The human whole blood pyrogen test - lessons learned in twenty years.

The whole blood pyrogen test was first described in this journal exactly twenty years ago. It employs the cytokine response of blood monocytes for the detection of microbiological contaminants with the potential to finally replace the still broadly used rabbit pyrogen test. The article reviews its development process, the current status of the test as well as the challenges and missed opportunities. The article highlights the enormous efforts of many people to get the test to where it is today. But it also shows the incredible missed opportunities for implementation and thus sparing about 400,000 rabbits still used for this purpose per year worldwide; in the EU, since the official acceptance of the test, the number of animals used for pyrogen testing did not fall but increased by about 10,000 to 170,000. The test is the first solution enabling adequate pyrogen testing of cell therapies, including blood transfusions, and medical devices, but has not been implemented for either application by authorities. As the test can quantitatively assess human-relevant airborne pyrogens, the contribution of pyrogens to chronic obstructive lung diseases and childhood asthma can for the first time be defined and home and workplace safety improved in the future.

A brave new animal for a brave new world: The British Laboratory Animals Bureau and the constitution of international standards of laboratory animal production and use, circa 1947-1968.

In 1947 the Medical Research Council of Britain established the Laboratory Animals Bureau in order to develop national standards of animal production that would enable commercial producers better to provide for the needs of laboratory animal users. Under the directorship of William Lane-Petter, the bureau expanded well beyond this remit, pioneering a new discipline of "laboratory animal science" and becoming internationally known as a producer of pathogenically and genetically standardized laboratory animals. The work of this organization, later renamed the Laboratory Animals Centre, and of Lane-Petter did much to systematize worldwide standards for laboratory animal production and provision--for example, by prompting the formation of the International Committee on Laboratory Animals. This essay reconstructs how the bureau became an internationally recognized center of expertise and argues that standardization discourses within science are inherently internationalizing. It traces the dynamic co-constitution of standard laboratory animals alongside that of the identities of the users, producers, and regulators of laboratory animals. This process is shown to have brought into being a transnational community with shared conceptual understandings and material practices grounded in the materiality of the laboratory animal, conceived as an instrumental technology.

FRAME, animal experimentation and the Three Rs: past, present and future.

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.

FRAME: the early days.

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.

Personal reflections on Russell and Burch, FRAME, and the HSUS.

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 Dr Hadwen Trust for Humane Research: 39 years of replacement science.

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.

Finding the courage: the unconventional lives of WMS and Claire Russell.

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.

Keeping the archives at 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.

FRAME, the Three Rs and the Russell Archive at the University of Nottingham.

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.

The FRAME Research Programme under the direction of Dr Richard Clothier.

The work of Dr Richard Clothier (Reader in Cellular Toxicology and Director of the FRAME Alternatives Laboratory in the University of Nottingham Medical School) in relation to the FRAME Research Programme, is reviewed. He made a very substantial contribution to FRAME's laboratory research work over the last 20 years, by publishing many research papers, mainly with respect to method development and the application of new replacement toxicity test methods, particularly those involving the use of human cells in tissue culture. In addition, he participated in a number of international validation studies that have facilitated the regulatory acceptance of certain new methods. Lastly, he has been closely involved in the logistical aspects of obtaining and maintaining external research funding for FRAME from industrial sponsors.

Richard Clothier: an appreciation.

The career of Richard Clothier is reviewed in the light of his long-standing collaboration with Michael Balls and Laurens Ruben at the University of East Anglia (UEA), the University of Nottingham, and Reed College, Portland, Oregon, USA. It began with work at UEA on the aetiology of the lymphosarcoma of Xenopus laevis, followed by studies on the effects of exposure to N-nitroso-N-methylurea on T-cell functions, which led to many contributions to comparative immunology. This was followed by the establishment of the FRAME Research Programme, which led to participation in extensive studies on the development of in vitro cytotoxicity tests and their application in acute and topical toxicity testing. A FRAME Trustee since 1983, Richard Clothier was a co-founder, and subsequently Director, of the FRAME Alternatives Laboratory in the University of Nottingham Medical School, where he led successful collaborations with a number of industrial partners and, in particular, with the European Centre for the Validation of Alternative Methods (ECVAM).

Working together to respond to the challenges of EU policy to replace animal testing.

This paper presents a personal perspective on efforts during the past 15 years to replace animal testing for assessing the safety of chemicals and products. It is based on an invited lecture--the FRAME Annual Lecture--given in October 2005, with the theme of "making progress by working together" (government-industry-academia-NGOs). Where we have achieved some successes, these have clearly been due to effective cooperation and collaboration between the relevant stakeholders. In recent times, there has not been this same level of active commitment and coordination. This needs to change, since, if we are to make good progress in the years to come in responding to the new challenges of the EU policy to replace animal testing, this will undoubtedly require us to work together, hopefully facilitated by effective leadership and coordination from the EU policy-makers themselves.

Use of animals in the development and control of viral vaccines.

Animal models were central to the development of poliovaccines and remain essential in some form in the routine quality control of both live and killed vaccines. The necessity of an animal model is illustrated by the examples of mumps and measles vaccines where the existing materials, while satisfactory, have a number of drawbacks and where changes in current practice raise concerns for safety and efficacy.

A short history of the use of animals in vaccine development and quality control.

Man has been using animals since early times to gain an insight into health, illness and death. The oldest known medical standard work, the Corpus Hippocraticum (circa 350 BC), contains descriptions of experiments on pigs. Although the first attempt at immunoprophylaxis dates as far back as the 6th century (variolation was practised in China to protect people against smallpox), it was not until the middle of the 19th century that animal experimentation acquired full scientific status in the development and quality control of immunobiological products. It was Louis Pasteur and Robert Koch who, through studies on animals, succeeded in underpinning the causal relationship between infectious diseases and micro-organisms, thus opening the way to the discovery of effective therapeutic and prophylactic agents for a number of these diseases. In several respects, the experimental animal work carried out in the last decade of the 19th century to find an effective and reliable way of treating and preventing diphtheria determined the use of animals. Many common routine animal tests in the quality control of immunobiologicals arose from diphtheria research. Conversely, diphtheria was one of the first diseases where experimental animal research laid the foundation for effectively reducing child mortality. This had a very profound impact on the attitude of society towards animal experiments in those days and almost completely eliminated the growing influence of the antivivisection movement. The interest in the possibilities of replacement, reduction and refinement (the Three-Rs concept) of the use of laboratory animals is increasing for several reasons, including concern about animal welfare. The root of animal welfare can be traced back to the 18th century with the formulation of utilitarian ethics. One characteristic feature of these ethics was that the interests of any creature which is submitted to any procedure should be taken into consideration. This presentation sets out some major historical contributions of animal experiments to the development and quality control of immunobiologicals. Attention is also paid to the changing attitude of society towards animal experiments and its impact on the development of alternative methods. It is concluded that, although animal experiments have played an important part, a new area is now beginning in which increasing emphasis will be placed on in vitro methods.