marvelled at “the present large-scale choice of laboratory species”, but regretted that, “out of the almost astronomical number of vertebrate species, only a minute selection are employed … this includes about 20 mammal species, three bird species, about four reptile species, half a dozen or so amphibians, and half a dozen or so fish”. Of the mammalian species, they said, “only about half the species are used in numbers over 1,000 per annum, the overwhelming bulk being made up of the four chief species (mouse, rat, guinea-pig and rabbit), and, of these, more than two-thirds are mice”.

Lack of sufficient understanding of the animals used for experimental purposes is still rife today. For example, the customary feeding ad libitum of caged rats and mice fundamentally alters their endocrinological, neurological and behavioural status. In real life, they spend most of their time searching for food, not eating it, while keeping alert because of the threat of predators. Also, the feminisation of male fish and amphibians by so-called endocrine disruptors, was taken as a warning of threats to human masculinity, whereas it is a normal part of the adaptability of these lower vertebrates. Even worse are attempts to genetically humanise laboratory animals, in order to make them better models for humans, without sufficient understanding of the cascade of complications likely to result from the consequent distortions of the very nature of the animals concerned.

Russell and Burch said rather little about choosing between the higher mammals, except to say that they were pleased to note that the Indian Government had “imposed salutary regulations” on the shipment of monkeys to provide kidney cells for vaccine production, and that the Medical Research Council had “issued recommendations on humane shipment”, which had been “adopted by all the British airlines concerned with livestock transport”. They welcomed “such action being taken on behalf of animals, which, although our near relatives, receive none of the privileges accorded by the Home Office to cats, dogs and the equidae” (the commonest animals to be encountered in Victorian England, when the Cruelty to Animals Act 1876 became law).
Over the years, I have had many discussions with veterinarians about whether there should be a hierarchy of laboratory mammals in the terms of the need to justify their use, with rats and mice near the bottom, and dogs and non-human primates at the top, or whether all the species should be afforded the same standards of consideration and care. I take the former view, and that is the position laid down in the Animals (Scientific Procedures) Act 1986, as amended to comply with Directive 2010/63/EU.

But what about the substitution of one species high in the hierarchy with another species high in the hierarchy. This point arose when somebody occupying a high position in the Three Rs movement, commenting on our study on the use of tests in dogs for predicting human toxicology and drug safety,3 warned us that “dropping the dog on the basis of your existing evidence could result in an increase in the use of nonhuman primates”. That would present advocates of the routine use of a second, ‘high-fidelity’, nonrodent species in toxicity testing with a dilemma and a challenge. How could they justify replacing pointless tests in one highly-protected species with pointless tests in another highly-protected species?

Professor Michael Balls
c/o FRAME
Russell & Burch House
96–98 North Sherwood Street
Nottingham NG1 4EE
UK
E-mail: michael.balls@btopenworld.com

References
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, P42–P43.
3 Bailey, J., Thew, M. & Balls, M. (2013). An analysis on the use of dogs in predicting human toxicology and drug safety. ATLA 41, 335–330.
The Principles of Humane Experimental Technique is now out of print, but the full text can be found at http://altweb.jhsph.edu/pubs/books/humane_exp/het-toc. An abridged version, The Three Rs and the Humanity Criterion, can be obtained from FRAME.

Download a pdf of this article. Comparative Substitution

Rex Leonard Burch: Humane Scientist and Gentle Man

Michael Balls

Rex Burch played a vital role in collecting background information
about practical animal experimentation, and was the first person
to use the term ‘alternatives’ in that context. The senior author of
The Principles, William Russell, greatly valued their collaboration

 

Whereas The Principles of Humane Experimental Technique1 reveals a great deal about its first author, it gives us very little insight into the character and contributions of its second author, Rex Burch. As a result, his role in the origins of the Three Rs concept could be underestimated. Happily, that can be avoided, not least because his co-author, William Russell, was solicitous in ensuring that his partner received the credit properly due to him.2 In addition, a few of us had the privilege of knowing Rex,3-5 and he recorded his own thoughts in a report produced under contract to ECVAM and published in ATLA.6

Soon after the UFAW project began, Russell informed Charles Hume that he would need some assistance, and the UFAW Council somewhat reluctantly agreed to the appointment of Burch. The plan was that Burch would “discuss with existing research workers, their techniques and attitudes to modifications, in terms of humaneness, and the idea of replacement techniques which did not require animals”. 6 To facilitate this, a letter of introduction was prepared (not without a struggle2) and sent to 20 individuals in December 1954. The response was positive, so Burch was able to begin his visits. He carried a tape recorder with him, then sent the interview tapes to Russell, who had their contents transcribed and placed in the records on which their eventual report and The Principles would be based.

Rex Burch in the lab

Russell later commented that, “As fieldwork for our project, Rex travelled widely over Britain, interviewing well over a hundred experimentalists, and every single one of them was cooperative. This shows, I think, not only the goodwill in the British scientific community, but the confidence Rex must have inspired by his friendly approach and his real understanding of the issues. These interviews were, of course, vitally important for our project, but I feel that there was more to them than that. Rex sowed many seeds, and helped to channel the goodwill of scientists into the more systematic approach to humane technique which has produced so many advances in recent years.”4 That was an immense achievement, since it must not be forgotten that, in those days, before the publication of The Principles with its introduction of the Three Rs concept, there was virtually no activity in the middle ground between the pro-vivisectionists and the anti-vivisectionists. There were only two positions on animal experimentation — for or against.

Burch’s success in gaining the confidence of research scientists undoubtedly stemmed from his own considerable experience in laboratory work, even though he was only 28 years old when he joined the UFAW project. He put it like this,6 in his own words: “In the early part of the Second World War, I worked in the North Riding Laboratory of Pathology and Public Health at Scarborough in North Yorkshire. One of my duties was to test milk for tubercle bacilli, and I had a constant stock of 200 guinea-pigs for this purpose. After their intraperitoneal injection of a centrifuged deposit of the milk sample (two guinea-pigs were used for each sample, one being killed after three weeks, the other after six weeks), their inguinal glands were examined for tubercle bacilli. My concern, before taking charge of this work, was about the humane killing. I was shown the method — a short, sharp blow to the nape of the neck with a specially made wooden instrument, which certainly caused instant death. I was made to practice on dead animals, and my first live guinea-pig did die instantly. From here I joined the army, serving in the Middle East and still using guinea-pigs for this diagnostic work. After the war, I read medicine at Guy’s Hospital Medical School in London (UK), but had to abort my studies and find paid work. I was offered work in the research department of Boots Pure Drug Company, where a large variety of laboratory animals were used. My appointment was that of an assistant in tropical medicine. At an early stage, disease broke out in a large mouse unit which supplied the various laboratories, and all of the mice had to be destroyed. I suggested that there should be a diagnostic laboratory for all of the laboratory animals, in order to provide early warning of disease. Within a matter of days, the Head of Research instructed me to set up such a unit. This work gave me wide experience in animal husbandry and experimental procedures, because I became deeply involved with work in the breeding units and with all those working experimentally in different disciplines. After a few years, I resigned from my appointment to set up my own research unit and breeding unit, in Huntingdonshire. My bank manager soon made me aware that there was a Professor Alastair Worden, only a few miles away, carrying out what he thought was similar work to my own. I soon made my acquaintance with Alastair Worden and, at our first meeting, he invited me to carry out histological and microbiological work for him on a casual basis. In the course of what seemed a comparatively short time, he told me that UFAW was appointing a very talented zoologist from Oxford University, Dr William Russell, to carry out a laboratory animal survey.” Worden knew that Russell needed an assistant, and suggested that Burch should contact Hume about the possibility of an appointment.

It is clear that, in 1954, Burch had greater, and wider, experience in practical laboratory work than his senior partner. Nevertheless, Burch’s crucial role in the project was not recognised at first, even by UFAW’s President, Edward Hindle FRS, who refused to support his application for membership of the Institute of Biology. Happily, largely as a result of Russell’s vigorous support, Burch became an MIBiol in mid-1959, at the time of the publication of The Principles. He was elected a Fellow of the Institute in 1987.2

For many years, there was confusion about when the term ‘alternatives’ was first used in relation to experiments on living animals. For a long while, the credit was given to Terry Hegarty, a FRAME Trustee and the son of FRAME’s Founder Chairman, Dorothy Hegarty. However, on a visit to the Russell Archive at the University of Nottingham, I discovered that the fact is that it was Burch himself who first used the term ‘alternatives’ in the context of the Three Rs — in October 1954, even before he had joined William Russell to work on the UFAW project! The story is as follows.2 Russell produced a draft of the letter of introduction to be sent to heads of university departments and research institutions, which was amended by Burch. In a sentence in which Russell wrote, “Mr. Burch is on a fact-finding mission, and with the information we hope to be able to suggest improvements in routine methods of research…”, Burch crossed out “improvements”, and suggested, as indicated in a footnote, that “some possible alternatives” should be used instead. Russell rejected that suggestion, crossed out “to suggest possible alternatives to techniques used at present” and suggested that “to produce a review of progress in the development of humane techniques” should be used. His position was supported by Charles Hume, Head of UFAW, who said, “The only thing that worries me a little is the reference to suggesting possible alternatives. Of course we do hope to do this, but if we say so bluntly I fear there may be a counter action — ‘Who are you to tell me how to do my job?’, I would suggest deleting the line ‘to suggest …at present’ and substituting something of this sort: ‘to present a review of progress in the development of humane techniques’.”

Happily, this temporary difficulty did not have a lasting effect on the excellent relationship between Russell and Burch, which was crucial to the development of the Three Rs concept. However, the publication of The Principles was not without controversy, largely because Russell rejected any external attempts to edit his text, but correspondence with Hume again bears witness to his respect for Burch. The original agreement with Methuen, publishers of The Principles, was that 80% of any royalties would go to UFAW and 20% would go to Russell, as its author, who would also own the copyright. Russell asked that his 20% should be shared equally with Burch, whereupon Hume impatiently commented that 10% of not very much would not be very much.2

Friday 5 August 1994, was a very special day for me, as I went to Sheringham, Norfolk, UK, to meet Rex Burch for the first time. As I said later,4 “I was totally captivated by his enthusiasm, his genuine excitement about the activities of FRAME and ECVAM, and his kindness. Within a few minutes, I felt as if I had known him for many years, and I knew that I would never forget him for the rest of my life”. That meeting had two important practical consequences. Firstly, the ECVAM contract, which led to a fascinating article in ATLA, The Progress of Humane Experimental Technique since 1959: A Personal View.6 That is the closest we will ever get to the autobiography he had hoped to write. It tells of his life before the UFAW project, gives his perspective on what went on between 1954 and 1959, and comments briefly on what had happened since the publication of The Principles.

Secondly, since Rex was too ill to travel far from home, I went back to Ispra, and arranged with Alan Goldberg that we should organise a workshop on the Three Rs, to be held in Sheringham, and with Russell and Burch as special participants. This was the first and, sadly, the last scientific meeting which the two authors of The Principles had attended since 1959. It resulted in a report with 58 far-reaching recommendations,7and it was a memorable event of very special significance to Rex Burch, humane scientist and gentle man.
Professor Michael Balls
c/o FRAME
Russell & Burch House
96–98 North Sherwood Street
Nottingham NG1 4EE
UK
E-mail: michael.balls@btopenworld.com

References
1 Russell, W.M.S. & Burch, R.L. (1959). The Principles of Humane Experimental Technique, xiv + 238pp. London,UK: Methuen.
2 Balls, M. (2009). The origins and early days of the Three Rs concept. ATLA 37, 255–265.
3 Balls, M. (1994). A day with Rex Burch. FRAME News 36, 1.
4 Russell, W.M.S., Sainsbury, D., Self, K. & Balls, M. (1996). Editorial. Rex Leonard Burch (1926–1996). ATLA 24, 313–316.
5 Goldberg, A. (2010). The Principles of Humane Experimental Technique: Is it relevant today? ALTEX
27, Special Issue, 25–27.
6 Burch, R.L. (1995). The progress of humane experimental technique since 1959: A personal view. ATLA
23, 776–783. Reprinted in ATLA 37, 269–275.
7 Balls, M., Goldberg, A.M., Fentem, J.H., Broadhead, C.L., Burch, R.L., Festing, M.F.W., Frazier, J.M., Hendriksen, C.F.M., Jennings, M., van der Kamp, M.D.O., Morton, D.B., Rowan, A.N., Russell, C., Russell, W.M.S., Spielmann, H., Stephens, M.L., Stokes, W.S., Straughan, .W., Yager, J.D., Zurlo, J. & van Zutphen, B.F.M. (995). The Three Rs: The way forward. The report and recommendations of ECVAM workshop 11. ATLA 23, 838–866.
The Principles of Humane Experimental Technique is now out of print, but the full text can be found at
http://altweb.jhsph.edu/pubs/books/humane_exp/het-toc. An abridged version, The Three Rs and the
Humanity Criterion, by Michael Balls (2009), can be obtained from FRAME.

‘One R’ is the new ‘Three Rs’

Craig Redmond

The Lush Prize, which rewards initiatives to end animal testing,

believes that more attention needs to be given to the ‘One R’

of absolute replacement, and that research methods that

exploit animals in any way (including tissues and cells)

should not be considered as ‘alternatives’

Introduction
Replacement of animal experiments is one of the Three R concepts (alongside Reduction and Refinement) first put forward by Russell and Burch in 1959.1 However, this can be either absolute replacement (i.e. methods that do not involve animals or animal tissues) or relative replacement (e.g. methods that use only cells or tissues of animals in vitro or ex vivo).

It has become accepted by many in the research community that some uses of animals can be classed as ‘alternatives’. In particular, the use of whole animals of species thought to either not experience pain or to have a lower level of sentience (e.g. fruit flies, nematodes and zebrafish), or of animal parts (including tissues, embryos, sera and cells). The use of these methods is reinforced by regulatory bodies, making it more difficult to reach a time when no animal use will occur in scientific research. André Ménache, of Antidote Europe, believes that in the region of 80% of ‘alternatives’ validated by ECVAM (the European Union Reference Laboratory for alternatives to animal testing) still use animals or animal tissues (personal communication, 04.09.13).

Founded in 2012, the Lush Prize rewards global initiatives to end animal testing, particularly in the area of toxicology. A total of £250,000 is shared annually between five prize categories covering science, training, young researchers, lobbying and public awareness. Lush Prize believes that more attention needs to be given to the ‘One R’ of absolute replacement, and that research methods that exploit animals in any way (including tissues and cells) should not be considered as ‘alternatives’.

Alternatives’ that still exploit animals
The United States Department of Agriculture refers to ‘alternatives’ as “a term that has different meanings to different people, and this difference largely depends on which side of the issue one is found”.2 So, for example, animal researchers might use relative replacement methods in addition to their use of animals (or look to refine existing animal tests), whereas abolitionists see ‘alternatives’ in terms of absolute replacement. Other examples of where the use of the term ‘replacement’ serves to reinforce the idea that relative replacement is routinely acceptable are:

— where Russell and Burch defined a replacement technique as “any scientific method employing non-sentient material which may in the history of animal experimentation replace methods which use conscious living vertebrates”.3 The words ‘non-sentient’, ‘conscious’ and ‘vertebrates’ ensure that the use of invertebrates and species considered as ‘lower organisms’ continues to be accepted.
— when, in its current “step-by-step approach to an alternatives search”, the Johns Hopkins University Center for Alternatives to Animal Testing (CAAT) suggests that, in addition to cell culture, tissue culture, models, simulations, etc., researchers “might look for a non-mammalian animal model
— fish or invertebrates, for example — that would still give you the data you need”. 4

Perhaps as a direct result of this widespread inherent acceptability of relative replacement alternatives, researchers at the University of British Columbia, looking into people’s acceptance of the use of particular species in laboratories, found that species such as fish and invertebrates “are typically rated below mammals, and, as such, are often considered an appropriate replacement for mammals in research”. 5

The philosopher Joel Marks notes that “developing alternatives to the use of animals can mean simply using a different animal” and considers that “the characterisation of the other animal […] as ‘lower’ on a phylogenetic ‘scale’ is arbitrary and disputed. The alternatives movement is therefore at risk of becoming a bait-and-switch con”.6 By this, Marks means that ‘alternatives’ are advertised as one thing (i.e. absolute replacement), but often turn out to be something completely different (i.e. simply the use of another species).

Some examples of relative replacement alternatives are:
Invertebrates: The horseshoe crab, Limulus polyphemus, is used in the Limulus amoebocyte lysate (LAL) assay. This method replaces the rabbit pyrogen test for the detection of endotoxin in, for example, hepatitis B vaccines. 7 The rabbit test involves injecting the test substance into a marginal vein of the ear of each of three rabbits.8 However, the LAL assay uses blood cells from the horseshoe crab, with up to 30% mortality resulting from the bleeding procedure.9

Fish: Zebrafish (Danio rerio) are widely used in research, including research on genetics, cancer and, increasingly, toxicology. The maintenance costs of zebrafish are less than one thousandth of the costs of maintaining mice,10 and they can produce 100–300 eggs per week, making their embryos useful for high-throughput screening.11 It is widely acknowledged that fish can feel pain, 12 with as much evidence for this as there is for birds and mammals.13 Other studies have shown that they have conscious awareness.14

Tissues: Hundreds of thousands of animals are bred and killed each year in Britain alone, solely to provide tissues for research.15 Human tissues to be preferred, due to species differences, yet animal tissue is often used on the grounds of cost and availability.16 Human tissue can be obtained from patients during diagnosis, removed as ‘waste’ during surgical operations, placentas or ‘afterbirth’, or tissues obtained after death.15

People can voluntarily donate blood or other tissue for transplantation or research, or their organs or bodies after death. Human tissue removed from the body in the course of disease diagnosis or treatment is the main source.17 However, although upwards of 600,000 residual surgical tissues are generated each year in England and Wales, only a tiny fraction of them are made available to researchers.18

The use of fetal calf serum
The move toward the use of in vitro cell culture to provide both human and animal cells for alternative methods is a step in the right direction. However, the use of fetal calf serum (FCS) as a cell culture media supplement is unacceptable, in the light of the availability of serum replacements and serum-free culture methods.19 collected for FCS production is obtained by cardiac puncture, performed by inserting a needle directly into the heart of the non-anaesthetised fetus.20 according to Jochems et al.20 it is very likely that the fetus is alive at the time of blood collection, and “will experience pain and/or suffering at the moment of heart puncture for blood collection and possibly for a period after that, until it actually dies”. The scientific validity of using FCS has been questioned. Risk of contamination is an issue,21 with the potential presence of viruses, bacteria, mycoplasma, yeast, fungi, immunoglobulins and endotoxins.20

Conclusions
These are just a few examples of animal use that some see as ‘alternatives’. The use of sentient animals, such as fish and horseshoe crabs, should not be accepted by those working in the field of alternatives to animal testing, despite the entrenched position within the research community and regulatory bodies. Neither should cruel processes such as the collection of FCS be condoned. In addition to greater humanity and greater acceptability, there are a multitude of clear scientific benefits to avoiding the use of animals or animal products.

The Lush Prize promotes the ‘One R’ of Replacement over all of the ‘Three Rs’, believing that the  true absolute replacement of animals is essential for ethical and scientific progress.

Craig Redmond
Lush Prize
Unit 21
41 Old Birley Street
Manchester M15 5RF
UK
E-mail: craig@lushprize.org
References
1 Russell, W.M.S. & Burch, R.L. (1959). The Principles of Humane Experimental Technique, 238pp. London, UK: Methuen.
2 Taylor Bennett, B. (1996). Alternative methodologies. In Essentials for Animal Research. A Primer for Research Personnel, pp. 9–17. Darby, PA, USA: Diane Publishing.
3 Balls, M. (1994). Replacement of animal procedures: Alternatives in research, education and testing. Laboratory Animals 28, 193–211.
4 Altweb Project Team (undated). Search for Alternatives. Baltimore, MD, USA: CAAT, Johns Hopkins
University. Available at: http://altweb.jhsph.edu/resources/searchalt/index.html (Accessed 22.10.14).
5 Ormandy, E.H., Schuppli, C.A. & Weary, D.M. (2012). Factors affecting people’s acceptance of the use of zebrafish and mice in research. ATLA 40, 321–333.
6 Marks, J. (2012). Accept no substitutes: The ethics of alternatives. The Hastings Center Report 42, Nov–Dec (Special Report), S16–S18.
7 Park, C.Y., Jung, S.H., Bak, J.P., Lee, S.S. & Rhee, D.K. (2005). Comparison of the rabbit pyrogen test and Limulus amoebocyte lysate (LAL) assay for endotoxin in hepatitis B vaccines and the effect of aluminum hydroxide. Biologicals 33, 145–151.
8 WHO (2013). The International Pharmacopoeia. Preface: 3rd Supplement. Geneva, Switzerland: World Health Organisation. Available at: http://apps.who.int/phint/en/p/docf/ (Accessed 07.09.13).
9 Leschen, A.S. & Correia, S.J. (2010). Mortality in female horseshoe crabs (Limulus polyphemus) from biomedical bleeding and handling: Implications for fisheries management. Boston, MA, USA: Massachusetts Division of Marine Fisheries. Available at: http://www.mass.gov/eea/docs/dfg/dmf/publications/mortality-in-female-horseshoe-crabsabstract.
pdf (Accessed 25.10.14).
10 Reed, B. & Jennings, M. (2011). Guidance on the housing and care of zebrafish Danio rerio, 64pp. Horsham, West Sussex, UK: Research Animals Department, Science Group, RSPCA.
11 van Vliet, E. (2011). Current standing and future prospects for the technologies proposed to transform toxicity testing in the 21st century. ALTEX 28, 17–44.
12 FAWC (1996). FAWC report on the welfare of farmed fish, 43pp. London, UK: Farm Animal Welfare Council.
13 Braithwaite, V. (2010). Do Fish Feel Pain?, 208pp. Oxford, UK: Oxford University Press.
14 Cottee, S.Y. (2012). Are fish the victims of ‘speciesism’? A discussion about fear, pain and animal consciousness. Fish Physiology & Biochemistry 38, 5–15.
15 Focus on Alternatives (undated). Focus on Human Tissue in Research, 4pp. Available at: http://www.frame.org.uk/dynamic_files/foa_humantissue.pdf (Accessed 03.09.13).
16 EMA (2012). Committee for Advanced Therapies (CAT) Scientific Workshop: Reducing the number of laboratory animals used in tissue engineering research — 11th October 2012 — European Medicines Agency, London [EMA/CAT/708346/2012], 4pp. London, UK: European Medicines Agency. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Report/2012/12/WC500136419.pdf (Accessed 25.10.14).
17 Nuffield Council on Bioethics (1995). Human Tissue: Ethical and Legal Issues, 182pp. London, UK: Nuffield Council on Bioethics. Available at: http://nuffieldbioethics.org/project/human-tissue/ (Accessed 25.10.14).
18 Bunton, D. (2011). The use of functional human tissues in drug development. Cell & Tissue Banking 12, Issue 1, 31–32.
19 Newman, C. (2003). Serum-free cell culture — the ethical, scientific and economic choice. The Biomedical Scientist, September 2003, 941–942.
20 Jochems, C.E., van der Valk, J.B., Stafleu, F.R. & Baumans, V. (2002). The use of fetal bovine serum: Ethical or scientific problem? ATLA 30, 219–227.
21 Focus on Alternatives (2009). Serum-free Media for Cell Culture, 52pp. http://www.frame.org.uk/dynamic_files/foa_fcs_free_table_may09.pdf
(Accessed 03.09.13).
 

Beyond the Three Rs

For a long while after the Three Rs were first proposed by Russell and Burch, anti-vivisectionists rejected the concept, on the grounds that experiments on living vertebrates which cause them pain, suffering, distress or lasting harm, were ethically unacceptable and scientifically unnecessary, so there was no point in reducing, refining or replacing them. In recent decades,
however, some organisations, such as the BUAV and PETA, have moved tentatively into the middle ground, and have made positive contributions toward the Three Rs, without comprising their fundamental beliefs.

The ultimate goal of Russell and Burch themselves was replacement, which they said, “is always a satisfactory answer”, with reduction and refinement merely being steps along the way. That was also the position of the founders of FRAME, the Fund for the Replacement of Animals in Medical Experiments, although the charity has made many contributions in support
of the other two Rs, since its foundation in 1969.

The latest issue of ATLA contains two important articles about the future of the Three Rs, as well as the latest in an important series of outstanding exposures of the insurmountable limits of laboratory animals as models of humans.

In this issue of PiLAS, Craig Redmond argues the case for replacing the Three Rs with One R (Replacement),1 but goes further in saying that only what Russell and Burch defined as absolute replacement (where “animals are not required at all at any stage”) should be considered acceptable, since relative replacement can still involve suffering, as in the use of invertebrates,
less-sentient vertebrates, or cells and tissues taken from protected animals and used in vitro or ex vivo.

Michael Balls goes further in his ATLA Comment,2 proposing that “the time has come to plan for a future where the Three Rs will have served their purpose, animal experimentation will have been consigned to history, and humane biomedical science in research, testing and education will have become the norm, for the benefit of humans and animals alike”.

Finally, the article by Jarrod Bailey in the latest ATLA issue, on monkey-based research,3 demonstrates that major molecular differences, revealed by comparative
genomics and molecular biology, underlie inter-species phenotypic disparities. The collective effects of these differences are striking, extensive and widespread, and show that the superficial similarity between human and monkey genetic sequences is of little benefit for biomedical research.
Therefore, the extrapolation of biomedical data from monkeys to humans is highly unreliable, and the use of monkeys must be considered of questionable value, particularly given the breadth and potential of alternative methods of enquiry that are currently available to scientists.

References
1 Redmond, C. (2014). ‘One R’ is the new ‘Three Rs’. ATLA 42, P50–P52.
2 Balls, M. (2014). Animal experimentation and alternatives: Time to say goodbye to the Three Rs and hello to humanity? ATLA 42, 327–333.
3 Bailey, J. (2014). Monkey-based research on human disease: The implications of genetic differences. ATLA 42, 287–317.

William Russell: Polymath, Wordsmith, Classicist and Humourist

Michael Balls

Reading the The Principles of Humane Experimental Technique is a very special
privilege, not only because of the importance of the messages it conveys,
but because of the unique character and qualities of its principal author

The Principles of Humane Experimental Technique1 was based on a report submitted to the Universities Federation for Animal Welfare (UFAW) in 1956, and was completed in 1958. Rex Burch had left UFAW’s employment in 1956, but it is likely that it was always the intention that William Russell would write the text of the book. He owned the copyright, but always insisted that Burch be regarded as a full co-author and should share the meagre royalties that were received.2

Methuen & Co. were reluctant to publish it at all, possibly because of the resistance of its author to  suggestions for modifying its length or content.2 At one point, in 1957, Charles Hume, the founder of UFAW and the originator of the project, intervened, telling Russell that, while the book “contains factual matter of great importance and also original thinking which is quite fundamental” … “the style is high-falutin’, complicated and obscure, and too long-winded. The references to psychoanalysis are of great interest to psychoanalysts, but hardly interesting to readers who have no knowledge of psychoanalysis, who will be in the majority. Many of the sentences have to be read more than once before the readers can construe them and see the point.” He suggested that the book should “be revised, little by little over the next year or two … one thinks of improvements in one’s bath, and then again the whole thing matures — and maturation means simplification and abridgement, rather than proliferation”.

I have read the complete Principles at least 30 times, and I have some sympathy with what Hume was trying to say, not least because I edited a number of Russell’s later manuscripts. This included the first joint Russell & Burch publication since 1959,3  which was submitted to ATLA along with a letter, which said, “We don’t want the wording fiddled with and split infinitives introduced”. It was because The Principles is not an easy read that, to mark its 50th anniversary, I produced the abridged version, with explanations of some of the most difficult passages and concepts.4

Nevertheless, that having been said, in addition to the importance of The Principles in terms of the Three Rs, it also represents a remarkable legacy, left to us by a unique scientist, who was also a polymath, wordsmith, classicist and humourist. In this brief comment, I would like to give some illustrations of what made William Russell so very special.

A polymath is somebody who excels in a wide variety of subjects or fields. Russell was an author, classicist, composer, entertainer, linguist, philosopher, pianist, psychologist, psychotherapist, raconteur, singer, sociologist and soldier.5 His publications covered animal behaviour, comparative sociology, demography, ecology, ethology, evolution, folklore, genetics, geography, history, human behaviour, mythology, primate sociology, science fiction, statistics, population control, and zoology.

A wordsmith is a skilled user of words. I have been an author and editor for more than 50 years, but I could not claim to approach his skill in using the English language. For example, two words, in particular, made me immediately reach for my dictionary — adumbrate and limn. Adumbrate can be used to mean “represent in outline”, “foreshadow” and “overshadow”. Russell clearly meant the first of these, when he wrote, “An attempt has been made to adumbrate the outlines of such a theory [of replacement]”. Limn means to depict in painting or in words, and Russell wrote, “We have sought only to limn the barest of outlines [on humane experimental technique]”. I also appreciate his use of the “bludgeon of stress” to describe the unnecessarily severe procedures used in some studies on animal behaviour.

After he returned from the Second World War, Russell had been expected to go to Oxford University to read Classics, but he changed his mind and studied Zoology instead. Nevertheless, his classicist leanings come to the surface at various points in The Principles. In a section on Choice of Species, he makes the following comment: “This subtle matching of procedure to species, and species in turn to objectives, is more significant than appears at first sight for the humanity of technique. For the only alternative is to try to correct the mistaken choice of a wrong species by forcing it to conform to the requirements of the investigation. This results in just those roundabout methods we should guard against, and is
all too liable to end in gross inhumanity. It is the method of Procrustes, and Procrustes would have been less deservedly unpopular if he had selected his guests instead of dissecting them.”

Procrustes was a cruel figure in Greek mythology. He invited guests into his stronghold, where he had an adjustable bed, so he could make sure that his guests were either too long or too short for it. He amputated the excess length of the former, and stretched the latter on a rack!

Russell referred to refinement as “protean in its aspects”, which means displaying great diversity. Proteus was a Greek god of rivers and oceans, who knew all things — past, present, and future — but was reluctant to divulge what he knew. He would try to escape enquirers by assuming all sorts of shapes, but, if caught while asleep and bound, he would return to his proper shape, give the desired answer, and, on being released, plunge into the sea.

Another historical, although not strictly classical, reference is used to illustrate the point that we cannot extend the concept of inhumanity to non-sentient material, in which “we include higher plants, microorganisms, and the more degenerate metazoan endoparasites, in which nervous and sensory systems are almost atrophied. 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 — the Erewhonian philosopher who inquired whether salt can feel”.

Erewhon is the title of a book by Butler, published in 1872, which is a satire of Victorian society. Erewhon is a fictional country and its name is based on Nowhere backwards, albeit with the letters “h” and “w” transposed. In the book, among many other adventures, the narrator visits the Colleges of Unreason and meets, among others, the Professor of Worldly Wisdom, who was also the President of the Society for the Suppression of Useless Knowledge. The Professor of Botany there contended that “vegetables are only animals under another name”, so, “if it was sinful to kill and eat animals, it was not less sinful to do the like by vegetables or their seeds”.

Russell was well known as a humourist to all those who met him or witnessed his performances at, for example, the world congresses on the Three Rs, held in Utrecht in 1996 and in Bologna in 1999. The Principles is essentially a serious a book, but Russell’s sense of humour comes through at various points. For example, in referring to discrepancies between his analysis of data from the 1952 Laboratory Animals Bureau Survey and the published figures, he says, “I seem to have produced rather more rabbits from the common hat, and my conjuring skill is further attested by the transformation of 108 canaries into 78 ducks”. Later on, in a discussion on the use of lower vertebrates, including birds, instead of  mammals, he says that, “In its recruiting campaign, experimental psychiatry would be ill-advised to look the humblest gift-finch in the beak”. This is an analogy with “don’t look a gift-horse in the mouth”, where it is considered ungrateful to look inside the mouth of a horse given as a gift, although this is a common practice in judging the age and state of health of horses.

The Principles conveys very useful messages. Perhaps we should be more concerned about worldly wisdom and useless knowledge, especially when animals are used as models of humans. The problem is that we rarely know whether or not the models are relevant and reliable. Russell referred to an oft quoted remark attributed to Lord Kelvin, who so said, “If ye canna mak’ a model, ye dinna understan’ it” [if you can’t make a model, you don’t understand it], which could also be paraphrased as, “If ye dinna understan’ it, ye canna mak’ a model” [if you don’t understand it, you can’t make a model]. Lord Kelvin (1824–1907)6 was a physicist and mathematician, but the problem is much worse in our world of biomedical
research and testing. Why is that? Because we rarely have sufficient understanding of what we are trying to model (e.g. carcinogenesis, embryotoxicity, Alzheimer’s disease, Parkinson’s disease) or of the model we are trying to use (e.g. the rat, mouse, rabbit, dog, macaque). That is the point that Russell made, very forcefully, in his excellent and vitally important discussion of fidelity and discrimination, and the danger of the high-fidelity fallacy.6

References and Notes
1 Russell, W.M.S. & Burch, R.L. (1959). The Principles of Humane Experimental Technique, xiv + 238pp. London, UK: Methuen.
2 Balls, M. (2009). The origins and early days of the Three Rs concept. ATLA 37, 255–265.
3 Russell, W.M.S. & Burch, R.L. (1995). Prefatory note. ATLA 23, 11–13.
4 Balls, M. (2009). The Three Rs and the Humanity Criterion, 19 + 131pp. Nottingham, UK: FRAME.
5 Paskal, C. (2006). Bill Russell: The singing scientific detective. ATLA 34, 470–472.
6 It is not surprising that Russell quoted Lord Kelvin, who, like Russell himself, was a polymath. William Thomson, first Baron Kelvin of Largs, was one of the most famous scientists of his time. He was Professor of Natural Philosophy at the University of Glasgow for 53 years, having been appointed in 1846, at the age of 22. He was as famous for his inventions as for his academic work on mathematical physics and electrical engineering. His research on the nature of heat led him to formulate the second law of thermodynamics. He proposed an absolute scale of temperature, now known as the Kelvin Scale, worked on planning a Trans-Atlantic Telegraph cable, and invented the Kelvin Compass. He was the first scientist to be elevated to the peerage, and is buried in Westminster Abbey, next to Isaac Newton. Further information can be found at: http://special.lib.gla.ac.uk/exhibns/Kelvin/kelvinindex.html
7 Balls, M. (2013). The Wisdom of Russell and Burch. 3. Fidelity and discrimination. ATLA 41, P42–P43.
The Principles of Humane Experimental Technique is now out of print, but the full text can be found at http://altweb.jhsph.edu/pubs/books/humane_exp/het-toc. The abridged version, The Three Rs and the Humanity Criterion, can be obtained from FRAME.