IMI projects are using advanced computational analysis, human cell lines and tissues, and better models to ‘reduce, replace and refine’ the use of animals in research
By Pierre Meulin, IMI Executive Director
For a long time, animals have been used as models for human biology in drug development. Growing ethical concerns surrounding these experiments led, in the 1950s, to the introduction of a concept called the three Rs – which refers to replacement, reduction, and refinement of animal use in experiments – a framework for a new approach to improving animal welfare.
The introduction of new EU legislation a decade ago was intended to further lead to new alternative methods of testing drugs that would give researchers the same or better data as those obtained via animal testing, but that either don’t involve the use of any animals at all, used fewer animals, or involved less painful procedures. Since its inception in 2008, IMI has been fully committed to achieving this goal of humane experimentation, and IMI-funded projects have resulted in a number of innovations that are directly or indirectly contributing to reducing, refining and replacing the use of animals in drug development.
Developing and validating alternative, non-animal testing approaches for both human and veterinary vaccines was the main goal of the VAC2VAC project. In routine vaccine production, the current quality control approach requires large numbers of laboratory animals. VAC2VAC aims to provide data to support the ‘consistency approach’ for quality control that promotes the use of in vitro, analytical, non-animal based systems. Other IMI vaccine projects have been working towards the same goal: ZAPI developed in vitro tools to generate vaccines and antibodies for emerging zoonotic diseases that could reduce the number of animal experiments necessary in vaccine development.
Human cells and tissues, and intelligent in silico innovations
New in vitro models using human cell lines, tissues and organoids, from human induced pluripotent stem cells, are being developed and validated in a number of projects: RHAPSODY, INNODIA and BEAT-DKD have been able to develop models that help identify new diabetes drugs for preventing beta cell stress and death in human pancreatic islets, and for studying insulin resistance, sensitivity and restoration. ADAPTED used iPSCs to determine the effect of the APOE genotype on inflammation, for example, in in vitro models of Alzheimer’s disease – basically human brain cells in a dish.
Indeed, the stem cells for these studies were provided by another IMI project, EBiSC, which has built a robust and reliable supply chain for standardised and quality-controlled disease-specific iPSC lines. The StemBANCC project is also working on high-quality human iPSC lines that can be used for predictive toxicology, further eliminating the need for animal testing. Innovations in computer modelling means predicting drug safety is increasingly done without the use of animals: NEURODERISK created a prototype to carry out toxicity profiling using 3D models, a software tool that is freely available to the public, while ETRANSAFE is developing a system that would allow for the replacement of animal control groups in toxicology studies with a ‘Virtual Control Group’ (VCG), based on existing data. EU-AIMS, an autism project, made and validated a set of tools that render mouse models more precise and more predictive.
There is also a drive to increase the use of more relevant animal models, meaning models that are more ‘matched’ to humans, adhere to certain standards, and are of lower phylogenetic levels. The more relevant the model, the fewer that need to be used. COMBINE are working on standardised rodent models that will lead to harmonised data and better infection models, while ITCC-P4 have created the starting materials for ‘humanised’ models of paediatric cancer tumours, meaning they will be more human-like, and thus result in more relevant data.
Other examples of IMI research in this area include EUROPAIN’s confirmation that suppressed burrowing behaviour in animal models as a measure of the effect of pain in rodents is robust and reproducible; on the other hand, BTCure showed that some models were unreliable and represented a waste of animals, and as a result, their use could be reduced or even eliminated.
The principles of the 3Rs are increasingly embedded in legislation and regulatory practice, as well as in the policies of organisations that fund research. Polling consistently shows public support. IMI has throughout its lifetime supported the development of alternative methods to animal testing, and will continue to do so in the new programme.
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Virtual control groups: shared, reused data could reduce animal use in drug safety studies