A Tale of Two Chimeras: Applying the Six Principles to Human Brain Organoid Xenotransplantation

Abstract

Cerebral organoid models in-of-themselves are considered as an alternative to research animal models. But their developmental and biological limitations currently inhibit the probability that organoids can fully replace animal models. Furthermore, these organoid limitations have, somewhat ironically, brought researchers back to the animal model via xenotransplantation, thus creating hybrids and chimeras. In addition to attempting to study and overcome cerebral organoid limitations, transplanting cerebral organoids into animal models brings an opportunity to observe behavioral changes in the animal itself. Traditional animal ethics frameworks, such as the well-known three Rs (reduce, refine, and replace), have previously addressed chimeras and xenotransplantation of tissue. But these frameworks have yet to completely assess the neural-chimeric possibilities. And while the three Rs framework was a historical landmark in animal ethics, there are identifiable gaps in the framework that require attention. The authors propose to utilize an expanded three Rs framework initially developed by David DeGrazia and Tom L. Beauchamp, known as the Six Principles (6Ps). This framework aims to expand upon the three Rs, fill in the gaps, and be a practical means for assessing animal ethical issues like that of neural-chimeras and cerebral organoid xenotransplantation. The scope of this 6Ps application will focus on two separate but recent studies, which were published in 2019 and 2020. First, they consider a study wherein cerebral organoids were grown from donors with Down syndrome and from neurotypical donors. After these organoids were grown and studied, they were then surgically implanted into mouse models to observe the physiological effects and any behavioral change in the chimera. Second, they consider a separate study wherein neurotypical human embryonic stem cell-derived cerebral organoids were grown and transplanted into mouse and macaque models. The aim was to observe if such a transplantation method would contribute to therapies for brain injury or stroke. The authors place both studies under the lens of the 6Ps framework, assess the relevant contexts of each case, and provide relevant normative conclusions. In this way, they demonstrate how the 6Ps could be applied in future cases of neural-chimeras and cerebral organoid xenotransplantation.

Brain organoids and organoid intelligence from ethical, legal, and social points of view

“…This needs to be weighed against animal welfare and rights, and concerns related to the use of nonhuman primates they replace. A framework known as the Six Principles (6Ps) (Beauchamp and DeGrazia, 2020;DeGrazia and Beauchamp, 2021) aims to expand upon the 3Rs and be a practical means for assessing animal ethical issues like neural-chimeras and cerebral organoid xenotransplantation (Barnhart and Dierickx, 2023). In her 2021 thesis "Protecting In Vitro Human Brain Organoids: Why, When, and Which?, " Das (2021) delves into the ethical implications of using human brain organoids in research.…”

The Ethics of Human Brain Organoid Transplantation in Animals

“…Thus, if a broad neural network is necessary to realize consciousness, it is unlikely that conscious brain organoids would be created during the Generation stage. 7 That said, concerns regarding the creation of conscious organoids in vitro are not unrelated to transplantation. Consider the possibility that in vitro non-conscious brain organoids are transplanted into host animals and become conscious in vivo (9).…”

“…For human brain organoid transplantation into animals, the welfare of the host animal must be given due consideration (both now and in the future). A recent study utilized the principles of animal ethics to analyze two cases of human brain organoid transplantation in animals and concluded that such transplantations would be morally inappropriate [7]. 16 It also pointed out that the behavior of chimeric animals has not been sufficiently examined to fully assess their welfare.…”

“…If a nonconscious human brain organoid transplanted into a host brain remains non-conscious (7), there would be no unique ethical concerns about its welfare, moral status, or mental capacities. However, they may mature in vivo and become conscious (9).…”

“…More generally, in a study on the ethical issues surrounding human brain organoid transplantation in animals, H. Isaac Chen and colleagues considered human brain organoid transplantation an example of general neurological chimera research [5]. 1 Similarly, a detailed ethical analysis of two cases of human brain organoid transplantation focused on issues related to chimeric animals produced via the implantation of brain organoids [7]. 2 However, to generate a comprehensive analysis of human brain organoid transplantation in animals, it is necessary to go beyond issues related to chimeric animals and consider the transplanted human brain organoids and their potential moral status.…”