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.
摘要：
脑类器官模型本身被认为是研究动物模型的替代方案。但是它们的发育和生物学限制目前抑制了类器官完全取代动物模型的可能性。此外，这些类器官的限制，有点讽刺的是,通过异种移植将研究人员带回动物模型，从而产生杂种和嵌合体。除了试图研究和克服大脑类器官的局限性，将大脑类器官移植到动物模型中，为观察动物本身的行为变化提供了机会。传统的动物伦理框架，例如众所周知的三个Rs(减少，精炼,并替换)，以前已经解决了组织的嵌合体和异种移植。但是这些框架尚未完全评估神经嵌合的可能性。虽然三个Rs框架是动物伦理学的历史里程碑，框架中存在可识别的差距，需要注意。作者建议利用最初由DavidDeGrazia和TomL.Beauchamp开发的扩展的三Rs框架，被称为六项原则（6Ps）。这个框架旨在扩大三个卢比，填补空白，并成为评估动物伦理问题的实用手段，例如神经嵌合体和大脑类器官异种移植。这个6Ps应用程序的范围将集中在两个独立但最近的研究，分别于2019年和2020年发布。首先,他们考虑了一项研究，其中大脑类器官是从唐氏综合征的供体和神经典型供体中生长的。在这些类器官生长和研究之后，然后将它们手术植入小鼠模型，以观察嵌合体的生理效应和任何行为变化。第二,他们考虑了一项单独的研究，其中神经典型的人类胚胎干细胞来源的脑类器官生长并移植到小鼠和猕猴模型中。目的是观察这种移植方法是否有助于脑损伤或中风的治疗。作者将这两项研究置于6Ps框架下，评估每个案例的相关背景，并提供相关的规范性结论。这样,他们展示了如何将6Ps应用于未来的神经嵌合体和脑器官异种移植。
