Development of new methodologies
Animals are used in medical research for investigating the causes and mechanisms of human disease, identifying potential drug targets and testing therapeutic approaches. Animals are also used in testing the safety of drugs as part of regulatory processes. Although the predictive value in humans of animal studies is variable, their use is well established, standardised and understood. In recent years, non-animal methods have been developed that can complement the use of animals and sometimes provide a replacement.
When the use of animals can be replaced by non-animal methods that are scientifically appropriate to answer the questions being researched and are more predictive of human biology, then animals should not be used. The UK Animal (Scientific Procedures) Act 1986 requires that work does not involve any regulated procedures for which there is a scientifically satisfactory alternative method or testing strategy that does not entail the use of a protected animal.
There has been considerable progress in developing non-animal technologies such as in vitro organoid models that approximate tissues and organs, and computational in silico approaches (including the use of Artificial Intelligence (AI) and the construction of digital twins- see reference below) that use known biological information to model and predict the effects of altering steps in physiological pathways.
Organoid models are being developed for a variety of tissues and organs including brain, blood–brain barrier, gut, liver, heart, bone, lung and many others, and are better physiological models of tissues than simple 2D cultures. These in vitro models range from simple spheroids, but which are easily scalable, to more complex organs-on-a-chip combined with microfluidic systems. An advantage of these models is that they can use human primary cells or induced pluripotent stem cells that can be differentiated into the cell types of choice. Ideally these systems will combine multiple cell types typically found in the tissue of interest including immune cells and vasculature.
In vitro organoid models face several key challenges; ensuring reproducibility, achieving sufficient cellular complexity to accurately model real tissue, recapitulating diseases that involve the interaction of multiple organs over time, reaching appropriate maturity of differentiation and development and, critically, validating their use for specific applications. To address these issues, models must be standardised using well-defined components—such as cell types, defined synthetic media and support matrices—and then validated against in vivo data from both animals and humans to confirm their predictive value.
Animal research will still be necessary for studying traits that cannot be effectively modelled in vitro, such as cognition and behaviour. In addition, aspects of diseases that depend on ageing, sexual reproduction, environmental influences, or whole-body physiological responses remain challenging to replicate using in vitro models.
Similarly, in silico modelling in drug discovery and drug safety evaluation faces challenges related to the availability of high-quality, robust data, which is needed to develop or train models—in particular those using AI—and the need to validate these models against in vivo biological data from animals and humans.
Predictive data generated before in vivo experiments will ultimately reduce animal experimentation to only the most essential cases; those that cannot be addressed by other methods prior to testing in humans.
Ensuring progress
As part of the grant preparation and Home Office project licence application process, we support applicants in considering replacement by highlighting relevant information sources, facilitating contacts with organisations and groups focused on replacement, and providing replacement checklists as prompts, thereby assisting the Animal Welfare and Ethical Review Body (AWERB) in its 3Rs review of applications.
We will facilitate researcher access to expert advice on replacement from other scientists—for example, within the MRC National Mouse Genetics Network (NMGN) where replacement approaches are already being implemented. We will also encourage the use of NC3Rs networks and facilitate connections with centres specialising in replacement strategies.
We lead a national network discussion group, the Best Models Working Group, to provide a forum for researchers to learn about models and disseminate information.
We plan to facilitate replacement training in the UK through the Advance Training Centre to help overcome barriers to the adoption of non-animal methods.
We will continue to promote advancements in Reduction and Refinement, and high standards of animal welfare—areas in which we have a strong track record—by providing researchers with local expertise, systems and resources.
Useful sources of further information
National Centre for the Replacement, Refinement & Reduction of Animals in research:
https://nc3rs.org.uk
EU Reference Laboratory for alternatives to animal testing (EURL ECVAM):
https://joint-research-centre.ec.europa.eu/reference-measurement/european-union-reference-laboratories/eu-reference-laboratory-alternatives-animal-testing-eurl-ecvam_en
Organoids review:
Verstegen, M.M.A., Coppes, R.P., Beghin, A. et al. Clinical applications of human organoids. Nat Med 31, 409–421 (2025). https://doi.org/10.1038/s41591-024-03489-3
Organs on a chip review:
Human organs-on-chips for disease modelling, drug development and personalized medicine. Ingber. Nat Rev Genet 23, 467–491 (2022). https://doi.org/10.1038/s41576-022-00466-9
Adverse Outcome Pathways:
https://www.oecd.org/en/topics/sub-issues/testing-of-chemicals/adverse-outcome-pathways.html
An example of in silico models:
Immune digital twins for complex human pathologies: applications, limitations, and challenges. Niarakis. et al. npj Syst Biol Appl 10, 141 (2024). https://doi.org/10.1038/s41540-024-00450-5