The committee’s findings fall into six areas:
- Value of this research
- State of the science
- Issues of ethical concern
- Assessment of consciousness and pain in human neural organoids, transplants, and chimeras
- Oversight and regulation
- Public engagement and communication
Finding I.1: Brain diseases—neurological and psychiatric disorders—are the leading cause of morbidity worldwide, resulting in mortality and untold suffering, as well as enormous financial burdens in health care costs and lost wages. There are few if any highly effective treatments for many of these disorders, which include traumatic injury; neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis; psychiatric diseases, such as schizophrenia and bipolar disorder; developmental disorders, such as autism spectrum disorder; and brain cancers. The lack of progress in developing therapeutics for these disorders in large part reflects a lack of knowledge regarding the underlying disease processes in the developing or adult brain and how brain aging contributes to disease onset and progression. The development of new therapies will require a foundation of greater basic knowledge about human brain development, maturation, and function and greater translational knowledge about
the mechanisms of brain diseases. However, research on the human brain itself is limited by a combination of legal, practical, and ethical restrictions, as well as technical hurdles. Small animal models provide a valuable alternative, but they are insufficient for studying complex human brain disorders.
Finding I.2: Recent advances in human stem cell research now enable ready access to human neurons and glial cells, facilitating the development of more sophisticated models with which to study brain diseases and disorders in greater depth. Human neural organoids, transplants, and chimeras are powerful models that use stem cells to circumvent many of the limitations noted above, providing novel ways to understand normal and abnormal human brain development, analyze disease mechanisms, and assess therapeutic approaches. Thus, they have the potential to be invaluable additions to human studies and animal models. The promise of these novel human brain cell models is that they will contribute to understanding of the mechanisms of brain development and function, and pave the way for the development of transformative therapies that can relieve the significant burden of neurological and psychiatric diseases. However, this promise must be carefully weighed against the ethical concerns such models may raise.
State of the Science
Finding II.1: Human neural organoids are cellular aggregates derived from human stem cells, in which multiple, diverse types of neuronal and glial cells differentiate and form three-dimensional organized assemblies. They have been used to model several aspects of human brain development and structure. Organoids generated from patient-derived stem cells sometimes exhibit disease phenotypes that can be used to elucidate pathogenic mechanisms and test potential interventions. However, organoids are limited in size and complexity and lack important cell types, brain regions, and anatomically organized neural circuits thought to be required for complex human brain function, including consciousness. Researchers are actively pursuing new techniques for overcoming these limitations of organoids, and this work will likely lead to organoids of increased size and greater complexity. Maturation is also likely to be improved, but the likelihood of generating a structure with the intricate organization, wealth of diverse cell types, and complex interconnectedness that would resemble in any significant way the mature functioning human brain is remote for the foreseeable future.
Finding II.2: Transplantation of human neural cells into the brains of nonhuman animals shows promise for improving models of neurological and psychiatric disease. Human glial precursors can be introduced into the brain of animal models, where they differentiate, integrate, and function. However, limitations exist that determine the level of maturation and integration of the transplanted cells within the host brain. These limitations are due to species-specific differences in
developmental times whereby, for example, human brain cells mature much more slowly than their mouse counterparts, even upon transplantation in the mouse brain. The result is a developmental mismatch that is likely to affect the contribution of human neural cells to the working circuits of the host.
In chimeric animals (as defined above), donor and host cells develop together from the earliest stages of embryogenesis. In one such method, blastocyst complementation, host cells that would normally contribute to particular brain regions are eliminated at an early stage, allowing extensive replacement of those regions by donor cells. To date, neural chimeras generated by these methods use donor and host cells from the same or closely related species. It is not currently possible to generate neural chimeras of human cells in embryos of any nonhuman species that survive postnatally or even to late fetal stages. Generation of such chimeras may eventually be more feasible in nonhuman primates than in rodents.
Issues of Ethical Concern
Finding III.1: Because of the human suffering and mortality caused by brain disorders, limitations of current animal disease models, and the uniquely human quality of some brain diseases, there are strong moral arguments in favor of research using organoids, transplants, and chimeras derived from human cells as long as such research is balanced with other ethical considerations, such as ensuring animal welfare, appropriate use of human biological materials, and safety.
Finding III.2: Some studies in which human neural cells have been integrated into the brains of nonhuman animals raise moral, ethical, and religious concerns regarding the mixing of humans and other animals, the special status of humans, animals acquiring attributes that could be viewed as distinctively human, or humans taking on roles that should be reserved for a deity. Similar objections may also be raised from a secular viewpoint—for example, that conducting such research shows hubris or that the resulting entity offends the dignity of human beings.
A key concern is that a fundamental distinction between humans and other animals could be blurred. The increasing ability to generate human-animal chimeras with greater integration of human neural cells heightens this concern. There may also be concerns that some human cells outside the body should not be treated as mere clumps of matter. Some types of cells, such as human blastocysts and embryonic stem cells that are considered potential or actual human beings, are accorded greater or special respect, depending on one’s religious and philosophical views.
Finding III.3: Under Subpart A of the Federal Policy for the Protection of Human Subjects, often called the Common Rule, existing biological materials that have been collected with appropriate consent and deidentified may be used in
future research projects. However, provisions of the Common Rule are seen by some as a minimal standard for meeting ethical requirements in this area. For biological materials collected in the past, specific consent for human neural organoid, transplant, and chimera research was generally not obtained. There is active discussion regarding the advantages and disadvantages of obtaining specific consent going forward for the collection of fresh tissue for such research.
As a practical matter, recontacting donors to obtain specific consent is sometimes impossible. Moreover, many induced pluripotent stem cell (iPSC) lines obtained from donor tissue have been extensively characterized or were derived from patients with very rare diseases, and deriving new lines would be extremely difficult in these cases. On the other hand, most donors were not aware that their tissues would be used for neural organoid, cell transplant, or chimera research, and some might have objected if directly asked for their consent for such uses. Past ethics violations during research with African American and Native American participants make this a sensitive topic for these populations.
Finding III.4: Nonhuman animals have interests and some believe they have rights. Humans should therefore respect their well-being and their intrinsic nature and telos. However, there is wide agreement that it is permissible to use animals for basic and translational research directed toward the goal of relieving human suffering as long as the research is justified in terms of prospective benefit to human health, harm to animals is minimized, and the needs of the animals are met. Well-established regulations and practices emphasize the requirements to minimize the number of animals used; replace them with other experimental models when possible and consistent with the approved scientific aims of the research; alleviate or minimize their pain and distress; and provide them appropriate living conditions, including nutritious food, safe shelter, housing, companionship, and opportunities for stimulation.
As transplantation and chimeric models of human brain diseases become better able to model key disease features, research animals are likely to show behaviors that resemble human symptoms and that would be viewed as distressing were they to occur in humans. Close observation of the animals can identify such behaviors, which may need to be avoided or mitigated to maintain animal welfare. Another concern is that host animals might acquire altered behaviors wholly atypical of their species, such as new forms of problem solving or substantially altered, complex social interactions. If so, objections to using such animals for research might increase. The committee found scant evidence that this is a realistic possibility in the foreseeable future, but surveillance of this rapidly developing research is essential.
Finding III.5: The complexity of neural organoids is currently limited. It is extremely unlikely that in the foreseeable future they would possess capacities that, given current understanding, would be recognized as awareness, conscious-
ness, emotion, or the experience of pain. Thus, it appears at present that neural organoids have no more moral standing than other in vitro human neural tissues or cultures. As scientists develop significantly more complex organoids, however, the need to make this distinction will need to be revisited regularly. Moreover, organoids can be transplanted into the brain, blurring the distinction between organoids and transplants.
Assessment of Consciousness and Pain in Human Neural Organoids, Transplants, and Chimeras
Finding IV.1: Decisions about how research on neural cell transplantation and chimeras should be conducted or overseen depend in large part on the possibility that the animal host will have altered capacities as a consequence of its brain cells being augmented or replaced by human cells. The possibilities of pain sensation, and altered consciousness are often raised as issues of particular concern, but both pain and consciousness are difficult to define or measure. While measurements of neuronal activity and circuit physiology are possible in organoids, these measurements are not considered sufficient to determine whether organoids may be conscious or feel pain. In contrast, when human cells are incorporated in a host brain, via either chimera formation or cell transplantation, it will be possible to devise and deploy methods for detecting differences in the behavior of that host compared with that of a host in which human cells have not been integrated. Some metrics and indicators already exist, particularly for pain. Likewise, there are quantitative methods for assessing behavior with high temporal and spatial resolution. Research veterinarians, ethologists, and animal behavior researchers are well suited to providing guidance on how to identify and interpret behaviors that are not typical of the species or the individual.
Finding IV.2: Most current methods for assessing consciousness (sometimes called awareness or sentience) and pain cannot be applied to organoids because understanding of these capacities depends largely on observing behaviors in whole animals. With the current state of knowledge, it would be difficult to use these measurements as evidence for the existence of pain or consciousness in organoids.
Oversight and Regulation
Finding V.1: Many ethical concerns raised by current and near-future research can be addressed by current oversight mechanisms, which are often created for specific ethical purposes. Nonetheless, some concerns will need be reassessed as the science develops.
Finding V.2: Neural organoids will not raise issues that require additional oversight until and unless they become significantly more complex.
Finding V.3: Transplantation of human neural cells or human neural organoids into nonhuman animals falls under a well-developed oversight system for animal research. In the United States, this system is built on the Animal Welfare Act and the Public Health Service Policy on Humane Care and Use of Laboratory Animals (PHS Policy). It includes review and approval of research protocols by institutional animal care and use committees (IACUCs), as well as on-the-ground monitoring by research veterinarians and animal caregivers. As currently constituted, however, some IACUCs may not contain sufficient independent expertise in neural cell transplant or chimera research or interpretation of animal behavior after transplantation of human neural cells.
Finding V.4: The animal welfare concerns raised by the generation of neural chimeras through blastocyst complementation in rodents also fall under significant and capable oversight by IACUCs and research veterinarians. Again, however, additional expertise on topics such as behavioral capabilities may be required.
Finding V.5: Some future research, including that involving more complex human neural organoids, transplants, and chimeras and the generation of transplants and chimeras in nonhuman primates, will benefit from additional discussion of ethical and social issues that extend beyond reviews of individual research projects currently carried out by IACUCs. Examples include injection of human stem cells into nonhuman animal blastocysts and indications that suggest enhanced capacities in transplant recipients or chimeras. Possibilities for additional oversight or safeguards include pilot studies followed by re-evaluation, implementation of novel measures to monitor capacities of research animals, and designation of research that should not be conducted at this time. There are advantages to carrying out such discussions at the national level, where a wide range of viewpoints and disciplinary backgrounds could be convened.
Finding V.6: Interdisciplinary research organizations, such as the International Society for Stem Cell Research (ISSCR), periodically analyze the updated state of the science, but no national or governmental bodies in the United States have this task as part of their mandate. Moreover, there is currently no national body in the United States whose charge is to review emerging science in key areas or to assess their ethical and regulatory implications.
Finding V.7: In several fields of innovative and rapidly developing biomedical research that raise social and ethical concerns, such as human embryonic stem cell research and human genome editing, a three-tiered system of oversight has been recommended and, in some cases, adopted:
- research that can be carried out under current oversight procedures,
- research that requires heightened oversight, and
- research that should not be carried out at this time.
This system allows ethically uncontroversial research projects to be carried out without imposing an administrative burden while providing additional scrutiny of research projects for which attention to emergent issues or additional expertise in the review body is helpful.
Prohibition of some types of research can reflect widely accepted limits on research that have been articulated by public and scientific groups. A prohibition on conducting such research at present also allows for later reconsideration once the science has matured enough to understand its consequences, along with an updated assessment of ethical considerations.
Public Engagement and Communication
Finding VI.1: Calls have been increasing for greater public engagement in assessing the value of emerging areas of biomedical research. Such engagement has several benefits, including helping the public understand the research, identifying public concerns, facilitating informed public discussion, and influencing science policy. However, the United States currently lacks robust mechanisms for facilitating this public engagement. Analysis of lessons learned from efforts on related topics could support the design of effective strategies for engaging the public in discussion of human neural organoids, transplants, and chimeras.
Finding VI.2: Well-designed social science research could also help scientists, regulators, and policy makers better understand the views of the public. Social science research on public attitudes toward and perspectives on human neural organoid and chimera research is currently lacking in the United States.
Finding VI.3: During its meetings and deliberations, the committee appreciated hearing the perspectives of religious scholars of several faith traditions and engaging in discussions with experts in medicine, biology, philosophy, law, theology, religious studies, and other disciplines. These discussions were mutually enlightening and should be continued. Because of the plurality of religious and secular views in the United States, ongoing dialogues between religious and secular perspectives and among different viewpoints are important. There are currently few if any established forums for fostering this exchange.
Finding VI.4: In some cases, terms used to describe human neural organoids, transplants, and chimeras have been inaccurate, inadequately descriptive, or misleading. These terms can evoke, intentionally or unintentionally, emotional responses that do not reflect the science being described, and they can be used to pull the public toward acceptance or rejection of a technology. As one of many examples, neural organoids are often referred to in the press as “mini-brains,” but in reality, they model only some limited aspects of brain tissue. Closer attention to issues of nomenclature by scientists and their institutional representatives in their interactions with the press and public would facilitate a more informed public debate about brain research.
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