By Easha Vigneswaran
Chimeras are organisms that are composed of two distinct interspecific cell types and since their initial discovery they have forever changed the medical world. Providing a solution for the time-old issue of organ availability for transplantation, chimeras allow scientists to synthesise organs in an animal model that can then be inserted into humans. However, as with all animal-related experimentation technologies, there are numerous ethical concerns that must be considered in the debate to justify such techniques.
The technique of generating a chimera works by the fusion of two animal embryos, where each has been slightly altered to allow the two to become compatible. One of most common chimeras is the human-pig embryo used to grow human organs in a pig. Using CRISPR-Cas9 technology, the genes to develop certain organs are knocked out of the pig embryo. Human stem cells (specifically iPSCs) are then injected into this embryo which is then implanted into a pig. The injected iPSCs from the human embryos can then develop into the organs that are ‘missing’ from the pig embryo ultimately allowing for the formation of functional human organs inside the pig (Koplin & Wilkinson, 2019).
The use of chimeric organisms is nothing new for the scientific world, with rat-mouse chimeras being some of the first model organisms to be used. However, the true ethical concerns lie in crossing the human-animal species barrier (Bourret et al., 2016). The ultimate benefit for using human-animal chimeric models is the immense research potential. It is often very difficult to study virus pathogenesis in animals due to our distinct immune systems. However, production of lymphoid tissue in animal models could further our medical understanding about immunology (Porsdam Mann et al., 2019).
One of the major concerns with interspecific chimeras is that the research surrounding them is quite recent. The understanding of the technology for chimeric organ culture is relatively new therefore it is understandable as to why people are dubious towards the feasibility and safety of such techniques. A further issue with the technology is that often the probability of producing viable chimeric embryos is quite low. It is often quite difficult to predict if and how the embryo develops. In most trials, only about 25% of the injected embryos developed into chimeric organisms (Wu et al., 2017). Researchers have also found that even if the embryos do end up being viable, they often end up uncontrollably developing into tumours that have the potential of becoming cancerous (Kroon et al., 2008).
Over the years many questions have arisen as to how one can justify the production of human organs in animal hosts. The experimentation on pigs for human organ production is a process that is strictly controlled. This high level of regulation is maintained to ensure animals are not suffering and that they are properly cared for. In addition to this, many also argue that this sort of experimentation should face no more ethical backlash than what animal consumption does (Bourret et al., 2016). Ultimately both consumption and experimentation for organ culture on animals are both used for human gain at the expense of the animal. Therefore, is it completely justified to suggest one is any more ethical than the other?
Some of the ethical concerns over chimera produced organs specifically is surrounding specific organs. Amongst scientists, there are many questions concerning how chimeric brain development is controlled. Many medical ethics councils believe the restriction on brain chimera research needs to be more tightly regulated. The key issue raised concerns the potential of such non-human animals developing a human like consciousness. Henceforth, some scientists go as far to say research in this field should be prohibited in its entirety to eliminate any possible developments (Koplin & Wilkinson, 2019).
In fact, it is not just specific organs that scientists are cautious about developing with these techniques but also in what organisms. Recently the scientific world was met with a huge breakthrough following the successful production of a human-monkey chimeric embryos (Tan et al., 2021). Up until now, most chimeric research occurred in non-primate organisms however many scientists believe human-monkey chimeras could act as the ‘holy-grail’ model to study human disease response (De Los Angeles et al., 2019). However, with the close evolutionary relationship between humans and primates it is impossible to ignore the questions surrounding cognitive similarities between humans and these chimeric organisms. Some scientists argue that the sheer moral ambiguity on these topics is a string enough to justify the slowing down/halting of further advancements within the field until proper legislation is introduced (Koplin & Savulescu, 2019).
To conclude, the generation of chimeric human-nonhuman organisms show vast amounts of potential to revolutionize human organ treatments. The feasibility of such techniques does however face many barriers. Besides the obvious costs associated with these experiments, the ethical issues surrounding chimeras are likely the key barrier to its success. Until a universal international approach is agreed toward the legislation of chimeric embryos, it highly unlikely the scientific world will be met with live-born human-nonhuman embryos any time soon.
References:
Koplin J, Wilkinson D (2019) Moral uncertainty and the farming of human-pig chimeras
Journal of Medical Ethics. 45:440-446. Available from: https://jme.bmj.com/content/45/7/440.
Bourret, R., Martinez, E., Vialla, F., Giquel, C., Thonnat-Marin, A., De Vos, J (2016) Human–animal chimeras: ethical issues about farming chimeric animals bearing human organs. Stem Cell Res Ther 7, 87. https://doi.org/10.1186/s13287-016-0345-9
Porsdam Mann, S., Sun, R. & Hermerén, G (2019) A framework for the ethical assessment of chimeric animal research involving human neural tissue. BMC Med Ethics 20, 10. Available from: https://doi.org/10.1186/s12910-019-0345-2.
Wu J, Platero-Luengo A, Sakurai M, Sugawara A, Gil MA, Yamauchi T, Suzuki K, Bogliotti YS, Cuello C, Morales Valencia M, Okumura D, Luo J, Vilariño M, Parrilla I, Soto DA, Martinez CA, Hishida T, Sánchez-Bautista S, Martinez-Martinez ML, Wang H, Nohalez A, Aizawa E, Martinez-Redondo P, Ocampo A, Reddy P, Roca J, Maga EA, Esteban CR, Berggren WT, Nuñez Delicado E, Lajara J, Guillen I, Guillen P, Campistol JM, Martinez EA, Ross PJ, Izpisua Belmonte JC. (2017) Interspecies Chimerism with Mammalian Pluripotent Stem Cells. Cell. 168(3), 473–486.e15. https://doi.org/10.1016/j.cell.2016.12.036
Kroon, E., Martinson, L. A., Kadoya, K., Bang, A. G., Kelly, O. G., Eliazer, S., Young, H., Richardson, M., Smart, N. G., Cunningham, J., Agulnick, A. D., D’Amour, K. A., Carpenter, M. K., & Baetge, E. E. (2008). Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nature biotechnology. 26(4), 443–452. https://doi.org/10.1038/nbt1393
Tan, T., Wu, J., Chenyang, Si., Ji, W., Niu, Y., Belmonte, J.C.I. (2021) Chimeric contribution of human extended pluripotent stem cells to monkey embryos ex vivo. Cell. 184(8), 2020-2032. Doi: https://doi.org/10.1016/j.cell.2020.03.020
De Los Angeles, A., Hyun, I., Latham, S. R., Elsworth, J. D., & Redmond, D. E., Jr (2019). Human-Monkey Chimeras for Modeling Human Disease: Opportunities and Challenges. Methods in molecular biology (Clifton, N.J.), 2005, 221–231. https://doi.org/10.1007/978-1-4939-9524-0_15
Julian J Koplin, Julian Savulescu (2019) Time to rethink the law on part-human chimeras. Journal of Law and the Biosciences. 6(1), 37–50, https://doi.org/10.1093/jlb/lsz005
Imperial Bioscience Review 