The objective of this review is to report on whether, and if so, how, scientific research projects organised and managed within collaborative consortia across academia and industry are contributing to the Three Rs (i.e. reduction, replacement and refinement of the use of animals in research). A number of major technological developments have recently opened up possibilities for more direct, human-based approaches leading to a reassessment of the role and use of experimental animals in pharmacological research and biomedicine. This report reviews how projects funded by one of the research funding streams, the Innovative Medicines Initiative (IMI), are contributing to a better understanding of the challenges faced in using animal models. It also looks how the results from these various projects are impacting on the continued use of laboratory animals in research and development. From the progress identified, it is apparent that the approach of private–public partnership has demonstrated the value of multicentre studies, and how the spirit of collaboration and sharing of information can help address human health challenges. In so doing, this approach can reduce the dependence on animal use in areas where it has normally been viewed as necessary. The use of a collaborative platform enables the Three Rs to be addressed on multiple different levels, such that the selection of models to be tested, the protocols to be followed, and the interpretation of results generated, can all be optimised. This will, in turn, lead to an overall reduction in the use of laboratory animals.
The Use of Neurocomputational Models as Alternatives to Animal Models in the Development of Electrical Brain Stimulation Treatments
Recent publications call for more animal models to be used and more experiments to be performed, in order to better understand the mechanisms of neurodegenerative disorders, to improve human health, and to develop new brain stimulation treatments. In response to these calls, some limitations of the current animal models are examined by using Deep Brain Stimulation (DBS) in Parkinson’s disease as an illustrative example. Without focusing on the arguments for or against animal experimentation, or on the history of DBS, the present paper argues that given recent technological and theoretical advances, the time has come to consider bioinspired computational modelling as a valid alternative to animal models, in order to design the next generation of human brain stimulation treatments. However, before computational neuroscience is fully integrated in the translational process and used as a substitute for animal models, several obstacles need to be overcome. These obstacles are examined in the context of institutional, financial, technological and behavioural lock-in. Recommendations include encouraging agreement to change long-term habitual practices, explaining what alternative models can achieve, considering economic stakes, simplifying administrative and regulatory constraints, and carefully examining possible conflicts of interest.
Expectations for the Methodology and Translation of Animal Research: A Survey of the General Public, Medical Students and Animal Researchers in North America
Ari R. Joffe, Meredith Bara, Natalie Anton and Nathan Nobis
To determine what are considered acceptable standards for animal research (AR) methodology and translation rate to humans, a validated survey was sent to: a) a sample of the general public, via Sampling Survey International (SSI; Canada), Amazon Mechanical Turk (AMT; USA), a Canadian city festival (CF) and a Canadian children's hospital (CH); b) a sample of medical students (two first-year classes); and c) a sample of scientists (corresponding authors and academic paediatricians). There were 1379 responses from the general public sample (SSI, n = 557; AMT, n = 590; CF, n = 195; CH, n = 102), 205/330 (62%) medical student responses, and 23/323 (7%, too few to report) scientist responses. Asked about methodological quality, most of the general public and medical student respondents expect that: AR is of high quality (e.g. anaesthesia and analgesia are monitored, even overnight, and 'humane' euthanasia, optimal statistical design, comprehensive literature review, randomisation and blinding, are performed), and costs and difficulty are not acceptable justifications for lower quality (e.g. costs of expert consultation, or more laboratory staff). Asked about their expectations of translation to humans (of toxicity, carcinogenicity, teratogenicity and treatment findings), most expect translation more than 60% of the time. If translation occurred less than 20% of the time, a minority disagreed that this would "significantly reduce your support for AR". Medical students were more supportive of AR, even if translation occurred less than 20% of the time. Expectations for AR are much higher than empirical data show to have been achieved.
The Use of In Vivo, Ex Vivo, In Vitro, Computational Models and Volunteer Studies in Vision Research and Therapy, and Their Contribution to the Three Rs
Robert D. Combes and Atul B. Shah
Much is known about mammalian vision, and considerable progress has been achieved in treating many vision disorders, especially those due to changes in the eye, by using various therapeutic methods, including stem cell and gene therapy. While cells and tissues from the main parts of the eye and the visual cortex (VC) can be maintained in culture, and many computer models exist, the current non-animal approaches are severely limiting in the study of visual perception and retinotopic imaging. Some of the early studies with cats and non-human primates (NHPs) are controversial for animal welfare reasons and are of questionable clinical relevance, particularly with respect to the treatment of amblyopia. More recently, the UK Home Office records have shown that attention is now more focused on rodents, especially the mouse. This is likely to be due to the perceived need for genetically-altered animals, rather than to knowledge of the similarities and differences of vision in cats, NHPs and rodents, and the fact that the same techniques can be used for all of the species. We discuss the advantages and limitations of animal and non-animal methods for vision research, and assess their relative contributions to basic knowledge and clinical practice, as well as outlining the opportunities they offer for implementing the principles of the Three Rs (Replacement, Reduction and Refinement).
Chris Langley, Chris Brock, Gerard Brouwer, Alun Brown, Lucie Clapp, Jon Cohen, Tom Evans, Carol Newman, Samantha Orr, Barry Phillips, Andy Rhodes, Nigel Webster and Karl Wooldridge
Sepsis and multiple organ failure are common causes of death in patients admitted to intensive care units. The incidence of sepsis and associated mortalities has been steadily increasing over the past 20 years. Sepsis is a complex inflammatory condition, the precise causes of which are still poorly understood. Animal models of sepsis have the potential to cause substantial suffering, and many of them have been poorly representative of the human syndrome. However, a number of non-animal approaches, including in vitro, in silico and clinical studies, show promise for addressing this situation. This report is based on discussions held at an expert workshop convened by Focus on Alternatives and held in 2004 at the Wellcome Trust, London. It provides an overview of some non-animal approaches to sepsis research, including their strengths and weaknesses, and argues that they should be prioritised for further development.
Can Drug Safety be Predicted and Animal Experiments Reduced by Using Isolated Mitochondrial Fractions?
Susana P. Pereira, Gonçalo C. Pereira, António J. Moreno and Paulo J. Oliveira
Mitochondrial toxicity has resulted in the withdrawal of several drugs from the market. One particular example is nefazodone, an anti-depressant withdrawn in the USA due to hepatoxicity caused by drug-induced mitochondrial dysfunction. Drug development and safety testing can involve the use of large numbers of laboratory animals, which, without a decisive pre-screening for mitochondrial toxicity, are often unable to pre-empt higher mortality rates in some patient groups. The use of isolated mitochondria as a screening tool for drug safety can decrease the number of laboratory animals used in pre-clinical studies, thus improving animal welfare and healthcare outcomes and costs. Novel techniques involving highthroughput methods can be used to investigate whether a molecule is a mitochondrial toxicant. Moreover, these screens are mechanistically-based, since the effects of the drug on oxidative phosphorylation, calcium homeostasis and mitochondrial genetics can be assessed. This review is intended to demonstrate that isolated mitochondrial fractions are suitable for predicting drug and general chemical safety in toxicological screenings, thus contributing to the refinement and reduction of animal use in laboratory research.
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.
Orsolya E. Varga, Axel K. Hansen, Peter Sandøe and I. Anna S. Olsson,
The use of animals to model humans in biomedical research relies on the notion that basic processes are sufficiently similar across species to allow extrapolation. Animal model validity is discussed in terms of the similarity between the model and the human condition it is intended to model, but no formal validation of models is applied. There is a stark contrast here with the use of non-animal alternatives in toxicology and safety studies, for which an extensive validation is required. We discuss both the potential and the limitations of validating preclinical animal models for proof-of-concept studies, by using an approach similar to that applied to alternative non-animal methods in toxicology and safety testing. A major challenge in devising a validation system for animal models is the lack of a clear gold standard with which to compare results. While a complete adoption of the validation approach for alternative methods is probably inappropriate for research animal models, key features, such as making data available for external validation and defining a strategy to run experiments in a way that permits meaningful retrospective analysis, remain highly relevant.
Guruprasad P. Aithal
The unmet needs of biomedical and clinical research are highlighted by reference to druginduced liver injury (DILI), non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic steatohepatitis (NASH). Examples in these areas highlight the major limitations of animal models with respect to predicting, examining and managing these clinically significant forms of liver injury. The way in which these knowledge gaps are being bridged by studies involving the use of human tissues and primary cells are described.