Response to the ISSCR guidelines on human–animal chimera research

Abstract The International Society for Stem Cell Research (ISSCR) has recently released the 2021 update of its guidelines. The update includes detailed new recommendations on human–animal chimera research. This paper argues that the ISSCR recommendations fail to address the core ethical concerns raised by neurological chimeras—namely, concerns about moral status. In minimising moral status concerns, the ISSCR both breaks rank with other major reports on human–animal chimera research and rely on controversial claims about the grounds of moral status that many people will rightly reject. A more robust framework for regulating human–animal chimera research still needs to be developed.

Human-animal chimera research is ethically controversial, particularly in the case of experiments where human cells could contribute to animal brains. One core concern is that neurological chimeras could develop enhanced cognitive capacities; this, in turn, could arguably affect the animal's moral status (and thereby whether it is appropriate to use them in research.) Perhaps surprisingly, the ISSCR guidelines do not offer guidance for managing moral status concerns. Instead, they sketch how existing animal research standards such as the Three R's (reduce, refine, replace) can be tailored to human-animal chimeras. This paper argues that the ISSCR's new guidelines fail to address the core ethical concerns raised by neurological chimeras. I first describe how questions of moral status have been addressed in other major reports and bioethical work on human-animal chimeras. Next, I describe the ISSCR's recommendations, focusing particularly on how they fail to address issues of moral status. Finally, I highlight and critique the philosophical basis for the ISSCR's suggestions.
The philosophical assumptions underlying these suggestions have implications that many people would wish to reject. Specifically, they would license not only blanket acceptance of human-animal chimera research but also infanticide and certain forms of child neglect. The ISSCR's assumptions about moral status, therefore, provide unstable ground on which to build global stem cell policy.

| EARLIER RECOMMENDATIONS REGARDING HUMAN-ANIMAL NEUROLOGICAL CHIMERAS
Human-animal neurological chimeras have many exciting potential applications, including for modelling and studying human brain diseases, testing drugs that interact with neural tissue, and potentially in regenerative medicine. Given the potential benefits of such research, there is a moral imperative not to restrict it without good reason. 3 At the same time, the biological 'humanisation' of animal brains raises difficult issues of moral status-issues that many believe do justify limiting certain kinds of chimera experiments. The concern here is that 'humanising' an animal's brain might alter its cognition in ways that affect our moral obligations to that animal. More recently, the U.S. National Academy of Sciences, Engineering, and Medicine (NASEM) released a report on the science, ethics, and governance of certain forms of stem cell research, including human-animal chimera research. The report notes that many capacities thought to be associated with higher moral status are 'located' in the brain, 10 and notes that it is theoretically possible that human-animal neurological chimeras could develop capacities that many people find relevant to moral status and should arguably rule out these animals' use in research. 11 The committee did not offer specific guidance on how such concerns should be managed, since it held that such concerns are unlikely to be realised in the near future.
However, the report emphasises the need for further ethical analysis and ongoing surveillance, and flags that additional oversight and restrictions might become necessary in the future. 12 These restrictions might include designating specific categories of chimera research that should not be conducted.
In the United Kingdom, a 2011 report by the Academy of Medical Sciences discusses similar issues. This report is likewise animated by concerns that 'humanising' animals' brains could enhance their cognitive abilities or create human-like consciousness or behaviour. 13 The report raises special concern about the potential effect of such research on the cognitive abilities of larger animals such as sheep, pigs, and nonhuman primates. If 'neural humanisation' enhances the animal's cognition to a great enough degree-for example, if a human-monkey brain chimera develops similar  Similarly, in the case of human-monkey brain chimeras-an area of chimera research widely thought to raise particularly serious moral status issues-the ISSCR white paper offers only practical advice about handling and housing nonhuman primates. There is guidance on how to manage bite and scratch risks to animal care staff and scientists, reduce animal distress, and minimise distress behaviours (such as self-inflicted wounding) that might complicate the task of assessing the effects of chimerism on the animal. 23 However, there is again no discussion of how the potential development of enhanced cognitive capacities would affect the permissibility of the research.
The second broad category of chimera research addressed in the guidelines is research with chimeric embryos and fetuses. In this case, the ISSCR recommends a specialised scientific and ethics review process if the embryo or fetus is developed in utero. Specific recommendations include that such experiments proceed only if no alternative models are available, that chimeric embryos not be gestated for longer than necessary to achieve the scientific aim, and that researchers attempt to restrict chimerism to specific organ systems. 24 In cases where chimeric animals are brought to term, the ISSCR recommends utilising existing institutional animal research ethics committee oversight, as per its recommendations for postnatal chimeric animals. 25 As described above, these recommendations aim merely to adapt and apply existing animal ethics principles, and therefore do not address worries about moral status enhancement.
The ISSCR White Paper describes its approach as a response to are unlikely to occur. 28 If these troubling applications remain far on the horizon, then perhaps for now a permissive approach is appropriate. Yet as I show below, the ISSCR subcommittee also offers two additional arguments in defence of its permissive approach, and these arguments seem to be consistent with allowing the most ethically troubling forms of chimera research to proceed once they become feasible. In other words, certain strands of argument used by the ISSCR subcommittee (and developed within the bioethical literature on human-animal chimeras that the subcommittee draws heavily from) would seem to commit the ISSCR to a highly permissive approach not just in the present, but also indefinitely into the future. It is these strands of argument that are the focus of this paper.
In short, the 2021 ISSCR Guidelines afford chimeric animals no greater protections than other research animals. This is not to say that chimeric animals would lack protection altogether. They would still be subject to existing principles of animal research ethics, such as the 3Rs. 29 These hold that animal models should be human-animal brain chimeras that can develop highly sophisticated cognitive capacities. Regardless of what one makes about the likelihood of chimeric animals developing such capacities in the next 5-10 years, these two additional (and more fundamental) arguments ought to concern us. Drawing on earlier work by Insoo Hyun (who is also the first author of the white paper), 35 the ISSCR subcommittee gives two reasons to doubt that human-animal chimeras would not develop traits that confer moral status on a par with humans. 36 The first is that sophisticated cognitive capacities and self-consciousness develop in humans only after years of attentive child-rearing. By contrast, chimeric research animals would not be raised under the necessary social and nurturing conditions, and in many cases would not reach full maturity. Second, regardless of the degree to which human cells contribute to a chimeric animal's brain, there will presumably be differences in brain size and structureand even if a fully human brain were to develop, it would be embodied in an animal whose sensory input and motor output systems are very different from those of a normal human. Accordingly, a human brain in the body of (say) a pig or a monkey would not develop a normal human mind.
The following two sections address these two arguments, beginning with the second. First, however, it is worth noting that Insoo Hyun adopts a highly demanding threshold for full moral status (or moral status of a degree that would render a being's use in animal research unethical.) According to Hyun, human beings' moral status is grounded in a distinctly human form of self-consciousness involving propositional beliefs, which Hyun holds can likely only arise in beings with a capacity for language. 37 (The ISSCR White Paper likewise references self-consciousness but does not specify what kind of self-consciousness is meant. However, given that the ISSCR subcommittee cites Hyun in support of its claims about the moral relevance of self-consciousness, they presumably have a similar account of self-consciousness in mind.) It might be asked whether this threshold is too high. Despite lacking language, chimpanzees and other Great Apes are sometimes argued to have full moral status by dint of their rationality, autonomy, and other complex capacities, 38 and many jurisdictions prohibit harmful experimentation with these animals for this reason. 39 Other philosophers argue that self-consciousness is insignificant to moral status, 40 and instead ground moral status in the nature and strength of a being's interests. 41 It is not obvious why chimeric animals should be required to achieve human forms of self-consciousness before being granted serious moral consideration. 42 I will, however, leave this issue to one side. Even if the ISSCR is right to set a highly demanding threshold for full moral status, their reasons for dismissing moral status concerns have deeply troubling implications.
4.1 | Can full moral status emerge only in a normal human brain and body?
What should we make of the claim that morally relevant capacities can emerge only in a human brain that is housed in a human body? This claim is speculative; there has been little research examining the cognitive capacities of human-animal neurological chimeras (and especially chimeric nonhuman primates and large mammals), for the simple reason that relatively few have so far been created. But perhaps more troubling for this claim is that there is a great deal of diversity in the brains and bodies of humans, including humans who are widely thought to have full moral status. Consider the striking case, first reported in 2007, of a 44-year-old whose brain formed in a thin layer around a large fluid-filled chamber, with a reduction of brain volume of more than 50%-75%. Despite this abnormality, the man's neurological development was otherwise normal, and he had a successful career as a civil servant. 43 The capacities that undergird humans' moral status have already been realised in brains that differ, sometimes quite significantly, from those of a normal human.
What of the differences between the body (and sensory apparatuses/motor output systems) of a human and that of, say, a pig or a monkey? The difficulty with this claim is that human bodies This view does have its defenders. Some philosophers argue that infants lack any right to life (among other moral rights) until they develop self-consciousness. Accordingly, practices like infanticide are sometimes thought not to be serious moral wrongs, given infants' lack of full moral status. 46 Despite the philosophical arguments that have been offered in its defence, many people reject this view. Those who reject this view in relation to human infants should likewise reject it in relation to human-animal chimeras. It, therefore, seems a tenuous basis for global stem cell policy.
There is a further implication of Hyun and the ISSCR subcommittee's argument which is even more troubling. This is linked to the claim that moral status concerns can be nullified by raising chimeric animals under conditions that prevent them from developing the requisite cognitive abilities. If it is permissible to curtail chimeric animals' moral status by raising them under conditions inimical to the development of selfconsciousness and higher-order intellectual processing abilities, then it seems it should also be permissible to curtail the moral status of human children in the same way.
This possibility is not entirely theoretical. Children who are deprived of language input during childhood (due, e.g., to extreme neglect) may never be able to learn to arrange words to form sentences. 47 Since Hyun's view of full moral status presupposes a capacity for language, such children would presumably lack the status of 'normal' humans.
Even more troublingly, this view of moral status is consistent with choosing to deliberately raise children that would never be  48 Alternatively, it might be the case that the bar for full moral status should be set much lower than the development of (sophisticated forms of) self-consciousness, so that human infants and children would possess it from a very young age. In this case, the problem with the ISSCR's approach is in where it sets the threshold for full moral status-a possibility we flagged earlier in the paper. KOPLIN | 197