The development of stem cell technology in recent years has transformed biomedical research and clinical care with the introduction of organoids, three-dimensional in vitro tissue culture models grown from pluripotent stem cells (PSCs), adult stem cells (ASCs), or embryonic stem cells (ESCs) [1]. Originally derived from human tissues, organoids have a self-organization mechanism that can spontaneously produce progenies that resemble the complex functionality and physiology of different organs in vivo via cell sorting [2]. Though miniature in size and possessing fewer cell types [3], organoids can be individualized in a superficial manner to architecturally mimic the structures and properties of several specialized organs of the human body at the cellular level [2]. Past research studies have successfully created organoids that resembled the heart, kidney, lung, retina, and thyroid [4,5,6,7,8]; in essence, the possibilities are manifold. In theory, organoids can serve as substitutes for common animal models to mitigate the ethical concerns associated with the latter [2]; moreover, organoids are more accurate models to work with relative to, say, mouse models because organoids are derived from the tissues of human donors, which would produce more effective results when used in applications such as regenerative medicine, drugs screening, and human development and disease modeling [1].
No organoid technology, however, is without ethical flaws of its own; after all, there are serious ethical issues raised as a result of the intimate connection between organoids and the tissue donors from which the stem cells are derived. The present case is reminiscent of HeLa cells, cancerous cells that can reproduce indefinitely but were unethically obtained from its donor, an African American woman named Henrietta Lacks who was diagnosed with cervical cancer [9]. The story of Henrietta Lacks, as portrayed in the biography The Immortal Life of Henrietta Lacks by Rebecca Skloot, scrutinized the critical issue of informed consent (along with other relevant bioethical issues), for Henrietta Lacks was unaware that her cells were taken for purposes that she did not permit before passing away [10]. Likewise, similar novel ethical issues pertaining to organoid technology are called into question and opened to debate. The ethical problems of three distinct subtypes of organoids of interest will be discussed herein in relation to the possible attribution of moral status to these entities: cerebral organoids, gastruloids, and chimeras.
Of all forms of organoids, cerebral organoids are by far the most ethically problematic subtype, as they are derived from neural tissues of the human brain [2]. Yet cerebral organoid models are scientifically and clinically promising in enhancing our understanding of the brain’s relationship with other organs of the body through the integration of various organoids to form a complex known as an ‘assembloid’ [11], as well as understanding the mechanisms that lead to neurodevelopment, neurodegeneration, and neurologic diseases by means of modeling. As a matter of fact, relative to early models that relied on cellular techniques to elucidate the complexity of the brain, cerebral organoids have successfully modeled the pathological pathways that underlie idiopathic autism and virus-induced microcephaly [2], thus shedding light on potential therapeutic strategies and remedies for neurologic disease prevention.
Notwithstanding the auspicious prospects of cerebral organoids, the ability of this in vitro system in conducting action potentials, forming neural networks, and producing oscillatory electroencephalogram (EEG) wave patterns has given rise to one intriguing possibility: the rise of consciousness in the neocortex of the organoid [3]. While the idea of consciousness is not universally conceptualized and is currently open to many physical and non-physical interpretations (e.g., multiple drafts model, integrated information theory, quantum mechanics) [12], it has been hypothesized that cerebral organoids have the capability to mature and thereby become sentient beings that can react to light or experience nociceptive pain; furthermore, higher-order cognitive functions such as working memory, self-awareness, and fine motor control are postulated to be attainable as well; but such claims are also subjected to intense skepticism [2]. However, under the premise that a cerebral organoid does in fact have the ability to spark consciousness within itself and even exhibit pleasure-seeking and pain-avoidant behaviors [13], it follows that moral status must be partially attributed to the organoid [3]. For a given being, to have moral status is to not be harmed but to be respectfully treated for the sake of the being and their best interests [14]. Hence, cerebral organoids may possess as much moral status as a human—if you acknowledge it as a human clone in this sense—or to a lesser extent, a laboratory mouse, only if it is capable of developing cortical activity-induced consciousness and the associated cognitive traits and sensory inputs over a base threshold. Speaking of which, there appears to be a growing interest in creating a test that can objectively assess consciousness in cerebral organoids. Currently, the perturbation complexity index (PCI) has been used as a measure of consciousness in unresponsive patients suffering from brain injuries [15]. Regardless of future research outcomes, the perception surrounding cerebral organoids is constantly changing; therefore, these models are no longer an exploitable biomaterial that can be arbitrarily subjugated to the interest of the individual who is in possession of the cerebral organoid.
Academic critics such as scientists and ethicists, however, have underscored the notion that cerebral organoids do not (and never will) have the capacity for consciousness due to the lack of social interactions in their given environment [2] and the lack of a vascular system and other relevant cell types that are essential to forming brain connectivity, thereby limiting the degree of neural computation, maturation, and functioning [16]. On the other hand, some members of the public think otherwise, arguing that cerebral organoids can have conscious experiences nevertheless without being faithful to the real human brain [3]. It is also worth noting that misunderstandings of organoid technology are surfacing as a result of false media portrayals [2]. While there are no definitive answers yet to address the fears and worries of organoids until further advances in stem cell biology are made, the problem of cerebral organoids, though, concerns itself around the ethics of this technology given the presumption that moral status is attributed. Under the condition that consciousness does reside within an organoid even after divorcing from its human of origin, are tissue donors able to withdraw their consent [2]? Who has the rightful ownership over the created organoids [2]? Such questions bring up the need for practical models of informed consent, considering that in some cases, donors may develop close ties with their respective cerebral organoids because of a shared identity that is genetically linked; this also implies the risk of privacy invasion [2]. Moreover, is it ethical to genetically manipulate cerebral organoids by means of activating suicide genes that would instigate programmed cell death or expressing specific genes (e.g., MIXL1) that would alter the fate of certain cells to prevent the neural processes that are required for consciousness, despite the underlying possibility? Again, it is difficult to give definitive answers without the necessary methods that can reliably detect consciousness, or lack thereof.
A conflict in interest also occurs when the donor’s intention is for the researcher to utilize the cerebral organoid for the welfare of others, but external third parties can purchase the organoid from companies who have property rights over the cerebral organoid (if it becomes a patent) and thus receive profits [2] while the donor is most likely not compensated or reimbursed in any form. The commercialization of organoids, in general, becomes more ethically challenging when the party who wishes to buy the organoid is the donor him or herself acting as a patient, because patient-derived, organ-specific organoids can be used as effective models in personalized medicine to help treat the patient and others with the same disease and genetic similarities [2]. Thus, this suggests that patients will become dependent on the companies who can either grant or refuse them access to the organoid, though the latter may lead to public distrust in such companies [2]. In reflection, how much oversight and protection should be granted to cerebral organoids by research ethics review boards and legislation [2]? While the attribution of moral status to cerebral organoids is still under deliberation, the possibility of consciousness should not be neglected even if it is far from fruition when estimating the value of this technology and weighing its benefits with the risks and uncertainties.
In addition to the discussion on cerebral organoids, another subtype of organoids is gastruloids [2], which follow the same bioengineering protocols as cerebral organoids. What distinguishes these two entities is that in lieu of recapitulating the entire human organ, gastruloids mimic the developmental process that is reminiscent of human embryos in vitro [2]. Structurally, gastruloids are similar to human embryos in that the formation of the primitive streak and cells that are intrinsic to the three germ layers are indeed present in these bioartificial gastruloids [17]. Serving as an alternative to mammalian embryonic models [18], in vitro gastruloids models offer insights into the early evolutionary development of human embryos with contrasts to other animal species, as well as enlighten our understanding of disorders that are linked to pregnancy loss during the first trimester [17].
The structural similarities of gastruloids with human embryos signify a paramount notion that was applied to cerebral organoids: the potential to have moral status [2]. What constitutes an embryo is still a question that is without clear answers; however, it is well-established that specifically 14 days [16] is the time span for a cultured embryo to undergo gastrulation—the process by which an embryo develops multidimensional structures from a one-dimensional layer [19]—and reach maturity to eventually become a developing fetus. For gastruloids, it may take less than 14 days to mature [17] and thus the attribution of moral status becomes controversial, and comparable to cerebral organoids, the ethical challenge that must be overcome is justifying the act of preventing gastruloids from becoming a living being through gene knockout so that the expression of the gene sequence that is essential for complete embryonic development is stopped, or in the instance of discarding gastruloids [2]—either of which eliminates the possibility for gastruloids to acquire or maintain life. In principle, the usage of human embryos in research is strongly discouraged or even prohibited in certain jurisdictions, but the moral concern of PSC-, ASC-, or ESC-derived gastruloids that are also found in cerebral organoids complicate their usage in the absence of clear ethical and legal frameworks in regulating the extent of gastruloids’ maturation [17].
One additional area of organoid research that is in need of ethical consideration is the farming of interspecies chimeras, living organisms that are created from the combination of cells from two or more species of different origins; for example, the combination of human cells with that of porcine cells to form a human-pig chimera [20]. Chimeras are useful in various aspects of medicine, notably in surgical practices, as they provide a solution to the apparent undersupply of transplantable organs for surgeries. One example includes implanting equine-derived heart values into patients with dysfunctional cardiac valves [21]. Even though organ transplants may cause fears over the unpredictability of zoonotic diseases or xenogeneic organ rejections, gene editing technology (e.g., CRISPR/Cas9) can potentially silence the exact animal genes that are causing such problems [20]. While ethical guidelines for chimerism vary from place to place [21], high concentrations of neurons that can be injected into a mouse brain to create neurological chimeras [22], for instance, have already prompted recommendations to limit the quantity of stem cells that can be derived from a human [2].
The farming of human-animal chimeras in vitro in which an animal come to possess human organs, moreover, creates an issue of humanizing chimeric animals, as it involves transplanting human-derived organoids into the body of the recipient animal, giving that animal human-like capacities such as consciousness. This overwhelming possibility is demonstrated through implanting cerebral organoids into the central nervous system (CNS) of a host animal (e.g., a mouse), in which the CNS of the host animal have come to exhibit characteristics such as increased size, vascularization, and a vast differentiation of neuronal and non-neuronal cells, thereby offering a more representative model of the human brain [2]. Nevertheless, in certain cases, chimeric animals can become vulnerable to human viruses when human cells are introduced to their biological systems [21], which, again, raises the ambiguous question of whether the chimera bears some level of moral status or not [2], along with other nuanced ethical challenges which pertained to cerebral organoids and gastruloids, considering the fact that consciousness is not uniquely a human characteristic [22]. Another way of humanizing chimeric animals is through implanting human gonadal organoids which would result in the production of human gametes that are capable of reproduction, thereby creating human embryos [21]. The moral concern, in this case, lies in the potentiality of cross-species breeding and reproduction to form hybrid embryos [21]. And while the possibility for chimeras to have human-like characteristics is not believed to be plausible such as in the case of consciousness [21], recent studies have shown that in the microenvironment of a mouse, glial progenitor cells that were derived from a human were more competitive than the mouse glial progenitor cells in composing white matter [23]. Therefore, in terms of applications, the advantages and disadvantages of humanizing animals and animalizing humans should be closely monitored with respect to moral permissibility when crossing the boundary between humans and animals.
Upon factoring in the ethics of organoid technology, the general consensus on the moral status of cerebral organoids, gastruloids, and chimeras in both research and clinical settings is pending. It is a decision that cannot be ill-considered, though the ethical challenges of such advanced stem cell technology and its potential development in the near future should be taken into current views for constructing the appropriate framework for organoid usage. Ultimately, it is the moral responsibility of all parties involved to address the given challenges, for the solutions are heavily connected to the fundamental philosophical question of what it truly means to be human.
References
Azar, J., Bahmad, H. F., Daher, D., Moubarak, M. M., Hadadeh, O., Monzer, A., ... & Abou-Kheir, W. (2021). The use of stem cell-derived organoids in disease modeling: an update. International Journal of Molecular Sciences, 22(14), 7667.
de Jongh, D., Massey, E. K., & Bunnik, E. M. (2022). Organoids: a systematic review of ethical issues. Stem Cell Research & Therapy, 13(1), 1-21.
Jeziorski, J., Brandt, R., Evans, J. H., Campana, W., Kalichman, M., Thompson, E., ... & Muotri, A. R. (2022, March). Brain organoids, consciousness, ethics and moral status. In Seminars in Cell & Developmental Biology. Academic Press.
Voges, H. K., Mills, R. J., Elliott, D. A., Parton, R. G., Porrello, E. R., & Hudson, J. E. (2017). Development of a human cardiac organoid injury model reveals innate regenerative potential. Development, 144(6), 1118-1127.
Xia, Y., Nivet, E., Sancho-Martinez, I., Gallegos, T., Suzuki, K., Okamura, D., ... & Belmonte, J. C. I. (2013). Directed differentiation of human pluripotent cells to ureteric bud kidney progenitor-like cells. Nature cell biology, 15(12), 1507-1515.
Wilkinson, D. C., Alva-Ornelas, J. A., Sucre, J. M., Vijayaraj, P., Durra, A., Richardson, W., ... & Gomperts, B. N. (2017). Development of a three-dimensional bioengineering technology to generate lung tissue for personalized disease modeling. Stem cells translational medicine, 6(2), 622-633.
Eiraku, M., Takata, N., Ishibashi, H., Kawada, M., Sakakura, E., Okuda, S., ... & Sasai, Y. (2011). Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature, 472(7341), 51-56.
Antonica, F., Kasprzyk, D. F., Opitz, R., Iacovino, M., Liao, X. H., Dumitrescu, A. M., ... & Costagliola, S. (2012). Generation of functional thyroid from embryonic stem cells. Nature, 491(7422), 66-71.
Skloot, R. (2017). The immortal life of Henrietta Lacks. Broadway Paperbacks.
Beskow, L. M. (2016). Lessons from HeLa cells: the ethics and policy of biospecimens. Annual review of genomics and human genetics, 17, 395.
Kanton, S., & Paşca, S. P. (2022). Human assembloids. Development, 149(20), dev201120.
Van Gulick, R. (2014, January 14). Consciousness. Stanford Encyclopedia of Philosophy. Retrieved January 15, 2023, from https://plato.stanford.edu/entries/consciousness/#RepThe
Cohon, R. (2018, August 20). Hume's Moral Philosophy. Stanford Encyclopedia of Philosophy. Retrieved February 2, 2023, from https://plato.stanford.edu/archives/fall2018/entries/hume-moral/
DeGrazia, D., & Millum, J. (2021). A Theory of Bioethics. Cambridge University Press.
Sinitsyn, D. O., Poydasheva, A. G., Bakulin, I. S., Legostaeva, L. A., Iazeva, E. G., Sergeev, D. V., ... & Piradov, M. A. (2020). Detecting the potential for consciousness in unresponsive patients using the perturbational complexity index. Brain sciences, 10(12), 917.
National Academies of Sciences, Engineering, and Medicine; Policy and Global Affairs; Committee on Science, Technology, and Law; Committee on Ethical, Legal, and Regulatory Issues Associated with Neural Chimeras and Organoids. (2021). The emerging field of human neural organoids, transplants, and chimeras: Science, ethics, and governance. National Academies Press.
Munsie, M., Hyun, I., & Sugarman, J. (2017). Ethical issues in human organoid and gastruloid research. Development, 144(6), 942-945.
Rossi, G., Giger, S., Hübscher, T., & Lutolf, M. P. (2022). Gastruloids as in vitro models of embryonic blood development with spatial and temporal resolution. Scientific Reports, 12(1), 1-12.
Muhr, J., & Ackerman, K. M. (2020). Embryology, gastrulation. StatPearls Publishing.
Koplin, J., & Wilkinson, D. (2019). Moral uncertainty and the farming of human-pig chimeras. Journal of Medical Ethics, 45(7), 440-446.
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 research & therapy, 7(1), 1-7.
Hyun, I. (2019). Ethical considerations for human–animal neurological chimera research: mouse models and beyond. The EMBO Journal, 38(21), e103331.
Windrem, M. S., Schanz, S. J., Morrow, C., Munir, J., Chandler-Militello, D., Wang, S., & Goldman, S. A. (2014). A competitive advantage by neonatally engrafted human glial progenitors yields mice whose brains are chimeric for human glia. Journal of Neuroscience, 34(48), 16153-16161.