Animals have long been involved in the scientific research process, testing treatments and drugs to ensure they are safe for humans. This role animals play has been highly criticised due to ethical and welfare concerns. New research methods, such as 3D cell culture and organoid engineering have been explored as a substitute for animal models. Could this be the future of research? By Christiana Chun Hei Chee
The use of animals in scientific research can be traced back to as early as the 6th century BCE. At the time, Alcmaeon of Croton, an Ancient Greek researcher, conducted experiments on dogs to study brain intelligence and sensory functions (Ericsson et al. 2013). Even today, in the 21st century, animal models are used widely in a range of contexts such as secondary school biology dissection classes to cancer therapy research. The ethical considerations surrounding animal welfare in research has pushed forward the 3R principle by William Russell and Rex Burch in 1959: to ‘replace’ animals with other alternatives, ‘reduce’ the number of animals used, and ‘refine’ procedures to minimise sufferings (Russell and Burch, 1959).
Before a drug is released into the market, it is tested on humans to ensure that the drug actually works. But, let us take a step back. Would you volunteer to test a new drug or procedure that has no evidence of working in a living organism? You will likely be sceptical about the efficacy and side effects of the drug, which is completely understandable! Therefore, clinical trials of drugs on animal models are crucial to ensure drug safety before proceeding to human clinical trials. Each year, the number of registered clinical trials increases. As of February 2025, according to ClinicalTrials.gov, 201 thousand drug or biological trial studies were registered. Shockingly, only around 7.9% of the clinical trials make it into the market (Kim et al. 2023), showing that there is often a loss in translation from bench to bedside. Animals such as mice and rabbits are often used in the early stages of clinical trials; however, a drug that works on a rabbit may not have the same therapeutic effect on a human, or may even cause unintended side effects, due to biological differences.
So, what is the solution to this long-standing problem? How do scientists abide by the 3R research integrity while keeping up to speed with the increasing demands for new disease therapies? The answer lies within more relevant disease models. Scientists have found and created ways to introduce techniques such as Three-Dimensional (3D) Cell Cultures (Bedard et al. 2020) and organoid engineering. 3D cell culture systems allow cells to grow in an environment resembling the spatial organization and environment of an organism, instead of the standard 2D monolayer stiff environment in a petri dish. This technique allows scientists to develop models based on human cells for a more accurate disease model to minimise animal testing.
Following 3D cell culture, patient-derived organoids are 3D structures generated from patient tissues. Organoids have opened avenues for personalised medicine in cancer research, mimicking the native tumour environment and characteristics of various primary tumours. A study using patient-derived organoids to identify specific markers for head and neck cancer (Millen et al., 2023) has facilitated head and neck cancer diagnosis. Another study has used organoids to test for bladder cancer therapies to find which treatment has better outcomes (Minoli et al., 2023).
In recent years, a lot of therapeutic research has been conducted on 3D cell cultures and organoid disease models to minimise the use of animal models and reduce the gap between research and clinical applications. The outstanding breakthrough of utilizing various hydrogels and cell lines to physically and chemically mimic the native tissue has brought various successes in medical research. However, various challenges remain, including the complexity of these 3D models and clinical translation. The transformation of these 3D models into complex organ-like structures requires various additional features including the presence of vasculature. Nevertheless, modern preclinical research often combines animal models with 3D models and new computational techniques. Perhaps, in the future, 3D cell culture and organoid-based technologies will be advanced enough to replace animal models!
References
Cover Image:
https://www.viennabiocenter.org/research/key-discoveries/human-brain-organoids/
Ericsson, A. C., Crim, M. J., and Franklin, C. L. (2013), 'A brief history of animal modeling', Mo Med, 110 (3), 201-5.
Russell, W.M.S. and Burch, R.L. (1959) The principles of humane experimental technique. Wheathampstead: Universities Federation For Animal Welfare.
Kim, E., et al. (2023), 'Factors Affecting Success of New Drug Clinical Trials', Ther Innov Regul Sci, 57 (4), 737-50.
Bedard, P., et al. (2020), 'Innovative Human Three-Dimensional Tissue-Engineered Models as an Alternative to Animal Testing', Bioengineering (Basel), 7 (3).
Millen, R. et al. (2023) 'Patient-derived head and neck cancer organoids allow treatment stratification and serve as a tool for biomarker validation and identification,' Med, 4(5), pp. 290-310.e12. https://doi.org/10.1016/j.medj.2023.04.003.
Minoli, M. et al. (2023) 'Abstract 182: Bladder cancer organoids as a functional system to model different disease stages and therapy response,' Cancer Research, 83(7_Supplement), p. 182. https://doi.org/10.1158/1538-7445.am2023-182.
