What are the alternatives to using mice and other animals in scientific research?
Image credit: Pogrebnoj Alexandroff
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Computer (in silico) modeling
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Research using human volunteers
The Digital Twin concept
Alber M, Buganza Tepole A, Cannon WR, et al. Integrating machine learning and multiscale modeling-perspectives, challenges, and opportunities in the biological, biomedical, and behavioral sciences. NPJ Digit Med. 2019;2:115. Published 2019 Nov 25. doi:10.1038/s41746-019-0193-y
Bruynseels K, Santoni de Sio F, van den Hoven J. Digital Twins in Health Care: Ethical Implications of an Emerging Engineering Paradigm. Front Genet. 2018;9:31. Published 2018 Feb 13. doi:10.3389/fgene.2018.00031
What about the ethical considerations?
Speciesism is behind animal experimentation
Why animal models are necessary (so far)
- Organ and Tissue Morphology: While the anatomical and histological basis of a lot of our tissues is relatively similar to that of the mouse, there are some major differences that have to be accounted for. A more similar animal model should reduce these differences as much as possible. To give an example, research focused on the retina has a major hurdle when working with mice: Their retina has a different composition than ours because they are night dwellers, while we live during the day. For this, while the composition of our photoreceptors is relatively similar, the structure of our retinas is very different. Humans have a macula (area with a high concentration of cones) and a lower frequency of rods, while mice have no macula and a very high frequency of rods. Something similar happens to the overall structure of the eye: the mouse eye has a very big lens for its size, and its small size only allows for injection of small volumes (1-3uL), while the human eye has a comparatively smaller lens and can receive injection volumes up to 300uL. This means that only on a large animal model we will be able to perform a surgery that is similar to what we want to perform on patients. For these reasons, for preclinical studies the dog, cat, pig and monkey eyes, which greatly resemble the human eye from an anatomical and histological standpoint, are used.
- Immune System: The mouse immune system is very rudimentary when compared to that of higher primates. That's why a lot of preclinical studies where the immune system is relevant (like gene therapy with viral vectors, for example) are made with monkeys, in order to better predict the potential immune reactions. An example is the development of anti-AAV and anti-transgene antibodies found in patients of gene therapy. These were not found in most experiments in mice because their immune system doesn't develop them. However, non-human primate models develop a response that is more similar to that found in the patients involved in the first clinical trials. Even so, even non-human primates may not be a good enough model to predict all the immune responses that are found in patients.
- Neuroanatomy and behavior: Different animals have evolved to follow different survival strategies and their brains reflect that. Small rodents have a neuroanatomy and behavior that cannot be compared to that of humans. Larger animals are more comparable to us in both neuroanatomy and behavior and thus a better model for translational applications.
- Biodistribution: That is possibly the most important point of all. A body that is most similar to ours in its overall conformation (shape, size, complexity, organ functions and even cell receptors) will be a better model for biodistribution of a drug after we deliver it. We can see where and how the drug goes and what effects it has, and that gives us a clear idea of what we can expect in humans.
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Making humans in the lab on microchips?
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3D hair follicle models
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Castro AR, Logarinho E. Tissue engineering strategies for human hair follicle regeneration: How far from a hairy goal? Stem Cells Transl Med. 2020 Mar;9(3):342-350. doi: 10.1002/sctm.19-0301. Epub 2019 Dec 26. PMID: 31876379; PMCID: PMC7031632.