A major reason that researchers seek to understand the human brain is to prevent, treat, and cure neurological and psychiatric diseases. These diseases, which affect tens of millions each year (Disease and Injury Incidence and Prevalence Collaborators, 2018), include neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, and psychiatric disorders such as autism spectrum disorder, depression, and schizophrenia. Treatments for these conditions are partially effective at best and in some cases are completely lacking. In addition to the suffering and disability faced by affected individuals and their families, brain diseases have a tremendous economic impact. In 2017, neurological disorders were estimated to cost more than $800 billion per year in the United States, including costs related to both clinical care and lost productivity due to disability and mortality (Gooch et al., 2017). Psychiatric diseases take a similar toll, annually imposing total costs exceeding $200 billion in the United States (Greenberg et al., 2015) and reaching up to $2.5 trillion globally (Trautmann et al., 2016). Depression and anxiety disorders alone account for 8 percent of years lived with disability worldwide (Disease and Injury Incidence and Prevalence Collaborators, 2018). In this context, the National Institutes of Health (NIH) has made brain research a priority, budgeting over $10 billion in 2020 to improve our understanding of the brain and its disorders (NIH, 2020).
Given the devastating toll of brain diseases, there is strong public interest in research advances that offer hope for their treatment or cure. Furthermore, the brain captures the public imagination: Everyone understands that the brain defines human beings in fundamental ways. However, news reports and blog posts sometimes fail to satisfy this curiosity in appropriate ways. Rather, they may describe brain research in terms that maximize attention at the expense of
scientific accuracy. Headlines regarding research described in this report include, for example, “Lab-Grown ‘Mini Brains’ Can Now Mimic the Neural Activity of a Preterm Infant” (Stetka, 2019), “Scientists Re-create Baby Brain Readings in a Dish” (Devlin, 2019; Fernandez, 2019; Grossman, 2018), “The smart mouse with the half-human brain” (Coghlan, 2014), and “These mice have brains that are part human. So are they mice, or men?” (Nogrady, 2018). These news articles draw from scientific publications and interviews with researchers and sometimes quote the scientists involved. Nonetheless, the implications are misleading—researchers are not currently developing miniature brains in a vat, and there are no mouse brains that are half human. These articles fuel uneasiness about brain research involving human neural organoids, transplants, and chimeras.
That is not to say, however, that uneasiness about such research is inappropriate. Most would agree with the statement, “If I receive your kidney as a transplant, I am still me, but if I receive your brain as a transplant, I’m not sure who I’d be.” Therefore, research that involves human brain cells, despite its potential to provide new therapies for brain diseases, raises legitimate concerns about what is appropriate and whether it might result in the erosion of moral distinctions. This report begins by describing some of the advances achieved in these areas of research and then goes on to examine the ethical and societal concerns that they raise.
Research on the brain is difficult, and advances in understanding of how the brain works have lagged progress in other biomedical fields. The human brain contains nearly 100 billion neurons interconnected by trillions of synaptic connections in complex circuits that process vast amounts of information. Unsurprisingly, such complexity presents formidable challenges, and tools for studying brain circuits are only now being developed. Another difficulty is a lack of good model systems for brain research. Animal models used to study brain structure and function have been useful, but there are key molecular, cellular, and organizational differences between the brains of rodents or even nonhuman primates and those of humans. Perhaps for this reason, treatments for diseases that have shown promise in animal models are often ineffective in humans (Hyman, 2018; King, 2018; Sierksma et al., 2020).
Over the past few decades, neuroscientists have greatly advanced understanding of how neurons develop, function, form complex circuits, and underlie at least some simple behaviors, to the point that it is now possible to begin using this knowledge to tackle human disease mechanisms and design effective therapies. However, making this leap is difficult largely because of practical, ethical, and legal limitations to studying the human brain. Noninvasive techniques such as functional MRI (magnetic resonance imaging) or EEG (electroencephalography) provide insight into the functioning brain, but they are limited in spatial resolution, physiological information, and the types of experimental manipulations that are possible. Investigating the cellular and molecular bases of brain function requires access to brain tissue, which is difficult to obtain and generally limited
to samples removed during surgery or postmortem. Therefore, novel methods for assessing the function and dysfunction of the human brain are needed.
To address these limitations, researchers in recent years have developed new models to better represent the human brain. The three models considered in this report are human neural organoids, human neural cell transplants (sometimes called xenografts), and human neural chimeras (see Chapter 2 for further detail).
Human neural organoids (see Figure 1-1) are three-dimensional aggregates of neural cells grown in the laboratory from human stem cells. While small (currently no more than 4 mm in diameter), neural organoids recapitulate some important developmental and molecular features of fetal human brains. Current neural organoids are limited in complexity and maturity, but researchers are working to overcome these limitations.
Human neural transplants1 (see Figure 1-2 A, B) are generated by transplanting human cells into the brains of model organisms. Although human cells have been transplanted into nonhuman animals for decades, the range of applications has steadily increased. How extensively the human cells grow and integrate into an animal brain depends on the developmental stages of the cells and of the host brain, with earlier transplantation and less differentiated donor cells leading to more extensive codevelopment and integration. These transplants enable the study of human brain cells in the context of a whole organism and its behaviors.
Human neural chimeras (see Figure 1-2 C) are a special case of transplants. To generate a chimera, human stem cells are injected into a nonhuman host very early in embryonic development. They then intermingle with the host cells that form the brain, thereby populating it from the earliest stage and developing in parallel with the host. In one variant of the method, called blastocyst complementation, the transplanted stem cells replace many of the host cells in particular brain regions. To date, viable neural chimeras have been generated only using rodent stem cells injected into rodent hosts, but research in this area is advancing rapidly. These methods may never be applicable to humans therapeutically, but their potential as a research model is great.
While the committee focused on issues related to human neural organoids, transplants, and chimeras, such research is part of a larger field wherein analogous methods are being applied to variety of organs, such as the kidney and liver. As with neuroscience research, work in other areas has the multiple aims of elucidating developmental principles, analyzing disease mechanisms, and identifying novel therapeutic targets. For nonneural chimeras, a stated aim is to generate human organs in nonhuman hosts for potential transplantation into humans with organ failure. While the committee took note of this groundbreaking work, the current report is limited in scope to discussions of human neural organoids, transplants, and chimeras.
Human neural organoids, transplants, and chimeras are already yielding important insights into the functioning of the human brain and human brain disorders. As they become more like real human brains and improve as model systems, however, they raise difficult ethical questions: As human brain organoids become larger and more complex, could they gain some degree of consciousness? Could they “feel” pain? As scientists successfully integrate more human cells into the brains of chimeric animals, could the resulting animal have capacities substantially different from those typical of their species? If so, would they
1 In this report, human neural transplant refers to the transplantation of human neural cells or groups of human neural cells into the brains of nonhuman animals. The transplantation of large portions of the human brain has not been proposed to date and is currently infeasible. Such transplants are excluded from consideration in this report.
need to be treated differently than other laboratory animals? Could the animals develop characteristics that are commonly thought of as human? Does creating these transplants or chimeras violate the distinction between humans and other animals that is deeply embedded in many cultures?
This report, funded by the National Institutes of Health and the Dana Foundation, examines the state of human neural organoid, transplant, and chimera research and considers some of these questions. The committee convened by the National Academies of Sciences, Engineering, and Medicine to conduct this
study was asked to review the status of this research, consider its benefits and risks, examine associated ethical issues, and consider what oversight mechanisms might be appropriate in this area. In contrast to many reports produced by the National Academies, and as directed by the charge to the committee, this report provides consensus findings on these topics but not specific recommendations. The committee was asked to consider such questions as
- How would researchers define or identify enhanced or human awareness in a chimeric animal?
- Do research animals with enhanced capabilities require different treatment compared to typical animal models? What are appropriate disposal mechanisms for such models?
- What types of brain tissue are appropriate for use as neural organoids?
- How large or complex would the ex vivo brain organoids need to be to attain enhanced or human awareness?
- What kind of “humanized” brain, in size and structures, would be acceptable in a research animal?
- Should patients give explicit consent for their cells to be used to create neural organoids?
- What regulatory mechanisms relating to organoid and chimeric animal research are currently in place? Are there gaps in the current regulatory framework?
- What regulatory mechanisms exist for similar research?
- What further regulatory mechanisms might be appropriate?
Examination of these issues required both assessment of the relevant science and consideration of ethical and philosophical issues related to humanness, consciousness, self-awareness, and the welfare of entities with altered or “enhanced” capacities. To carry out these tasks, the committee conducted an extensive literature review and held seven virtual meetings in which experts provided diverse perspectives in the areas of neuroscience, animal models, theories of consciousness, religious scholarship, and other relevant areas. The committee then consolidated the information obtained to formulate the findings presented in this report as guidance for scientists, clinicians, regulators, and the general public when considering how to balance the value of this research with the ethical concerns it raises. Agendas for the committee’s meetings are found in Appendix B.
Chapter 2 summarizes the state of the science of human neural organoids, transplants, and chimeras. It also provides information on current understanding of consciousness, awareness, and related capacities, and considers how these capacities might be observed and measured in these model systems. Chapter 3
focuses on ethical issues that arise in the course of research with human neural organoids, transplants, and chimeras. Some of these issues (such as animal welfare and consent from human subjects who provide tissue for research) are the same as those encountered in other areas of biomedical research, while others are more specific to the types of research discussed in this report. Chapter 4 summarizes current oversight of research involving human neural organoids, transplants, and chimeras, which occurs at different levels—the institution where the research is taking place; professional guidelines; state and federal laws and regulations; and, for international collaborations, regulations in other countries. This chapter also considers areas in which the current oversight system might be augmented to take account of the new technologies involved in this research. Chapter 5 considers the role of public engagement in the context of emerging issues of science, technology, and medicine. The information detailed in these chapters, which was gathered through the processes described above, served as the basis for committee deliberations and for the findings presented in Chapter 6.
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