3

Ethical Concerns

Research involving human neural organoids, transplants, and chimeras has an ultimate goal of preventing and treating the great suffering caused by serious neurological and psychiatric conditions for which no effective treatment is available. Current models for such diseases, which are essential for discovering mechanisms and testing therapeutic interventions, have significant limitations. As explained in Chapter 2, human neural organoids, transplants, and chimeras provide new models for such conditions and may lead to new knowledge about brain development and function, the discovery of disease mechanisms, new therapeutic targets, and better screening of potential new treatments.

As the power of these research models advances, however, so, too, do the ethical concerns they raise. Some of these concerns, such as ensuring the welfare of research animals and obtaining appropriate consent for the use of human tissues, also apply to many other areas of research, but may require special consideration for research with human neural organoids, cell transplants, and chimeras. Other concerns are more specific to these research models. One such concern is the possibility of altering the capacities or consciousness of a research animal in ways that may blur the lines between human beings and nonhuman animals. This concern becomes particularly acute when nonhuman primates are used as animal hosts.

Chapter 2 presents the science behind these models and describes the challenges of measuring and monitoring such characteristics and capacities in human neural organoids, transplants, and chimeras. These capacities are rudimentary at present, but because the field is developing quickly, it is important to consider both current ethical concerns and those that might be raised by enhanced capacities in the future. The current chapter first looks at ethical issues common to human

neural organoids, transplants, and chimeras, and then at issues specific to human neural transplants and chimeras or to neural organoids. Chapter 4 considers oversight and regulatory mechanisms that may address some of these concerns.

ISSUES COMMON TO ALL THREE MODELS

Ethical issues common to human neural organoids, transplants, and chimeras include (1) the ethical value of relieving human suffering and disease, (2) concerns about encroachment on divine roles, and (3) ethical issues related to human donors of biological materials.

Ethical Value of Relieving Human Suffering and Disease

A main justification for carrying out research, both basic and translational, with human neural organoids, transplants, and chimeras is that it will help in the discovery of new ways to understand and treat neurological and psychiatric disorders, which, as discussed previously, cause immense suffering and for which treatments are ineffective or lacking.

Given the complexity of the human brain and the particularly human nature of many key symptoms of these disorders, especially psychiatric disorders, animal and cell culture models of the types currently used to investigate diseases of other organs and tissues are valuable but inadequate. For example, mouse models of age-related neurodegenerative diseases fail to capture key features because the diseases typically strike humans in their 60s and 70s, whereas mice live for only 2 or 3 years. Likewise, behavioral disorders such as autism, depression, and schizophrenia involve alterations in emotional and cognitive capacities that may not exist in mice and may involve brain areas, such as prefrontal cortex, that are rudimentary in mice (Feng et al., 2020).

For many people, there are strong moral reasons to pursue this research to relieve human suffering and treat human diseases. The rationale is rooted in the widely shared values of preventing harm to human beings, advancing their well-being, and acting with compassion toward people in need (Parker, 2020). Acquisition of knowledge is also often seen as an ethical good. These benefits are not absolute, however, and must be weighed against other ethical values discussed next.

Concerns about Encroachment on Divine Roles

Some commentators invoke the phrase “playing God” to indicate opposition to biotechnology, such as research with human neural organoids, transplants, and chimeras, with the implication that human activities should not infringe on the role of a deity as the creator of life. Many others, however, believe that this injunction does not preclude the treatment of serious human diseases (Hauerwas, 1986). One scholar believes that it is more typical of Christians to believe that they are called

to intentionally “play God in the correct way” or “play God as God plays God” by, for example, healing the sick (Verhey, 1995). Similarly, many Jewish and Christian thinkers view human intervention in nature as completing God’s unfinished creation (Cole-Turner, 1993; Loike and Tendler, 2008).¹ They argue that since human beings were created by God with reason and intellect, God allows, encourages, and enjoins human beings to use their capacities to improve the earth, heal human disease, and relieve human suffering. Creation in this view is a continuous process, with humans being cocreators of the universe with God (Cole-Turner, 1993).

Some believe that nonhuman animals as well as humans were created by a deity and have their own purpose and nature—their own telos—that should be respected (Comosy and Kopp, 2014). This view is not, however, incompatible with the idea that human beings can be justified in utilizing other species. Speakers and writers representing several faith traditions and secular beliefs generally agree that humans are permitted to use nonhuman animals for the benefit of humanity, including in work, for food, and in well-justified research projects (Comosy and Kopp, 2014; Loike and Tendler, 2008; Tlili, 2018). However, they also agree that humans should be stewards of nonhuman animals and should not cause them to suffer needlessly or treat them cruelly. The committee notes, however, that beliefs and interpretations vary both within and among faith traditions, and people will differ in what aspects of human neural organoid, transplant, and chimera research, if any, cross an unacceptable line between the roles of a deity and humans.

Ethical Issues Related to Human Donors of Biological Materials

For research described in this report, the starting points are most often stem cells that can be treated to differentiate into neural precursors and then into neurons or glia. In some cases these are embryonic stem cells (ESCs) derived from early embryos, but increasingly they are somatic cells that can be reprogrammed to generate induced pluripotent stem cells (iPSCs). iPSCs are usually derived from skin biopsies as shown in Figure 2-3, but can also be generated from other tissues, blood, or even the few cells present in urine. Some research uses neural tissue that is resected during surgery or obtained postmortem, tissues that would otherwise be discarded.

There is broad agreement on the need to respect humans who provide biological materials used to generate human neural organoids, transplants, or chimeras. An ethical concern might arise when cells used to generate these models are derived from people who did not know that such research was being carried out, did not give permission for use of their tissues for this purpose, or would not have consented had they known. Respect for persons who provide tissues for such research plays out differently for new collection of biospecimens and for use of existing biospecimens.

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¹ John Loike, Columbia University, presentation to committee, October 29, 2020, virtual meeting.

Collection of New Biospecimens for Research

As described in Chapter 4, federal regulations for the protection of human research subjects mandate informed consent before researchers can collect fresh biological materials for research, whether by collecting tissue left over from surgery and biopsies, or by extracting tissue specifically for research. The ethical rationale is the need to respect donors as persons and to protect their liberty interests in being free of unwanted excision of tissue. (As noted earlier, this report uses the term “donor” rather than the longer and more cumbersome phrase “persons from whom biospecimens used in research are obtained, although they may not have made a conscious decision to do so.”)

For consent to be informed, the donor needs to be told about the research studies to be carried out and the risks entailed in obtaining the specimens. If human neural organoid, transplant, or chimera research is contemplated when new biospecimens are obtained, the donor should be so informed. However, because future research uses of biospecimens cannot always be envisioned in advance, consent forms for biopsies or surgical procedures commonly include a sentence granting broad permission to conduct unspecified research on materials that are not needed for clinical care. Some consent forms separate consent for surgery from consent for future research on the removed tissue to make clear that patients may have the clinical procedure without agreeing to research on their excised tissue. Later in this chapter is a discussion of debates over whether such broad consent should or should not be viewed as sufficient when cells are used to generate human neural organoids or chimeras.

Use of Existing Biospecimens for Research

Persons who provided existing biospecimens need to be respected when those specimens are used in research. Their privacy and autonomy are protected by removing specified identifiers from the biomaterials, prohibiting attempts to reidentify them, and not carrying out research that is contrary to the conditions of the original consent.

Research may be carried out without consent in several circumstances. With existing specimens, the overt identifiers can be removed so that the identities of the donors can no longer be readily ascertained. Consistent with common usage, this report refers to such biospecimens as “deidentified.” As discussed in Chapter 4, under current federal regulations, such deidentified existing materials can be used in research without obtaining additional consent because the persons who provided the biological materials are no longer human subjects; therefore, Part A of the Federal Policy for the Protection of Human Subjects (generally called the Common Rule and described in Chapter 4) does not apply to them. The underlying ethical rationale for this regulatory provision is that using a leftover biospecimen for research provides a social good compared with discarding the specimen, and the risks to the donor are minimal because the specimen has already been

removed from the donor’s body, and confidentiality will be protected. An additional rationale is that people should not retain control over biological materials that are already outside their body and that they have given away voluntarily or abandoned (Charo, 2006).

A common example is the use of leftover tubes of blood for research after clinical tests ordered by the treating physician have been completed, and explicit identifying information has been removed from the biospecimen. Generally, there is no written informed consent for “routine” clinical blood tests, and even oral consent is often perfunctory; consent is implied when the patient presents to the clinical laboratory for the test and makes no objection to the phlebotomy. However, ethical views and institutional and public policies can change. In 2007, for example, Vanderbilt Medical Center started a deidentified repository of genomic sequencing data extracted from leftover clinical specimens matched with electronic health records. Biospecimens and records were placed into the repository unless patients chose to opt out. The medical center offered the option to opt out even though it was not required to do so, because the creators of that resource believed it was important to allow some choice. In 2015, the medical center’s policy changed to an opt-in policy. It began to require signed affirmative consent from the patient to participate in genomic studies using biomaterials and clinical data from which identifiers had been removed, consistent with a new National Institutes of Health (NIH) policy (Vanderbilt University Medical Center, 2015). An ongoing challenge for biorepositories is that the increasing availability of genomic, transcriptomic, and other information about individuals is making true deidentification more difficult; this issue is discussed in Chapter 4.

There may be a disparity in some situations between what is legally permitted by the Common Rule and what is considered ethically acceptable. For example, “pinprick” blood samples (blood spots) are routinely obtained from newborns in the United States to screen for congenital diseases. These archived materials have been a valuable resource for public health research for many years. After the samples and accompanying data have been processed so that the identities of the babies can no longer be readily ascertained, secondary research is permitted without consent in all but a few states. In response to parental concerns, however, Texas now offers parents an opportunity to opt out of such research, and Michigan now requires affirmative consent.

Another example of requiring specific consent for a particular type of research with materials originally collected for clinical care is the NIH requirements for funding human embryonic stem cell (hESC) research (NIH, 2016). For research using hESC lines derived after 2009, consent forms to donate the embryos must explicitly state that the embryos would be used to derive hESCs for research and describe what would happen to the embryos in that derivation; a broad consent to donate embryos “for research” would not suffice.

For deidentified biological materials already collected and available in tissue banks, specific informed consent for use of cells to generate human neural organ-

oids, transplants, or chimeras typically has not been obtained; rather, consent has been obtained for broad use in research, or the identities of the donors of the biospecimens could no longer be readily ascertained. Under federal regulations, such biospecimens can be used to generate iPSCs without further consent, and the iPSCs can then be used to generate human neural organoids, transplants, or chimeras. Of note, the derivation and use of iPSCs render moot the objections that some people have to the derivation of hESCs, which requires destruction of early embryos.

Whatever the current requirements for informed consent, it is likely that some donors of biological materials may not want those materials to be used for such projects and would object to such use if they knew about it (Grady et al., 2015; Streiffer, 2008). Prospectively, it would be feasible to obtain specific informed consent for the collection of fresh tissue for production of iPSCs from which human neural organoids, transplants, and chimeras can be generated. However, logistical problems could arise in managing tissues and databases of thousands and even millions of samples, each with its own list of permissible experiments. Alternatively, tissue banks could institute review and governance procedures for determining whether future research projects fall outside the scope of the initial consent for research and whether the project might conflict with the values of the donors (Grady et al., 2015).

For existing biospecimens, requiring specific consent for such research might be considered ethically problematic for several reasons. First, some question whether donors of biological materials have an ethical right to control materials they have already given away voluntarily or abandoned (Charo, 2006; Rao, 2016). Second, in some cases, there are strong scientific reasons to use biological materials already collected even if the donors did not provide specific informed consent for human neural organoid, transplant, or chimera research. Some cell lines have been well characterized using many methods over a long period; redoing this foundational research with newly collected tissues would require considerable time and funding. For very rare diseases, moreover, it may not be feasible to identify and recruit new donors. Trying to recontact the original donors to obtain specific informed consent is sometimes impossible, could impede important research, and might not be welcomed by some donors. Policy in this area is actively debated in an effort to strike the right balance between anticipating and respecting donor preferences in sensitive areas and developing new therapeutics for serious diseases in a timely manner.

Consent in Groups That Have Suffered Health Disparities and Discrimination

Use of human cells to generate human neural organoids, transplants, and chimeras could elicit mistrust in such groups as African Americans that suffer health disparities, unequal treatment, and discrimination (IOM, 2003). Public awareness of past research abuses, such as in the Henrietta Lacks case, could fuel

this concern (see, e.g., Skloot, 2010). In that case, cancerous tissue was removed during clinical care of Henrietta Lacks, a Black woman, and given to researchers to create cell lines without telling the patient or family that this was being done. When the surgery was carried out in 1951, there were no federal regulations for human subjects research. The HeLa cell line derived from the tissue has been widely shared among researchers and “played an extraordinary role in scientific research,” enabling many important medical advances and generating substantial profits for some who used it (see Jones et al., 1971; Wolinetz and Collins, 2020). In 1971, Lacks’ name was published in a medical article on the eponymous HeLa cell line. In 2013, researchers published her complete genomic sequence online, which violated investigator responsibility for release of genomic sequences and for stewardship of sensitive data (Greely and Cho, 2013). In response to concerns about this case, NIH and the Lacks family held discussions and agreed that family members would serve on a data access committee for future use of her cells, and that all publications using this cell line would acknowledge her and her family.

Empirical studies provide evidence that the Henrietta Lacks case is salient today for persons from minority backgrounds. In a 2019 study, focus groups were convened with persons from five ethnic and racial groups regarding the collection of biospecimens and electronic health record data for research (Lee et al., 2019). The article reporting the study findings was titled “I don’t want to be Henrietta Lacks.” The researchers found that “many participants across our five racial and ethnic groups cited the case of Henrietta Lacks as a cautionary tale when discussing potential risks associated with biospecimens.” Respondents associated a range of concerns with the case in response to open-ended questions, including loss of control of the self, unfair profits to companies from samples of unsuspecting patients, and limited ability to conceive of potential future research.

Strengthening informed consent could be a component of an approach designed to build trust and increase participation of minority communities currently underrepresented in research. On the 100th birthday of Henrietta Lacks, leaders at NIH (Wolinetz and Collins, 2020) and the editors of Nature (Nature Editorials, 2020) called for a revision of ethical and regulatory standards for research with human biospecimens to require consent for use in research. “A genuine culture of respect for research participants demands that they be asked to agree to use of their biospecimens, regardless of identifiability” (Wolinetz and Collins, 2020).

Indigenous peoples might object to biological materials collected for one purpose being used in deidentified form in other research that they would not have consented to had they known about it. For example, the Havasupai tribe objected when materials collected under a consent for research on diabetes, which is highly prevalent in the tribe, were later used for projects on the genetic basis of schizophrenia and inbreeding because such research could stigmatize the tribe or violate cultural values (Garrison, 2013). To settle a lawsuit, Arizona State University, whose researchers conducted the disputed studies, apologized; returned the remaining samples to the tribe; made a monetary payment; and

agreed to work with the tribe on health, education, and economic development (Mello and Wolf, 2010).

These concerns among ethnic and racial groups regarding the use of biological materials for certain types of research without consent have not specifically addressed research with human neural organoids, transplants, or chimeras. Nonetheless, they resemble concerns that may arise in such research. It will therefore be important to engage these communities in discussions about such research to identify and address particular sensitivities.

Other strategies can also help overcome mistrust and increase minority participation in research. The federally funded All of Us project, which studies relationships among genetics, lifestyle, environment, and health outcomes, is making a determined effort to increase inclusion and minority enrollment (Mapes et al., 2020). The Jackson Heart Study, a community-based cohort study evaluating the etiology of cardiovascular, renal, and respiratory diseases among African Americans, has successfully recruited participants and followed them for 20 years. The research included genomic sequencing of participants, a type of research in which African Americans had historically participated at very low rates (Popejoy and Fullerton, 2016). This study has a strong commitment to community education and outreach to promote healthy lifestyles and reduce cardiovascular risk, research training programs for college and graduate students, and high school science and math enrichment programs to prepare and encourage underrepresented minority students to pursue biomedical careers. This sustained community engagement has enabled an important long-term study in a group whose medical care has suffered from a relative paucity of research on diseases that disproportionately afflict them.

ISSUES SPECIFIC TO HUMAN NEURAL ORGANOIDS, TRANSPLANTS, AND CHIMERAS

Ethical issues raised specifically by human neural organoids, transplants, and chimeras include (1) concerns related to distinctions between humans and other animals, (2) concerns about animal welfare and rights, (3) concerns about consciousness and enhanced capacities, and (4) concerns related to the use of nonhuman primates.

Concerns Related to Distinctions between Humans and Other Animals

Several concerns specific to neural transplants and chimeras revolve around a distinction between humans and other animals that is widely held across cultures (De Cruz and De Smedt, 2016). This distinction may be based on interpretations of religious texts and teachings: for instance, that humans were created by God as different from other animals, or were created in God’s image and thus have a higher status than other animals (Loike and Tendler, 2008). In a secular context, this distinction arises from the common-sense notion that “nature” made humans

different from other animals. Summarizing these views, Robert and Baylis (2003) suggest that there are moral if not biological boundaries between species that are common in public opinion, whether or not they correspond to biological distinctions (see also Baylis and Robert, 2007). From a perspective that need not involve religious views, some ethicists believe that each nonhuman animal species has a distinctive nature or kind that should be respected by humans and allowed to flourish in accordance with its own telos or end.

Every culture has foundational cultural distinctions, which people within that culture believe to a greater or lesser extent. Blurring these distinctions results in fascination and repugnance; many cultures have a fascination with mythical chimeras that violate the human/animal distinction. By eroding a foundational cultural distinction between humans and other animals, human neural cell transplants and chimeras might create “moral confusion,” which is, for some people, accompanied by a sense of repugnance (Robert and Baylis, 2003). For instance, some might feel revulsion at the possibility of a human brain being trapped inside an animal’s body. Beyond the intrinsic reasons to avoid mixing humans and animals, people who write about “moral confusion” are typically concerned that such confusion would lead some people to think of humans differently and treat them worse—more like nonhuman animals are treated. Others might be concerned about enhancing the capacities of animals to turn them into a “service” species that could be exploited by human beings. In contrast, still others hope that breaking down the human/animal distinction would lead to treating nonhuman animals better (Greely, 2020).

Immediate Negative Reactions to Perceived Violations of Distinctions between Humans and Nonhuman Animals

Kass (1997) forcefully argued for the moral value of feelings of repugnance toward situations that violate the distinction between human beings and nonhuman animals and threaten human dignity:

Such immediate reactions of repugnance and disgust are commonly if inelegantly called a “yuck” response. These reactions should not be dismissed: They represent views that are plausible, deeply felt, and consistent with core values. Moreover, they have had important policy impact on many topics, including genetically engineered

food (Scott et al., 2018), wastewater recycling (Miller, 2012), control of infectious diseases (Curtis, 2011), and human reproductive cloning (Kass, 1997). On the other hand, disgust may also lead to shunning, stigmatization, and prejudice (Curtis, 2011). With regard to the topics of this report, human neural organoids, transplants, and chimeras may elicit “yuck” responses (Devolder et al., 2020; Smith, 2020).

Culturally approved repugnance may shift dramatically over time, examples being the overturning of legal support for school segregation and bans on racial intermarriage in the mid-20th century. Thus, a consensus view is that repugnance should invite inquiry, reflection, and respectful dialogue, but not unquestioning acceptance (Schmidt, 2008; Smits, 2006). Most people readily accept the idea of using nonhuman animal tissues, such as heart valves or cartilage, for transplantation, but clearly there is some degree of admixture that will violate people’s intuitive moral sense, and neural tissue may well be problematic for many. Further inquiry and discussion can illuminate the point at which the technologies discussed in this report violate common feelings of repugnance or foundational distinctions. In terms of developing science policy and public policy regarding human neural organoids, transplants, and chimeras, there may be lessons to be learned from experiences cited above, such as those involving genetically engineered food or reproductive cloning (Miller, 2012; Scott et al., 2018).

Other writers have attempted to analyze the origins of these reactions. Rozin traces the biological and cultural evolution of disgust, whose triggers vary through history and across cultures (Rozin and Haidt, 2013; Rozin, 2015). Curtis (2011) shows how disgust evolved to motivate avoidance of infectious diseases. Niemela (2011) argues that “people have certain automatic and quick cognitive tendencies routinely used for categorizing and reasoning about living nature.” (p. 272). He continues, “As the cognitive tendencies routinely applied to the explanation of biological world are violated, an emotional response of fear, disgust and of something unnatural being underway is easily provoked.” (p. 267).

Importantly, faith traditions vary in the implications they draw for animal welfare and status from the distinction—whether clear or blurred—between humans and other species. For some, the distinction leads to a strong elevation in the worth of humans over nonhuman animals, with a consequent decreased regard for animal welfare. In other faith traditions, by contrast, nonhuman animals were created by God on the same day as human beings and participate in the afterlife (Tlili, 2018). Such views would require that human beings act as stewards of other animals and give greater consideration to their interests and welfare.

Concerns Related to Attributes of Chimeric Animals

Another concern is that a nonhuman animal that received a human neural cell transplant or a chimera could become human if it obtained enough “human-like” capacities. There is no single definition of what it means to be human, but rather several conceptions that are not mutually exclusive (Evans, 2016). One traditional

Jewish and Christian definition is that humans are made in the image of God and have a soul and free will (Loike and Tendler, 2008; Niederauer, 2010).² The importance of free will and other capacities can also be framed in secular terms. A second view is that human beings are conceived through the fertilization of human gametes, gestated in a woman’s womb, and born of a human mother. A third, biological view is that genes determine which entities are human. A fourth conception is based on capabilities that are believed to confer moral status, such as self-awareness (Evans, 2016) or high-level consciousness.

Yet another common definition of a human depends on appearance and behavior (Greely, 2020). By this criterion, neural transplants or chimeras that appear human, have a visible human feature, or act like a human would be particularly unsettling (Katsyri et al., 2015). Several years ago, a furor developed when tissue was attached to a rodent in a way that allowed it to differentiate into a structure vaguely resembling a human pinna (outer ear) (Cao et al., 1997; Hugo, 2017). A public consultation in the UK found that people were particularly concerned with “cellular or genetic modifications which could result in nonhuman animals with aspects of human-like appearance (skin type, limb or facial structure) or characteristics, such as speech” (Academy of Medical Sciences, 2011). In short, given this multiplicity of conceptions, it is helpful in discussions of ethical issues to specify which are or are not being referenced.

In some of these conceptions, human-nonhuman animal neural transplants and chimeras involving the brain arouse stronger concerns relative to those involving other organs because many of the capacities associated with higher moral status, such as consciousness, complex problem solving, self-awareness, and emotions, are “located” in the brain. From a more introspective view, the brain more than any other organ is believed to define who a person is. As the physical instantiation of characteristics that many people commonly associate with their humanness and individuality, the brain evokes greater concern relative to other organs.

Importantly, although these different definitions of “human” arise from different ethical perspectives, it is possible for people to reach agreement on specific issues and problems, even though they do not agree on the reasons for their common conclusions (Jonsen and Toulmin, 1988). This report aims to reflect how adherents of different positions would present their arguments. The committee was not asked to make recommendations on which views are most convincing; indeed, trying to do so would be fraught because positions often build from deeply held individual beliefs.

Concerns Related to Potential Capacities of Chimeric Animals

People concerned about nonhuman animals developing human-like attributes from any of a variety of ethical perspectives might believe that even the possibil

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² Charles Camosy, Fordham University, presentation to committee, October 30, 2020, virtual meeting.

ity that such animals would develop is to be avoided and oppose research that could lead this possibility to become reality. From a precautionary perspective, they would argue that in cases of uncertainty, it is advisable to close off areas of research that could lead to such troubling outcomes. There are many versions of this so-called “slippery-slope” argument. “The common feature of the different forms is the contention that once the first step is taken on a slippery slope the subsequent steps follow inexorably, whether for logical reasons, psychological reasons, or to avoid arbitrariness in ‘drawing a line’ between a person’s actions” (Young, 2020). In the specific case of neural transplantation and chimera research, the slippery slope concern is that if small increments in mental capacities develop in transplants or chimeras, there will be no logical point at which the research should be stopped, or it may not be possible later to institute policies to block research that could result in nonhuman animals with unacceptable human capabilities.

If barriers cannot be set far down the slope to protect against the ethically objectionable bottom, some would say that researchers should not step onto the slope at all. The difficulty with this view is that a strict application of precautionary principles would close off entirely the possibility of gaining new knowledge that could result in treatments to relieve suffering in patients with serious neurological and psychiatric diseases. To gain the benefits of such research, it is necessary to balance its prospective benefits with its risks. Such a balance could take the form of a tiered approach to oversight, with the final tier—research that should not proceed at this time—acting as a barrier on the slope. When the science began to approach that limit, a greater understanding of the science and the associated ethics could allow a more strongly justified limit to be set. Chapter 4 describes current guidelines for neural cell transplant and chimera research that represent an attempt to instantiate this approach.

Concerns Related to Human Gametes in Chimeric Animals

It is possible that in the course of generating human neural chimeras, some human cells could populate the germline—that is, become gametes. In this case, objections to chimerism would likely be far greater than if the human cells contributed only to somatic tissues. For those who see humans and nonhuman animals as created distinctly by God, the idea of creating nonhuman animals that could pass a human genome to future generations is more disturbing than that of creating animals that could not do so. Reproduction also has particular significance because it usually begins with an intimate and private encounter and results in the transmission of familial lineage. The idea of nonhuman animals with human gametes might lead people to fear that such an animal could give birth to a monster or that these important personal and social aspects of reproduction would be undermined. While such a phenomenon would not logically blur the human/nonhuman distinction itself, it would blur notions of the role of human female gestation.

In practice, it is unlikely that cells of human origin could become competent gametes in a nonhuman animal because of the multiple stringent biological restrictions used by each species to protect its germline. Moreover, current NIH guidelines prohibit the mating of any nonhuman animals in which human gametes could be formed (NIH, 2009), but this prohibition might provide scant comfort to some concerned people. Perhaps most useful would be to engineer human cells to prevent them absolutely from developing into gametes when used in chimeric animals, an option made feasible by available knowledge of genes required for gametogenesis. These engineered stem cells could be used—indeed, their use could be mandated—for the generation of chimeras.

Concerns about Animal Welfare and Rights

Some perspectives on animal ethics hold that nonhuman animals have their own inherent value quite apart from the benefits humans can derive from them. In this view, animals ought to be treated as the kinds of creatures they are—their intrinsic nature or telos should be respected—and they should not be treated as mere tools or things to be used for the benefit of humans (Carbone, 2019). Some animal rights advocates argue for banning all animal research, as well as killing of animals, whether it be for food or in research (Gruen, 2017).

In contrast, many people who believe that nonhuman animals have interests and deserve respect nonetheless accept their use for research directed toward the ultimate goal of relieving human suffering, as long as the research is well justified; harm to animals is minimized; and the physical, social, and psychological needs of the animals are met. Indeed, at least one prominent proponent of animal rights and vegetarianism endorses animal research under some circumstances, such as to relieve severe human suffering when there is a lack of alternative approaches (Crawley, 2006). This balancing of countervailing ethical values is the basis of current oversight of research involving animals in the United States.

In the United States, a major ethical framework to guide oversight of research with animals is known as the Three R’s. The Three R’s call on researchers to: reduce the number of animals, replace animals with other experimental models, and refine methods for alleviating or minimizing pain and distress consistent with the scientific aims of the research (see Table 3-1). In addition, the U.S. government requires compliance with the Guide for the Care and Use of Laboratory Animals, which states that those overseeing animal research are “obliged to weigh the objectives of the study against potential animal welfare concerns” (NRC, 2011).

The definitions of the Three R’s are evolving, with an increased focus on improving understanding of the impact of animal welfare on scientific outcomes. Moreover, there have been recent proposals to expand the Three R’s to provide a more comprehensive ethical framework (Beauchamp and DeGrazia, 2020). These proposals include placing additional emphasis on animal welfare, including the

TABLE 3-1 The Three R’s

SOURCE: Margaret Landi, GlaxoSmithKline, presentation to committee, October 30, 2020, virtual meeting.

obligation to meet animals’ basic needs, such as nutritious food, safe shelter, species-appropriate housing, companionship, and opportunities for stimulation and exercise. Other proposed additions focus on limiting harm to animal subjects and limiting potential suffering to that justified by the prospect of benefit to humans and required to address the research question. The expanded framework is still developing and more explicit discussion and analysis of how to balance the benefits of research to humans with the harms to research animals will be important to its further development.

Although the Three R’s formulation provides only a conceptual outline rather than practical guidance, a rich reservoir of expertise—including veterinarians, animal caretakers in research facilities, and animal ethologists and experts in animal behavior—can be called on to address more practical concerns (ASP, 2020; IPS, 2007; Weatherall, 2006). Research veterinarians in particular have expertise and experience in identifying whether an animal is suffering distress and if so, how to provide relief in the context of the research. Importantly, they generally report to the institution rather than the researchers, so they can provide a view that is less likely to be unduly influenced by a commitment to specific research objectives.

Animal rights advocates believe if research with nonhuman animals is permitted, the animals have a right to what is necessary for them to flourish as the kind of beings they are. According to this perspective, the researcher’s obligation to provide appropriate living conditions is similar to the requirements of the animal welfare perspective described earlier in this section. In some cases, however, animal rights advocates might object to some research that would be permitted by a balancing of countervailing values described earlier—for example, objecting to the creation of chimeric animals as violating their telos or nature.

Some countries have adopted principles for the treatment of animals broader than those that underlie U.S. regulations, incorporating animal rights perspectives that go well beyond the Three R’s. Directive 2010/63/EU in the European

Union states that animals have an intrinsic value that must be respected and that animals should always be treated as sentient creatures.³ The Swiss constitution and Animal Welfare Law includes the concept of “animal dignity,” which grants animals a moral value irrespective of their sentience, and recognizes the need to protect an animal’s inherent worth beyond avoidance of physical pain, injury, and anxiety (Bollinger, 2016).⁴ Some animal rights advocates object to research conducted even under such an “expanded Three R’s” framework. Many of the most restrictive policies for great apes were influenced by the Great Ape Project, which calls for chimpanzees, gorillas, bonobos, and orangutans to be accorded the same basic rights as human beings, including the rights to life, freedom, and not being tortured (GAP, n.d.). Additionally, animal rights advocates commonly have more concerns about the research use of higher nonhuman primates in research than about the use of other animals, such as mice. Issues specific to nonhuman primates are discussed below.

Finally, as human neural chimeras are developed to better recapitulate human disease, research animals may show altered capacities or behaviors similar to human symptoms of the disease, which may heighten concerns about animal welfare. Depending on the model, these behaviors could include changes in socializing, exploratory behavior, or eating patterns; increased anxiety; or other signs of distress. As noted above, veterinarians, animal caregivers, behavioral biologists, and ethologists can play a crucial role in identifying for institutional animal use and care committees (IACUCs) and researchers those behaviors in research animals that differ from the typical behavior of the individual animal or the species and how their care can be modified to take into account their changed needs and capacities (IACUCs are discussed in Chapter 4).⁵ Animals in these studies may need to be treated differently from other research animals of their species that have not undergone such interventions. Overall, ensuring animal welfare requires mitigating any distress, which may include making appropriate changes to the care of animals (for example, changes in caging, environment, feeding, or enrichment) or to the research protocol, provided this can be done without undermining the justified aims of the research or the validity of the research data (Carbone, 2019).

Concerns about Consciousness and Enhanced Capacities

As noted earlier, the possibility of generating consciousness, suffering, or markedly enhanced cognitive capacities in human neural organoids, transplants, or chimeras has generated ethical concerns. The presence of or potential for con-

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³ EU Directive 2010/63/EU, Recital 12.

⁴ Animal Welfare Act 7 U.S.C. § 2131–2159, A.S. 2965 (2008) § 3a.

⁵ Megan Albertelli, Stanford University, presentation to the committee, August 11, 2020, virtual meeting. Margaret Landi, GlaxoSmithKline, presentation to the committee, October 30, 2020, virtual meeting.

sciousness is, for many, an important determination of the moral status that should be accorded to living entities (Van Gulick, 2018). The concept of consciousness is reviewed in Chapter 2. That discussion suggests that the development of consciousness would be extremely unlikely and perhaps impossible in the neural organoids currently being developed for research, but also notes the difficulty of defining consciousness and the practical impediments to assessing the possibility of enhanced consciousness in animals. The current failure to generate viable human-nonhuman chimeras renders consideration of their consciousness moot. However, if such chimeras are generated in the future, heightened consciousness or capabilities cannot be ruled out. If detected in a chimeric animal, they would surely change how human beings regard the animal and increase the obligations owed to the animal. Likewise, it will be imperative to assess the capacity of such chimeras to experience pain, and to ask whether that capacity differs from that of the unmanipulated host species. Finally, the experiences of consciousness and pain are not the only causes for concern. For many other thinkers, the mere capacity to suffer or acquire consciousness is all that is needed to impose an obligation to refrain from experimentation.

It will be important to clarify which specific enhancements to consciousness or capacities might increase the obligations of humans toward chimeric animals. People have several distinct concerns. First, consciousness may be thought to raise the moral status of the research animal or organoid and justify more research safeguards, oversight, and restrictions. Second, for some people, the possibility that the entity might have or develop enhanced consciousness is itself an ethical concern based on considerations detailed above, such as altering the nature of the animal, blurring natural distinctions between species, undermining human dignity, or eliciting repugnance. Third, research that causes an animal to experience pain, particularly pain beyond what it would usually experience, could be regarded as failing to respect the animal and its nature. For some, the capacity of animals to suffer generates obligations for humans to refrain from harming them. The committee notes that there is a range of views on such issues and on how to balance obligations toward animals with other ethical obligations, such as relieving severe suffering in human beings.

Additional ethical concerns about heightened consciousness or capabilities in a chimeric animal arise in people who hold that human beings have a special moral status. For some, these concerns are based on Jewish or Christian religious beliefs that human beings were created in the image of God and should act as stewards for creation. Others have nonreligious reasons for such concerns, which may be based on a concept of human dignity or of natural boundaries between species. Several basic capacities in addition to consciousness have been claimed to be uniquely human, including empathy, altruism, imitative learning (replicating a model’s behavior rather than seeking alternative methods to achieve a goal), joint attention (a creature and social partner simultaneously attend to a stimulus and are aware of the shared attention), having a theory of mind (reasoning about

the minds of others of the same species as agents with intentions), and communicating about absent and displaced objects (that have been moved in space or are not present at the time) (CARTA, n.d.).

However, such claims have been contested. Some nonhuman animals have been shown to have many of these capacities, at least in rudimentary form (MacLean, 2016). It is therefore not clear whether humans can be distinguished from other animals on the basis of any single capacity, or even a group of capacities. Perhaps no set of such capacities can provide both necessary and sufficient conditions to distinguish human from nonhuman animals. Moreover, studies claiming to detect these capacities are difficult to carry out and are vigorously debated; many findings may be difficult to replicate; and conceptual frameworks, study methodologies, and interpretations have been debated (Bräuer et al., 2020; Lyn et al., 2014; Tomasello and Call, 2019). Critical literature reviews could help clarify the weight of the current evidence regarding whether animals have specific capacities, and to what degree. Of note, high-level intellectual and cultural achievements, such as proving mathematical theorems, building computers, writing books, and composing operas, are unique to human beings, but are of little help in assessing higher functions in neural organoids and chimeric animals.

Taken together, these considerations suggest that the most informative tests or observations may be those that can show some difference between chimeric and nonchimeric animals of the same species, rather than those that attempt to find “human-like” capacities in a nonhuman animal. These capacities can be assessed by a variety of formal tests described in Chapter 2. In addition, such responses as pain, distress, decreased activity, and social withdrawal can be observed by research veterinarians and animal keepers.⁶ If any signs of distress are observed, changes in housing, social environment, activities, and medications can be used to relieve them.

In addition to the above steps, researchers must justify any prospect of increased experience of pain or distress to the IACUC responsible for overseeing the research. If the animal falls under the scope of federal regulations or funding requirements, investigators have specific responsibilities discussed in Chapter 4. Briefly, the researchers must explain to the IACUC how the benefit to human beings of the knowledge gained from the research justifies the pain and distress experienced by the animal as a result of the experiment. Moreover, the IACUC must approve a plan for minimizing and alleviating pain and distress consistent with carrying out the justifiable scientific goals of the research. Although one philosopher suggested that enhanced consciousness would be particularly important ethically if a chimeric animal remembered or anticipated the pain and distress (Piotrowska, 2020), these capacities are not exclusively human or even mammalian characteristics.

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⁶ Megan Albertelli, Stanford University, presentation to the committee, August 11, 2020, virtual meeting. Margaret Landi, GlaxoSmithKline, presentation to the committee, October 30, 2020, virtual meeting.

At present, the issue of altered capacities in chimeric animals is addressed by modifying their care so that pain or suffering is alleviated. In the long term, however, it is possible that a human neural chimera might develop altered capacities, such as those enumerated in Chapter 2, so resembling those of humans that some people might believe such research should not be carried out or that animals of that species should no longer be used in such research, even if the chimera remains a nonhuman animal (Streiffer, 2019). As noted above, others may object to creating any entity that has altered or enhanced capacities, or perhaps even the potential to develop such capacities. A precautionary approach might be warranted, in which enhanced oversight would be introduced at an earlier stage. For example, the field might proceed carefully by pausing when researchers identify changes that differ from species-typical behavior to consider whether those changes are qualitatively different or only small enhancements and whether they have ethical significance. This reflection might be carried out, for example, through bodies that review and oversee such research.

It should be kept in mind that human beings already create nonhuman animals with altered capacities, such as resistance to disease; increased size or speed; or enhanced production of milk, eggs, or wool, In some cases, the selected characteristics are behavioral and therefore likely affect the brain—for example, breeding dogs to have particular skills or greater docility. These modifications have generally been accomplished through selective breeding, but are now beginning to be made by genome modification. Selective breeding at least is widely accepted as falling within responsible human stewardship over nonhuman animals. Generating novel mental capacities in neural transplants and chimeras resembles this type of stewardship in some superficial respects, but differs in the methods used, the involvement of human cells, and the explicit focus on the brain.

Concerns Related to the Use of Nonhuman Primates

Although most neural cell transplants and chimeras currently use rats and mice as the host species, it is likely that some future studies will use nonhuman primates for this purpose. As discussed in Chapter 2, such research holds promise in two respects: Monkeys are likely to be more successful hosts than rodents for generating human neural chimeras or transplants and chimeras are likely to be better models of human brain diseases when the host is a primate rather than a rodent. However, the evolutionary proximity of nonhuman primates to humans that constitutes a scientific advantage also heightens moral and ethical concerns (Feng et al., 2020; Greely, 2021). For example, symptoms of psychiatric disorders, including sadness, decreased interest in activities, disordered sleep, and social isolation, will be more recognizable in nonhuman primates as distinct from species-typical behaviors, but also may be difficult for researchers and veterinarians to ameliorate, as required by animal welfare regulations and ethics. Should they develop, moreover, such enhanced capacities as enhanced problem solving,

memory, and self-awareness may appear to be more similar to those of humans in nonhuman primates than in small animals, and may be seen as violating human dignity. Such chimeras could also evoke the specter of more human-like intermediate animals, heightening concerns about the blurring of boundaries between species. For related reasons, animal welfare regulations are already more stringent for nonhuman primates than for rodents, and it is likely that there will be pressure from many quarters to increase this differential for human neural cell transplants and chimeras generated in primate hosts.

Regulatory issues specific to nonhuman primates are detailed in Chapter 4.

ETHICAL ISSUES SPECIFIC TO HUMAN NEURAL ORGANOIDS

This chapter has enumerated a wide range of concerns related to human neural organoid, transplant, and chimera research, as well as concerns specific to transplants and chimeras. Are there concerns specific to neural organoids? In fact, the committee heard about very few ethical concerns regarding current and near-term neural organoid research other than those detailed above.

Because there are no animal hosts, there are no animal welfare concerns and no violations of the foundational cultural distinction between humans and nonhuman animals. Indeed, if the use of human neural organoids can decrease the use of animals in research, that would represent an ethical benefit under the Three R’s framework for animal welfare. None of the religious scholars who spoke to the committee or whose work the committee consulted suggest that human neural organoids in vitro would ever acquire the moral status of a human being, undermine the special status of human beings, or otherwise raise theological concerns because in their view, the mere presence of human cells would never make an organoid human.

However, some express revulsion at the possibility that cells taken from their bodies could be used to generate organoids or that brain organoids might develop “human-type awareness” (Smith, 2020). More information is needed to determine whether such responses might be common. For the moment, some of these concerns are alleviated by the fact that, as discussed in Chapter 2, human neural organoids are currently very limited in size, complexity, and maturity and are likely to remain so. They do not meet any current criteria for consciousness and awareness. In the future, however, the complexity of organoids and the circuits they contain will surely increase. It will therefore be essential to revisit these questions as models improve and as understanding of consciousness and awareness changes.

Bioethical analysis could begin by identifying features or capacities that signify moral status and might therefore lead to restrictions on certain types of research. One concern might be that an organoid comprised of human cells achieves consciousness and can experience pain or distress. Aach and colleagues (2017) have discussed ways of considering concerns related to “synthetic human

entities with embryo-like features” (SHEEFs), which are not organoids, but the discussion is highly relevant. The authors emphasize the importance of paying attention to concerns that bother people, calling for consideration of “features that directly trigger moral concern…” through “a multi-tracked exploratory inquiry process that both solicits opinions on how SHEEFs might be morally concerning from a wide range of disciplines, traditions, and institutions…” (p. 3 and p. 15). This approach bears some similarity to the consideration of repugnance (the yuck factor) described above. In this inquiry, it will be essential to “identify the biological substrates” of these morally important features or capacities—for example, the neural organization, circuits, and functions that together would be necessary for them to develop—and then “threshold levels for these features and functions that must not be allowed to appear jointly” in a neural organoid or chimera. Thresholds should allow “safety margins to be built into the limits against the possibility of generating” organoids with morally concerning features.

At the level of science policy, if there is broad agreement on features or capacities that raise moral concern and the neural substrates jointly required to achieve them, oversight policies based on avoiding these neural substrates could be crafted. The history of policy debates regarding other technologies, such as genetically modified foods (Scott et al., 2018) and wastewater recycling (Miller, 2012), suggests the value of engaging with the public, understanding and addressing their concerns, and linking research to important unmet needs—for example, unmet needs for treatments for brain diseases—that all can recognize (Lassen, 2018).

SUMMARY

This chapter has reviewed a number of important ethical issues regarding human neural organoid, transplantation, and chimera research. First, there are strong ethical reasons for working to relieve serious human suffering caused by neurological and psychiatric diseases for which effective treatments are lacking or limited (Parker, 2020). Second, there may be concerns about human beings encroaching on divine roles or overreaching appropriate human activities. Third, there may be ethical issues involved in carrying out such research using cells derived from biological materials of persons who did not know their materials were being used for such research and, had they been told, would have objected. Such concerns may be particularly salient in groups that have suffered health disparities and discrimination. Fourth, there are various concerns related to the distinctions between human beings and other animals. Fifth, there are concerns about animal welfare and animal rights. Sixth, there are concerns about consciousness and enhanced capacities in research animals or neural organoids. Finally, there are concerns about the use of nonhuman primates in such research. The committee emphasizes that there are a range of positions on these issues, and that many important issues require discussion among people with different perspectives.