Introduction
Throughout history, animals have played a central role in biomedical research, ranging from anatomical study to drug testing, to better understand human physiology and pathology [1]. According to the National Centre for the 3Rs (replacement, reduction and refinement), it is estimated that 2.76 million procedures were carried out on living animals in Great Britain alone in 2022, with 96% of this figure involving mice, fish, birds and rats [2]. In recent years, animal-based research has often raised ethical concerns and has come under scrutiny for how biologically relevant it is, and whether it reliably can predict human outcomes [3]. This month, congress at Washington, D.C. introduced the FDA Modernization Act 3.0, a new bill that establishes clear guidelines for development and adoption of new testing methods to reduce or replace the use of animals in non-clinical testing, including cell-based assays and computer modelling [4]. In the UK, a parliamentary debate on animal research took place on the 19th February in response to one petition calling for a ban on the use of dogs for research purposes and another to replace animals in toxicity testing, both with large numbers of signatures [5]. With recent advancements in these animal-free technologies, such as 3D stem cell research, there is a promising shift towards approaches that uphold ethical standards and are more relevant to humans, which will be discussed in more detail below.
Ethical considerations
First and foremost, traditional animal experimentation raises ethical dilemmas regarding the use of sentient beings that involve procedures that oftentimes cause pain, discomfort and distress. Genetic modification of animals in recent years has also introduced moral considerations, such as the large numbers of animals it requires and the unpredictability of the welfare impacts on the animals [6]. Whilst one of the 3Rs “Refinement” can help mitigate this by ensuring that any individual using animals for research undertakes proper handling and care through strict regulation [7], reducing the number of animals used in the first place and finding suitable replacements benefits more animals overall. The transition to animal-free research methodologies therefore better aligns with animal welfare principles and can help to foster a more compassionate approach to scientific endeavours.
Sustainability and environmental considerations
Another potential limitation of animal-based research is the potential contribution to environmental degradation and carbon emissions it can have. Animal-based research facilities use large amounts of energy and emit high carbon emissions due to environmental factors that must be kept constant for the animal as control variables. These include ventilation, protection from outside pathogens, lighting and heating. In addition, a large amount of resources are required to maintain the animal’s welfare, including housing, food and medical care. Finally, animal-based research produce large amounts of waste, including the animal’s excrement, bodies and used animal care materials such as bedding. This waste can be chemically and biologically hazardous and therefore must be handled with caution and disposed of properly, usually via incineration, which contributes to air pollution [8]. Other forms of pollution that could occur due to runoff of animal waste and improper disposal of research materials include soil and water pollution, which together with air pollution can pose health hazards including increased risk of asthma, stroke and cardiac diseases [8]. In conclusion, animal-free approaches therefore promote sustainability and environmental stewardship as they generally use less materials and energy overall.
Relevance to human biology
In addition, animal-free research can offer distinct advantages in terms of relevance to human biology. Whilst animal models have been valuable tools throughout history to better understand aspects of human physiology and disease, they do not always accurately model how humans will react to a drug or a disease process. For example, a systematic review in the British Medical Journal of hundreds of animal experiments and human clinical trials found a discordance in outcomes depending on the disease studied, with half of the diseases investigated showing no agreement with human studies [9]. Furthermore, of the 12% of drugs that pass preclinical testing to go onto human clinical trials, 89% of these then fail subsequent phase trials in humans, mainly due to toxicity in humans that was not found in animals [10]. Even drugs that survive human trials and end up going to market can then be recalled later due to unanticipated effects months or years later. In vitro testing, including 2D and 3D cell culture, synthetic biomaterials and tissue samples, as well as in silico tests such as computer modelling have revolutionised the research field to better replicate the conditions found in humans in vivo to more accurately predict drug efficacy and toxicity. Depending on the animal-free methodology used, researchers can create more defined and complex models that mimic the microenvironment of the human tissue being studied, and can even include the patient’s own cells in the model, allowing individualised research outcomes that more accurately reflect in vivo results.
Scientific discovery and therapeutic development potential
Another significant benefit of animal-free research is the potential to accelerate the field of therapeutic developments and discoveries by removing hindrances that slow this process down. Animal testing is much slower than most in vitro approaches, where the animal has to be brought up and looked after for weeks to months prior and during testing. This can add significant amounts of time to test a single drug, such as in the field of cancer therapeutics where rodent testing adds 4-5 years to drug development [10]. The time frame issues along with the costing of animal testing being 1.5-30x more expensive than in vitro testing significantly decreases the number of potential drug compounds that can be screened in a given period of time [10]. Moreover, in vitro testing methods have the ability to be high-throughput enough to test thousands to millions of compounds in a relatively short amount of time, using robots, detectors and software that analyse much smaller quantities of the compound than would be used in animal tests [11]. This overall allows researchers to streamline the drug discovery and development of therapeutics process, accelerating scientific discoveries to benefit humans in a shorter time span.
Conclusions
In conclusion, the transition towards animal-free research approaches in recent years represents a significant paradigm shift in multiple research fields involving understanding disease processes and drug discovery. By supporting these innovative technologies, researchers can better uphold ethical standards, as well as promote the sustainability of their research for future generations. In addition, by embracing more human-relevant models, researchers can expect their research outcomes to be more applicable to human biology, and therefore accelerate scientific discovery and desired clinical trial outcomes. As we continue to advance our understanding and applications of animal-free methodologies, they will play an increasingly pivotal role in shaping the future of biomedical research, from drug discovery to regenerative, personalised medicine.
About the Author
Mikayla is a cancer research scientist who recently completed her PhD at Leeds Beckett University. Her PhD project focused on the bidirectional crosstalk between melanoma and cells of the tumour microenvironment via secretion of extracellular vesicles. This project involved study of a wide variety of cellular phenotypic and expression changes, as well as determination of cargo within the vesicles. She also has a background as a bioassay scientist in industry in a multitude of client projects.
References
4. Republicans and Democrats Introduce the FDA Modernization Act 3.0, Requiring FDA to Implement Animal Testing Reforms Passed by Congress Over a Year Ago (animalwellnessaction.org)
5. Debate on e-petitions relating to animal testing and non-animal research methods - House of Commons Library (parliament.uk)