The 3Rs call on science

After 50 years of the 3Rs – replacement research lacks the strategic punch needed to decrease the number of animals used says Dr Gemma Buckland

The year 2009 has marked the 50th anniversary of the birth of the 3Rs concept - the Replacement, Reduction and Refinement of animal experiments . Despite some progress, notably in safety testing, replacement research is still lacking the strategic commitment needed from scientists and politicians to progressively decrease the number of animals used.

At the 7th World Congress (WC7) on alternatives in Rome this year it was encouraging to see the first ever platform for replacement science in medical research but the congress was still heavily overshadowed by alternatives in toxicology research. With 33% of animal experiments in the EU performed for basic biological research as opposed to 8% for safety testing, medical research is still not receiving proportional representation of time and funding in the development of replacement alternatives . We urgently need to redress the balance.

Experts from around the world who convened in Rome agreed that the current challenge in alternatives is to devise a global vision and strategy to revolutionise alternatives research. A pledge from all relevant stakeholders to focus on replacement research would produce compelling returns - better quality and relevance in medical research, economic and time benefits in the laboratory with high-throughput research methods, a humane science that avoids animal suffering whilst reflecting the views of citizens and keeping European science competitive at the cutting-edge of biomedical technology development. 

The Dr Hadwen Trust has been developing and promoting the use of advanced techniques to replace animals in medical research for almost 40 years through funding high quality research in universities and research institutes across Britain. Whilst most researchers, funders and regulatory authorities today accept the scientific and ethical imperative to replace animal procedures, they still too often lack the strategic and co-ordinated approach that is so essential to make ultimate replacement a realisable goal for the future. That is why the Dr Hadwen Trust, in our pursuit of excellence in medical research without using animals, strives to combine an innovative scientific agenda with progressive policy development.

Despite a growing acknowledgement that many traditional scientific practices do not always represent the most cutting-edge approach, millions of animals continue to be used each year – an estimated 115 million worldwide , 12.1 million in the European Union  and a 22-year high of 3.6 million in Britain . This continued trend of increase is indicative of a replacement strategy vacuum; not just bad news for animal welfare but crucially it also indicates an over reliance on outdated science. 

Animals widely used as surrogates for humans in fundamental disease research include mice, rats, rabbits, dogs and non-human primates. Symptoms are usually artificially created by chemical, surgical or genetic means with the aim of mimicking selected aspects of the human form of the disease. This approach rarely achieves an accurate representation of human disease and is limited by the physiological, biochemical, anatomical, pharmacological and biological differences between humans and the model species.

The mouse is the most commonly used species in medical research, despite approximately 70 million years between the divergence of our species and the existence of at least 67 known immunological discrepancies . The consequences of such differences create significant hurdles for research scientists struggling to make animal models relevant to the clinical situation.

Medical conditions are studied in animals because of the lack of knowledge that surrounds them; the causes, progression of symptoms and characteristics are often unknown or unclear. However, studying an artificial condition in physiologically distinct animals can too often produce questionable results. A number of independent systematic reviews have so far revealed the extent to which unreliable data is being obtained from animal studies. In 2005 a study found that from a series of 51 experiments on 5,000 animals, 99.7% of the results were not applicable to human patients . Similarly in 2007 the British Medical Journal published a review of experiments using 71 animals in research for six different treatments for five human illnesses, which found that half of the experiments failed to correctly predict human responses to treatment . When faced with evidence of the scientific disadvantages of underachieving animal models, it is clear that we cannot rely on serendipity to produce the non-animal approaches that will replace them.

At this year’s World Congress, nine Dr Hadwen Trust-funded scientists presented their advanced research into alternatives. Amongst them, Dr Brian Thomson from the University of Nottingham presented his work on developing models of human liver that will permit both the long term growth and preservation of function of primary human hepatocytes in vitro for research into liver diseases such as hepatitis. Professor Arun Holden from Leeds University demonstrated the use of computational models of human tissues that can be used in drug design and how models of the human heart are being used to pre-screen candidate anti-arrhythmics on the heart and to evaluate mechanisms of preterm and full term labour . Dr Hadwen Trust funding of work in Professor Paul Furlong’s laboratory at Aston University, has enabled the development of Magnetoencephalography as a neuroimaging tool to study human pain, pain perception and the influence of pain relief drugs with human volunteers . Other advanced replacement techniques such as using human cell cultures and microarray analysis to identify disease marker genes in chronic wound healing and 3D cell models for skin cancer, also formed part of the exciting discussions.

This encouraging range of advanced research projects presented at WC7 was only a snapshot of a larger portfolio of annually funded research by the Dr Hadwen Trust, applications for which are currently open for 2010 grants. (For details on applying visit www.scienceroom.org/apply-for-funding). Our current multi-disciplinary research profile encompasses a wide range of techniques applied in medical areas. This includes, transcranial magnetic stimulation to study brain damage in humans and diffusion tensor magnetic resonance imaging to trace pathways in the living human brain and determine relationships between brain connections in health and disease. We also fund experimental approaches in fundamental research such as in vitro human intestinal mucosal cells to observe the pathogenicity of clostridium toxins, or the establishment of 3D cell models of breast cancer, the first stage of which was awarded a 2009 National Centre for the 3Rs (NC3Rs) animal replacement prize. Our research, and that of other replacement experts around the world, is demonstrating how a targeted approach can produce new techniques yielding more relevant information about specific diseases without the need for animals.

This vital experience must be shared and duplicated more widely, nationally and internationally, to inspire a change in attitude and working practice.The European Union currently has the opportunity to shift the practices in Europe regarding the use of animals in science with the revision of its twenty year old animal experiments law, Directive 86/609. Proposals to establish an EU Centre of Excellence in alternatives encompassing, for the first time, animal use not just in toxicology but in all areas of biomedical research, testing and education, could be the single most important development to emerge from the negotiations. If successful, it could provide the vital focus for coordinated and strategic efforts to engage stakeholders and identify key target areas for increased funding, technological development and political support. Focusing primarily on areas where animal use has a low level of human relevance, would be a logical start point.  However bureaucratic hurdles to speedy method validation, insufficient scientific enthusiasm or expertise in replacements, and a lack of political will to proactively ensure the development and implementation of alternative methods, must also be tackled. 

Without a doubt, a number of challenges lie ahead in replacing all animal experiments, but the biggest of these is not a technological one. In 2007 the US National Academy of Sciences proposed their highly influential Toxicity Testing in the 21st Century: A Vision and a Strategy concept which is already revolutionising the toxicity testing regime in the USA. It is being applauded by experts in the field as a rightly ambitious and bold modernisation of an old fashioned system. A similar approach and mindset across the board would surely pave the way to more robust and humane medical research for the future, benefiting both humans and animals alike.