Dynamic models of human development and concepts of the individual

Stem cells can be coaxed to self-organize into dynamic models of human development and early embryo formation. Despite their scientific promise, might widespread use of these technologies alter people's beliefs about what it means to be a human individual? Attention to some important philosophical distinctions may help navigate our thinking. Stem cells can be coaxed to self-organize into dynamic models of human development and early embryo formation. Despite their scientific promise, might widespread use of these technologies alter people's beliefs about what it means to be a human individual? Attention to some important philosophical distinctions may help navigate our thinking. Over the past few years, innovative stem-cell-based technologies have led to the creation of powerful new tools for scientific discovery. In particular, novel methods have emerged for modeling human development in real time, revealing biological processes that were previously hidden or far less accessible. Broadly, these approaches recapitulate aspects of human development important to us all, be it the holistic modeling of weeks-old human embryos in cell culture systems, in vitro recreations of how vital organs like the brain first form, or the generation of stem-cell-based chimeric animals to study the growth of humanized regions in the brains of host animals. Despite their rapid progress and potential to extend to applications outside developmental biology—or perhaps precisely for these reasons—it is appropriate to ask what impact these modeling technologies could have on our understanding of ourselves beyond the scientific aims of these experiments. For many people, these investigations strike at the core of who we are and how we came to be. By reconstructing how our body plans first sprang into existence or by remaking the structural origins of our complex brains, researchers can use these models to repeatedly probe the enigmatic biological foundations of our sense of self. These foundations include not just the orchestrated patterning of our bodies as the human form first arises, but also the self-organization of the brain itself, the physical seat of all our thoughts, feelings, and consciousness. Paradoxically, in the process of illuminating these biological mysteries, human stem-cell-based modeling could recast much of what we take to be special about ourselves as simply a reproducible series of physical events. What does it mean for individuality, for example, if the early embryonic history of each cell line donor can be replayed again and again through the artificial generation of identical human embryo models? Observers may shrug off these concerns as mere philosophical handwringing in the face of technological progress. It is indeed easy to see why there is much scientific enthusiasm around these advances. By leveraging the pluripotent properties of embryonic stem cells—or, more commonly, donors' somatic cells that have been reprogrammed into induced pluripotent stem (iPS) cells—researchers can produce many valuable types of models. First, when packed closely together in three-dimensional (3D) cell culture systems, pluripotent stem cells can be coaxed to self-organize into complex models of early human embryos representing either pre-implantation or post-implantation stages.1Yu L. Wei Y. Duan J. Schmitz D.A. Sakurai M. Wang L. Wang K. Zhao S. Hon G.C. Wu J. Blastocyst-like structures generated from human pluripotent stem cells.Nature. 2021; 591: 620-626Crossref PubMed Scopus (272) Google Scholar,2Weatherbee B.A.T. Gantner C.W. Iwamoto-Stohl L.K. Daza R.M. Hamazaki N. Shendure J. Zernicka-Goetz M. Pluripotent stem cell-derived model of the post-implantation human embryo.Nature. 2023; 622: 584-593Crossref PubMed Scopus (66) Google Scholar These embryo models could be studied in vitro to glean insights into the beginnings of human development, including the causes of developmental defects and early pregnancy loss. Embryo models could also be generated in large numbers for drug screening to promote safer pregnancies. Second, pluripotent stem cells can recapitulate the development of specific organs by self-organizing into organoids—i.e., small stem-cell-derived 3D models that mimic the basic functions of various organs, such as liver, kidney, lung, brain, and many others.3Simian M. Bissell M.J. Organoids: a historical perspective of thinking in three dimensions.J. Cell Biol. 2017; 216: 31-40Crossref PubMed Scopus (419) Google Scholar Organoids can be used to study the self-organization of human organs and tissues, to promote effective drug development, and to advance safety testing prior to clinical trials. This last use case has been identified as a worthwhile alternative method of preclinical inquiry by the National Institutes of Health. Third, organoids can make it easier to conduct stem-cell-based human-to-nonhuman chimeric studies, especially regarding the central nervous system, where stem cell research has had very little success in producing meaningful human-to-nonhuman biological integration. For example, a team at Stanford University recently succeeded in transplanting healthy and psychiatric-disease-specific human brain organoids into the brains of neonatal rats, resulting in basic physiological integration and cell circuitry readouts.4Revah O. Gore F. Kelley K.W. Andersen J. Sakai N. Chen X. Li M.Y. Birey F. Yang X. Saw N.L. et al.Maturation and circuit integration of transplanted human cortical organoids.Nature. 2022; 610: 319-326Crossref PubMed Scopus (133) Google Scholar Several months post-transplant, the human brain organoids expanded to occupy about one-third of each rat's brain hemisphere. This chimera study showed that transplanted brain organoids can not only survive and proliferate in a foreign neural environment but also reveal the physiology of human disease-specific neurons and their circuit-level differences in a living animal host. In light of the many scientific benefits to be had by modeling early human development and brain physiology and function, it would be prudent to consider the possible downsides. Might there be any unanticipated social consequences of heading in these scientific directions? Much has been written about the ethics of human embryo modeling, brain organoids, and human/nonhuman chimera research. These issues have included discussions about donors' autonomy rights over the generation of pluripotent cell lines and their use as well as concerns about human-like self-awareness arising in brain organoids and neurological chimeras. Rather than surveying these familiar debates, I wish to draw attention to an underexplored general concern that seems to operate at an inchoate level of people's awareness. Stem cell research oversight committees sometimes wrestle with this concern during protocol review meetings. Versions of this concern are alluded to by researchers asking for benchside ethics consultations and by science journal editors seeking ethics reviews of manuscripts on human stem-cell-based modeling. It is also raised by science reporters whenever breakthroughs of the kind described above are broadcast to the general public. Basically, the concern is this: while these new technologies are poised to disrupt developmental biology and biomedical science in many fruitful ways, might their widespread use also alter individuals' beliefs about themselves? This sort of query is not new. As we have already seen since the development and prevalent use of technologies that can easily decode our DNA, people across many segments of society have come to embrace a reductionist tendency to equate "who they are" with their genes. Perhaps there are reasons to be wary of a similar seismic shift in thinking as we stare down the next round of scientific possibilities afforded by human biological modeling. Could these new technologies change our view of ourselves? What is the concept of an individual, and what do these new technologies mean for this concept? Questions like these do not fall under the remits of Institutional Review Boards (IRBs) and Institutional Animal Care and Use Committees (IACUCs). In fact, IRB members are specifically instructed in their training not to consider whether research projects might change how people view the world. Furthermore, stem cell and embryo research oversight committees, while not held to this same stricture as IRBs, still may struggle to articulate and address these concerns when they lack a clear conceptual framework to organize their intuitions. These big questions are worthy of consideration; nevertheless, they remain quite hazy. Perhaps the following distinctions could help cut through the fog. First, the term "individual" itself needs to be unpacked. Here the distinction between "biological individuals" on the one hand and "persons" on the other may be useful. Following a Western philosophical tradition in secular ethics, we can say that individuals in the strict biological sense are not the same as persons. In calling something a biological individual, we can refer to many things—a single human being, a single animal, or even a single lab-generated entity such as an embryo model, an organoid, or a chimera. All that is needed to be called a biological individual is to be a single member of a class. Thus, one can add up the number of individuals in a study and express that number in terms like N = 1,000 whether one is referring to the number of cardiac patients in a clinical trial, liver organoids in a drug toxicity assay, or even legally dead organ donors in a transplantation network. From these examples, it should be clear that not all individuals are persons. Persons are a special type of individual. In the Western philosophical tradition, individuals are classified as persons only when they presently possess the ability to make rational decisions and when they act thoughtfully on desires they can endorse on a higher cognitive level of self-reflection (Figure 1).5Frankfurt H.G. Freedom of the will and the concept of a person.J. Philos. 1971; 68: 5-20Crossref Google Scholar,6Hyun I. Authentic values and individual autonomy.J. Value Inq. 2001; 35: 195-208Crossref Scopus (20) Google Scholar For this reason, severely brain-injured adults with permanent loss of consciousness are no longer considered persons in biomedical ethics, even though they may persist as biological individuals in intensive care units. Their functioning bodies remain, but their personhood is no more. On issues concerning the beginning and the end of life, what seems to matter most is the waxing and waning of human consciousness. To the best of our knowledge, it is our brains that enable our experiences, memories, agency, and all the other mental properties that go into forming our sense of identity, distinct from other forms of animal life and distinctive from one another. Thus, it makes sense why we place so much value on the status of the physical brain as a surrogate indicator for personhood in general and for our specific sense of self in particular. Indeed, the brain is so important for personhood and the self that the prospect of a severe and irreversible brain injury casts doubt as to whether the "same person" persists post-injury even if the body survives. Catastrophic injuries to other vital organs do not raise the same concerns about whether a person's identity will survive the injury or an organ transplant. That there is a strong link in secular ethics between personhood and the brain cannot be overstated. While most human biological individuals have functioning brains to support consciousness, not all do. This is a point almost too obvious to bother making, but it must be kept at the forefront of the issues we are dealing with here. It is easy to conflate the concept of a biological individual with the concept of a person, especially when it comes to the ethical discourse around early human development. For example, the UK's Warnock Committee in 1984 famously set the time limit for human embryo research at 14 consecutive days post-fertilization in vitro.7Department of Health & Social SecurityReport of the committee of inquiry into human fertilization and embryology.https://wellcomecollection.org/works/pxgeeqnf/items?canvas=3Date: 1984Google Scholar For some ethicists and religious thinkers, this limit was appealing because 14 days roughly marks the time at which primitive streak formation is initiated in the developing embryo. During this developmental stage of gastrulation, the embryo's potential to divide spontaneously into twins is halted, thereby assuring its ontological status as a biological individual.8Hulbut J.B. Hyun I. Levine A.D. Lovell-Badge R. Lunshof J.E. Matthews K.R.W. Mills P. Murdoch A. Pera M.F. Scott C.T. et al.Revisiting the Warnock rule.Nat. Biotechnol. 2017; 35: 1029-1042Crossref Scopus (43) Google Scholar However, further thought on this issue exposes the problem that there is nothing uniquely human about an embryo's primitive streak formation and subsequent biological individuation. All animals with a backbone undergo primitive streak formation and individuation early in their development. It is not biological individuation per se that matters for human embryo advocates; rather, it is the unstated presumption that a single human embryo will, under the normal circumstances of pregnancy, become an infant that will subsequently become a person if all necessary developmental and social conditions align. For human embryo advocates, the ethical importance they place on embryonic individuation seems be derived from the implicit ethical importance of personhood, whether they realize this or not. This is why most people are not as concerned about the use of mouse and other animal embryos for research as they are about the use of human embryos, even if human and nonhuman embryos are studied at the exact same developmental stages. One further related point: while a biological individual's potential for personhood is certainly of great importance from a secular ethics point of view, the notion of potentiality itself must be understood in terms of yet another important distinction. Whether it is at the beginning of life for natural embryos in vitro and their embryo-like lab counterparts or at the end of life for people with severe brain injuries, full potentiality for personhood is not rooted in just one type of trajectory. Rather, full potentiality is the confluence of at least two vectors: (1) biological potential in the quasi-Aristotelian sense of an individual's innate ability to actualize its physical potential and (2) circumstantial potential outside of the individual grounded in other people's social choices and technological support. Personhood needs both types of potential in place to become actualized. Ex corporeal embryos, for example, must not only be genetically and morphologically robust to have a biological chance at becoming a human person, but just as crucially, they must also be chosen—normally by those for whom they were created—to be implanted into a uterus and carried to term. Likewise for patients at the end of life, not only must they have the biological potential for their brains to recover functioning, but they must also be cared for in a hospital setting by decision-makers who have the right technologies at their disposal. Without the vectors of biology and circumstance coming together, potentiality would be little more than a wish for hypotheticals to materialize. With the distinction between biological individuals and persons in hand and the complexities of full potentiality in mind, one can start to tease apart what may truly lie beneath people's concerns outlined above. Since the cognitive bar is set so high for personhood, it seems premature to worry about whether brain organoids, neurological chimeras, or embryo models deserve the ethical protections normally afforded to persons. The science is simply not there to support these concerns now and would have to depend on major technical innovations to get there in the future. Not even the most extreme forms of human-to-nonhuman neurological chimerism one could imagine would support fears about personhood emerging in acutely altered animals. This is because any brain, whether partially or fully human, must be nurtured through social interactions with caregivers for years before it can produce higher-order self-awareness in an individual.9Hyun I. From naïve pluripotency to chimeras: a new ethical challenge?.Development. 2015; 142: 6-8Crossref PubMed Scopus (24) Google Scholar Given all that personhood requires, especially the socially enabled environments necessary to support its realization, researchers should be able to work with dynamic models of human development without undermining how we view ourselves as persons. This is because for the foreseeable future, stem-cell-based models of human development have very little to do with the concept of a person. This does not mean there is nothing left to ethically consider when contemplating the use of dynamic models of human development. What we should be asking instead of the personhood question is when it would be appropriate to be concerned about what happens to nonperson biological individuals. A reasonable answer to this question is if and when they are likely to become sentient. Sentience can be understood as the actualized ability to have sensory experiences like pleasure and pain.10Broom D.M. Cognitive ability and sentience: Which aquatic animals should be protected?.Dis. Aquat. Organ. 2007; 75: 99-108Crossref PubMed Scopus (114) Google Scholar It is a familiar and widely used basis for ethical consideration. For example, sentience is one of the main ethical grounds for necessitating the proper care and use of research animals. It should be noted that except for neurological chimeras, the science of human developmental modeling involving organoids and embryo models is not at a point where sentience is an issue. Human embryo models are neither complete enough nor anywhere close to mimicking the developmental stages where sentience is believed to arise in human fetuses after 24 gestational weeks. Brain organoids in vitro do not have the architecture, full complement of cell types, or sensory inputs to support the experiences of pain and pleasure. This could change in the far future, but it would first require enabling technologies that have yet to be invented. Nevertheless, this additional distinction between sentient and non-sentient biological individuals can be used to organize our thoughts on whether research involving dynamic models of human development should be ethically scrutinized for the sake of the research entities themselves. In response to the question of whether new technologies for human developmental modeling could destabilize our view of ourselves, the answer is no, not if we remain mindful of the bedrock distinctions between (1) biological individuals and persons, (2) biological and circumstantial potentiality, and (3) sentient and non-sentient biological individuals. Rather than weakening the grounds on which we value human life, perhaps an increased familiarity with developmental models could strengthen our beliefs by reminding us of what really matters—the wellbeing of actual persons and sentient individuals. Indeed, that would be an excellent kind of unanticipated social consequence for human developmental modeling.