ReviewKeynoteHarnessing opportunities in non-animal asthma research for a 21st-century science
Introduction
Only two new classes of asthma drug have progressed from the laboratory to the clinic during the past 50 years despite considerable funding and effort [National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs); http://www.nc3rs.org.uk/news.asp?id51405]. In the meantime, some 300 million people worldwide currently suffer from asthma and it remains the most common chronic disease among children. Although most asthma-related deaths occur in low- and lower-middle income countries, asthma is a public health problem globally. Approximately one in every 250 deaths worldwide is asthma related, and the incidence continues to increase (WHO; http://www.who.int/mediacentre/factsheets/fs094/en/index.html).
During the past 10 years, the UK Medical Research Council (MRC) alone has provided £35 million in funding for basic research on asthma (MRC, personal communication). However, a recent call from NC3Rs for ‘new experimental models with improved scientific and clinical relevance and reduced reliance on the use of animals’ sheds light on the obstacles facing asthma research in the UK (NC3Rs; http://www.nc3rs.org.uk/page.asp?id51231). Recent European Union-funded projects under the Seventh Framework Programme for Research and Technology Development (FP7) have also sought to explore the asthma–environment link (Europa: Cordis; http://cordis.europa.eu). The Innovative Medicines Initiative (IMI), a European project aimed at bringing medicines more quickly to the market, was launched in 2009 and has injected €246 million into research, including asthma. It is hoped that a large patient cohort will enable validation of human biomarkers and development of diagnostic criteria for mechanistic and therapeutic trials (Europa press release; http://europa.eu/rapid/pressReleasesAction.do?reference5IP/09/802). The identification of this area as a bottleneck, along with the imbalance of progress and funding, signifies the need to reassess the way that asthma research is carried out and to realign its direction.
Asthma is characterised by airway inflammation, airway hyper-responsiveness (AHR, which is defined by exaggerated airflow obstruction in response to bronchoconstrictors), mucus overproduction, chronic eosinophilic inflammation, airway remodelling and episodic airway obstruction [1]. The response of atopic individuals is complex, involving an ordered interplay between mediators, cytokines and cell migrations throughout the respiratory tract, draining lymph nodes and blood. It is now clear that a wide range of environmental factors, superimposed on a genetic background, determine the occurrence and severity of asthma [2]. Although concerted international efforts of scientists and clinicians, the pathobiology of asthma is still relatively poorly understood [3].
Epidemiological studies can yield a great deal of information and clinical investigations are powerful tools; however, owing to ethical constraints and regulations surrounding clinical trials since the first mouse models were published in 1994, there has been a general reliance on animal models for asthma studies [3]. During this time, despite gleaning some information on the disease, progress has been slow in elucidating information on the causes, onset, persistence and treatments, owing in part to limitations associated with currently available models 3, 4. Despite asthma having originally been discovered as an inflammatory disease through human studies [5], artificially induced animal models of the disease have become increasingly prevalent, in particular murine models. Some investigators have described such models as ‘indispensable’ from a drug-screening standpoint [6]; whereas others have observed that animal models have intrinsic limitations [3].
The concept of ‘personalised medicine’ is especially relevant to a disease such as asthma, and the term ‘personalised research’ has been coined to demonstrate the need for basic research in asthma to reflect the variety of phenotypes that patients present. In many cases, only a reductionist approach is possible; however, complex behaviours of the larger system can be modelled computationally using systems biology tools. With this in mind, there are techniques outside of the mainstream asthma research field that have already shown great promise or that, with some targeted development, could be used to approach the asthma questions from a different angle. In this review, I analyse the current models used in asthma research and highlight the available components that could form part of a change in the way that asthma research is conducted.
Section snippets
The current climate: animal models
The species of animal most commonly used in asthma research include dogs 3, 6, sheep [7] and non-human primates (NHPs; principally rhesus and cynomolgus macaques) [8], as well as mice [9], rats [10], cats [11] and guinea pigs [12], with the most prevalent being the murine model. Mouse models have seen a dramatic rise in use over the past decade in an effort to probe the fundamental immunological causes of the disease and to identify and test novel therapeutic strategies [13]. However, in
Modelling without animals
In vitro studies are often cited as lacking the biological complexity of an in vivo system; yet it can also be said that animal models are a ‘black box’ of sorts that also do not permit a complete understanding of the complex mechanistic interactions within an animal, or the differences between humans and a model species. According to some researchers, the complex mechanisms underlying the genetics of sensitisation and pathophysiology necessitate in vivo studies. They regard the mouse model as
Concluding remarks
Unlike in regulatory testing, a common infrastructure for using 3Rs methods in basic research is rare. Notwithstanding achievements made to date in the treatment of asthma, the relevance of artificial animal models is considered to be overestimated in many cases, which could be contributing to the current disease research climate (i.e. sufficient research but insufficient progress). With animal research, some fundamental issues are often overlooked, such as species-dependent differences,
Acknowledgement
The author would like to thank Troy Seidle and Gill Langley for their reviews of this manuscript.
Gemma L. Buckland obtained her BSc (Hons) at King's College London in Immunology and Microbiology and her PhD from Imperial College London in T cell signalling. She currently works as a scientific consultant for the Humane Society International where her research interests include scientific advances in non-animal research methods for investigating infectious and immunologically based human diseases.
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Gemma L. Buckland obtained her BSc (Hons) at King's College London in Immunology and Microbiology and her PhD from Imperial College London in T cell signalling. She currently works as a scientific consultant for the Humane Society International where her research interests include scientific advances in non-animal research methods for investigating infectious and immunologically based human diseases.