Alternatives to Laboratory Animals

At the opening of a meeting to celebrate the 50th anniversary of the publication of The Principles of Humane Experimental Technique, by W.M.S. Russell and R.L. Burch, and the 40th anniversary of the establishment of FRAME, some comments on the early days of the Charity are made, with particular reference to the special contributions made by its founder-Chairman, Dorothy Hegarty, and the author's own appointment as a Trustee, and later as Chairman. Reference is made to some key events and successes, and especially to the importance of FRAME's move from London to Nottingham, and the establishment of an ongoing collaboration with the University of Nottingham, including the setting-up of the FRAME Alternatives Laboratory.

The article reviews the early history of FRAME from the perspective of its first “Scientific Administrator”. The roles of Mrs Hegarty the founder, and other early contributors to FRAME's development are described. In addition, the article discusses FRAME's strategic approach to the subject and how Mrs Hegarty's background influenced the development of that approach.

Having been involved with the biomedical sciences and alternatives for 30 of the 50 years since Russell and Burch published The Principles of Humane Experimental Technique, I feel well placed to speak of the contributions made by FRAME over the last 40 years. FRAME has promoted the development and use of alternatives by presenting the “better science” arguments to scientists, promoting informed discussion, changing opinions and changing behaviours. FRAME has also contributed constructively to the political debate, and was instrumental in promoting legislation which incorporated the principles of the Three Rs. Times are changing, and the Three Rs are increasing being politicised: and FRAME is particularly well placed to ensure that good science and good welfare, rather than ideology, remain the basis for interest in and progress with the Three Rs.

On FRAME's 40th anniversary, I had the opportunity to examine FRAME and CAAT's missions as closely linked to those of their universities. The roles of education, research and service are key, both to the universities and to our two centres. By examining the current programmes, and identifying the needs of the future, the research activities, policy studies and training, it becomes clear that the Three Rs of alternatives contribute significantly to our respective universities’ missions.

FRAME has more than any other institution contributed to the implementation of the Three Rs concept in Europe. The first step was achieved by establishing the European Research Group on Alternatives to Toxicity Testing (ERGATT), in which individual scientists in several European countries began to collaborate to promote the development and validation of in vitro toxicity tests in order to refine, reduce and replace the use of animals in toxicity testing. The first successful project was the start of the INVITOX in vitro toxicology database, which is today managed by ECVAM. Major milestones were the establishment in 1989 of ZEBET, the first national centre for alternatives, in Germany, and of ECVAM in 1991. In 1990, ERGATT and CAAT organised a workshop in Amden, Switzerland, at which European and US scientists developed the concept of experimental validation of toxicity tests, which today remains the basis for the independent, scientific validation process. ECVAM has applied this validation concept in all of its successful validation studies, which have provided in vitro toxicity tests that have been accepted for regulatory purposes by the EU Commission and by the OECD. By re-launching the ATLA journal in 1983, FRAME provided another powerful scientific tool for promoting the Three Rs in Europe and around the world. The close cooperation of scientists from FRAME, ZEBET and ECVAM has most effectively promoted and established the Three Rs as the basic scientific, ethical and legal concept for refining, reducing and replacing the use of experimental animals.

The coincidence of anniversaries associated with the publication of William Russell and Rex Burch's The Principles of Humane Experimental Technique, the founding of the Fund for the Replacement of Animals in Medical Experiments (FRAME), and the establishment of the collaboration between FRAME and the University of Nottingham, provides an opportunity to reflect on Russell and Burch's legacy and how it was carried forward by FRAME. The Principles, published in 1959, was the pioneering work in what later became the alternatives or Three Rs field of replacement, reduction, and refinement of animal use. Such was the book's initial and undeserved obscurity, however, that FRAME, following its founding in 1969, pioneered a similar approach independently of Russell and Burch's work. The Humane Society of the United States (HSUS) was also an early champion of the alternatives framework, and through the establishment of the Russell and Burch Award, helped unite Russell and Burch with what had emerged as the alternatives community. Thanks largely to FRAME, Russell and Burch were able to participate in Three Rs activity before their deaths. They lived long enough to see their ideas take hold, but not long enough to see the emerging revolution currently under way in toxicity testing, toward the use of non-animal methods.

The Principles of Humane Experimental Technique by William Russell and Rex Burch provides exceptional value, both to practitioners of alternative methodologies and to bibliophiles who enjoy the pursuit of an out-of-print book. I was stimulated to find an original edition by my first visits to FRAME and its Chairman, Michael Balls. The search continued for several years, until I was able to find an edition suitable for presentation to him. During this hunt, I was able to learn a great deal about the Three Rs of Replacement, Reduction and Refinement, and the programmes that FRAME initiated to educate scientists and the general public about alternative approaches. Very importantly, I was able to use many of FRAME's successful strategies to build up a similar organisation in the United States, the Institute for In Vitro Sciences. The double value of this book is now revealed — not only are its concepts scientifically and ethically valuable, but the price now being charged by secondhand booksellers means a more than ten-fold increase in the value of my investment!

The year 2009 will not be remembered mainly because it is the Chinese year of the ox, but probably, for many, because it is Charles Darwin's bicentenary, the 150th anniversary of the publication of his masterpiece, The Origin of Species, the 50th anniversary of the publication by Russell and Burch of The Principles of Humane Experimental Technique, where they introduced the concept of Three Rs, and also the 40th anniversary of the foundation of the Fund for the Replacement of Animals in Medical Experiments (FRAME). FRAME will always remain our senior, since the Dr Hadwen Trust for Humane Research is only celebrating its 39th anniversary this year! After four decades of learning, challenging, contesting, creating, promoting and advancing the Three Rs concept, the idea of the replacement of the use of animals in research has itself become a science, giving the old sterile debate between pro- and anti-vivisectionists a new dimension. Although scientific progress has been the main reason for such changes, it is important to remember that, without the people and organisations whose aim has been devoted to this cause, these changes might never have happened. Still, as illustrated by the 2008 statistics on animal procedures, many more changes will have to be made, and it is by considering the progress achieved during the last 40 years that we can find the strength and motivation to pursue our goal of scientific research and testing that no longer relies on animal-based techniques.

Taking the 110th anniversary of marketing of aspirin as starting point, the almost scary toxicological profile of aspirin is contrasted with its actual use experience. The author concludes that we are lucky that, in 1899, there was no regulatory toxicology. Adding, for the purpose of this article, a fourth R to the Three Rs, i.e. Realism, three reality-checks are carried out. The first one comes to the conclusion that the tools of toxicology are hardly adequate for the challenges ahead. The second one concludes that, specifically, the implementation of the EU REACH system is not feasible with these tools, mainly with regard to throughput. The third one challenges the belief that classical alternative methods, i.e. replacing animal test-based tools one by one, is actually leading to a new toxicology — it appears to change only patches of the patchwork, but not to overcome any inherent limitations other than ethical ones. The perspective lies in the Toxicology for the 21st Century initiatives, which aim to create a new approach from the scratch, by an evidence-based toxicology and a global “Human Toxicology Programme”.

This year marks a number of important anniversaries for the Three Rs and those organisations involved in their advancement. These include the 50th anniversary of the publication of Russell and Burch's book, The Principles of Humane Experimental Technique, the 40th anniversary of FRAME, and the 5th anniversary for the UK's National Centre for the 3Rs. These anniversaries provide an important opportunity to reflect on past achievements and future challenges.

FRAME is 40 years of age and has contributed much to reasoned debate on the need to use animals in responsible scientific enquiry. It has done this through the promotion of good science as best practice, as well as promotion of the Three Rs of Reduction, Refinement and Replacement of animal experimentation. However, unless the debate widens to question society at large over its attitudes to personal risk, to accepting responsibility rather than apportioning blame, and to its simplistic adoption of regulation as the panacea, we could see the pursuit of the Three Rs degenerate into a formulaic process, leading to imperfect animal models being replaced by imperfect alternatives which would not serve to improve our science. We must not lose sight of the ultimate goal of conducting good science without the need to use animals.

My contribution to FRAME's 40th Anniversary meeting started by looking back: offering some reflections on the benefits and difficulties of engaging in wide-ranging dialogue on laboratory animal issues, largely based on experience with two forums — both of which have involved FRAME. Drawing on this discussion, I then looked forward: arguing that such dialogue now has an especially important role to play in developing strategies to replace (and reduce or avoid) the use of animals in research.

The anniversary of the Fund for the Replacement of Animals in Medical Experiments (FRAME) provides an opportunity to celebrate the Charity's achievements over the past 40 years, and in particular, its contribution to the international acceptance of the Three Rs as the basis of an ethic for animal experimentation, and its role as a leader in the implementation of the Three Rs in the life sciences. The Canadian Council on Animal Care (CCAC) has based its work on the Three Rs, especially since the establishment of its fundamental CCAC Policy Statement on the Ethics of Animal Investigation (1989). Following recommendations from the evaluation of its programmes by external committees established by the national granting agencies, the CCAC recently launched a Three Rs Program. This programme will build on the work of FRAME and other similar Three Rs organisations, to further the promotion and implementation of the Three Rs in Canadian science.

In 1995, an international group of scientists met in Sheringham, Norfolk, UK, for a workshop entitled The Three Rs: The Way Forward. There, with the participation of William Russell and Rex Burch, the group discussed each of the Three Rs in detail, and made specific recommendations on how to promote them within the scientific community. The Institute for Laboratory Animal Research (ILAR) was established as part of the US National Academy of Sciences, to develop and disseminate information and guidelines for the care and use of laboratory animals. Over the years, the focus of ILAR has been to improve the health, welfare, and psychological well-being of the research animal, using the Three Rs as a foundation. ILAR's programmes include an international component, through which it reaches out to other countries via translations of its report; the ILAR Journal, a quarterly publication that focuses on animal models, animal welfare and protocol review; communications and outreach through the ILAR website and presence at scientific meetings; and special reports in which expert committees make recommendations to improve science and animal welfare. Through the efforts of ILAR and similar organisations, it is now recognised that high standards of humane care lead to better science. However, continued effort is needed to promote the Three Rs in developing countries.

Everybody's career depends on many chance factors: the people one meets, the opportunities which are available, or the state of a scientific discipline. Mine is no exception. I started out in agriculture, obtained a PhD in quantitative genetics, and spent most of my career concerned with the use of animals in biomedical research. Soon after I joined the Medical Research Council Laboratory Animals Centre in 1966, as their geneticist in charge of many species and strains of laboratory animals, I was introduced to Russell and Burch's book, The Principles of Humane Experimental Technique. It had a significant effect on my future, which has encompassed two related themes: the need for better experimental design, and the conviction that, in most research, inbred strains of rats and mice should normally be used in preference to genetically undefined outbred stocks. The establishment of the FRAME Reduction Committee has helped me to pursue both of these, although toxicologists continue to ignore basic design principles, by using outbred stocks.

Until I began working at FRAME, I was not really aware of the Three Rs or FRAME's work to promote and progress them. It soon became clear to me that it made scientific sense and that it could make a difference to many thousands of laboratory animals. As an alternatives advocate, I regularly experience optimism, frustration and determination. This is illustrated most clearly by the primate research dilemma. Here, I describe the positive and negative experiences I have had whilst working toward the goal of replacing primate experiments, and how these have led me to undertake a multidisciplinary PhD project on primate use in biomedical research. The aim is to examine how research scientists view the opportunities and challenges involved in the use of primates in biomedical science, and to investigate the feasibility of phasing out their use. As a result of the research, I hope to provide a new perspective, to depolarise the debate and bring about a constructive dialogue between all parties as to how and when primate research could be replaced.

The aim of research in the FRAME Alternatives Laboratory at the University of Nottingham Medical School is summarised, i.e. to use human cell culture-based projects and in vivo studies in human volunteers as alternatives to the use of rodent models in the study of human disease. This is especially important when the available animal models do not adequately represent the pathophysiological situation in humans. The approach is exemplified by summaries of studies on the effects of starvation on skeletal muscle in human volunteers, and on lipid metabolism in obese female volunteers.

In the current economic climate, even the best known charities are facing reduced income and need to raise their profiles to ensure continued support. FRAME has always been well known among scientific organisations, but is less familiar to the public. The traditional sources of funding are drying up, and FRAME needs to promote itself to new audiences, if it is to succeed for another 40 years.

Fifty years after the publication of The Principles of Humane Experimental Technique by Russell and Burch, this paper explores the contemporary role of the Three Rs. This is illustrated by reference to a recent social scientific study, which involved a total of 50 in-depth interviews with scientists who use animals and with other stakeholders in the debate. The data analysis shows how the Three Rs are conceptualised in at least three ways: firstly, as an ethical animal, either as a shorthand for a moral imperative, or as a route to managing an ethical dilemma; secondly, as a scientific animal, internal to the scientific method; and finally, as a political animal, with some stakeholders referring to the Three Rs as a way to promote consensus in a controversial domain. Pushing the metaphor a little further, the paper concludes that the Three Rs concept has become a kind of hybrid animal.

WMS and Claire Russell led lives of extraordinary intellectual adventure, spanning from the traditional formal education of Oxford University to the creativity of science fiction and the experimental world of mid-20th Century psychoanalysis. The verbal and pictorial illustrations presented in this article offer an insight into the vast collection of documents related to their lives and work currently being catalogued in the Manuscripts and Special Collections department of the University of Nottingham.

The role of the department of Manuscripts and Special Collections at the University of Nottingham is described, with reference to its early development, growth of collections across all disciplines, and current collection strengths. The professional activities of acquisition, cataloguing and providing access are set in the wider perspective of national standards and expectations of delivery. The recent establishment of the W.M.S. (Bill) and Claire Russell Archive is discussed in this context, with some account of the challenges and opportunities which the archive offers for both curators and researchers.

The objectives of the Fund for the Replacement of Animals in Medical Experiments (FRAME) are spelled out, as laid down in the Charity's Trust Deed of 1969, and the support of the Charity's trustees, consultants, patrons and staff in all that has been achieved during its first 40 years, are recognised. The recent establishment of the W.M.S. and Claire Russell Archive at the University of Nottingham is recognised as a further important link between FRAME and the University.