The Emerging Field of Human Neural Organoids, Transplants, and Chimeras Science, Ethics, and Governance (2021) / Chapter Skim
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4 Oversight and Governance
4 Oversight and Governance
Pages 65-90
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From page 65... ...
A particular challenge to government regulation and voluntary guidelines on research involving human neural organoids, transplants, and chimeras is the broad range of strongly held, and often inconsistent, views in the United States and internationally. Some views are based on religious commitments to different faith traditions, while others are based on secular arguments.
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From page 66... ...
USE OF HUMAN STEM CELLS Important protections for research participants are provided by the Federal Policy for the Protection of Human Subjects,3 with oversight by institutional review boards (IRBs) at the respective research institutions.
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From page 67... ...
Table 4-1 summarizes regulations and guidance on the use of human stem cells for this research. The Common Rule is heavily influenced by the 1979 Belmont Report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research,7 as well as, in part, by the Helsinki Declaration, which lays out ethical principles for medical research involving human subjects.8 Although there are a wide range of policies throughout the world (HHS, 2020)
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From page 68... ...
NOTE: Additional oversight is required if the use of human stem cells includes transplantation into a nonhuman animal (see Table 4-2)
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From page 69... ...
ESCROs, SCROs, or Embryonic Research Oversight (EMRO) committees could consider a wide range of ethical issues related to research involving human stem cells, including the possibility of altered capacities in chimeric animals or the development of consciousness in organoids, but there is very little information about how these committees function at different institutions.
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From page 70... ...
The most commonly used approach to obtaining consent for future research and sharing of biospecimens and information with other researchers is deidentification: donors are told that future research and sharing might be carried out in such a way that "the identity of the human subjects cannot readily be ascertained directly or through identifiers linked to the subjects, the investigator does not contact the subjects, and the investigator will not re-identify subjects."12 In everyday discussions, the literature, and this report, such specimens are called "deidentified," and the persons who provide the materials for research are called "donors." With such disclosure, future research and sharing are permitted without additional consent. An alternative to obtaining consent for future research and sharing of identifiable specimens and information is broad consent.
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From page 71... ...
In addition to situations that involve carrying out future research and sharing deidentified specimens, additional consent and full IRB review are not required in two other cases. First, as discussed previously, if biospecimens and information remain identifiable but were collected with broad consent for future research, the additional research may proceed without additional consent if the IRB ascertains that the proposed new research falls within the terms of original donation of the biospecimens.
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From page 72... ...
Federal regulations require that research protocols describe the research, approaches used to reduce animal numbers, justification for the use of animals, information on alleviation of pain and distress, methods of euthanasia, an understanding of the scientific literature, and plans for appropriate veterinary care. The committee notes that the requirement to justify the use of animals in terms of prospective benefit to human health in the case of neural cell transplant and chimera research goes conceptually beyond the Three R's framework (reduce, refine, and replace)
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From page 73... ...
Researchers working with animals with human neural cell transplants or chimeric animals would follow these same guidelines. The principles that underlie the U.S.
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From page 74... ...
. USE OF NONHUMAN PRIMATES IN RESEARCH The use of nonhuman primates raises obligations that go beyond those required for other research animals.
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From page 75... ...
. In recent years, however, the use of human stem cells for neural cell transplants into nonhuman animals or for generation of human neural chimeras has been the subject of policy discussions at NIH.
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From page 76... ...
to the animal brain by the human brain cells" Neural cell transplant Review by IACUC, with Proposal for additional oversight made by grafting human additional protections and of research that shows a cells into a fetal or oversight for nonhuman primates, "substantial contribution or a postnatal nonhuman including measures to promote substantial functional modification primate brain psychological well-being to the animal brain by the human cells" Chimera made by insert- Review by Funding moratorium. ing human cells into a IACUC nonprimate vertebrate (e.g., mouse)
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From page 77... ...
This type of research should not be conducted at this time (NRC and IOM, 2010) Specialized review when the degree of functional integration into the central nervous system may substantially alter the animal host or when human cells may contribute to gametes; especially rigorous for nonhuman primates; best practices for ensuring animal welfare (ISSCR, 2016)
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From page 78... ...
, NIH issued a notice of proposed changes to its guidelines to include the establishment of an NIH steering committee that would provide additional oversight for neural cell transplants and human neural chimeras. NIH proposed that this committee could oversee research involving the introduction of human stem cells early in embryonic development in any vertebrate animal, as well as studies (excluding those in mice)
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From page 79... ...
They state that research may require specialized review if human cells have the potential for a high degree of integration into an animal's central nervous system or if they may generate human gametes in nonhuman animal hosts. If the research involves nonhuman primates, this review should be "especially rigorous." The ISSCR guidelines also recommend best practices for ensuring animal welfare if and when "the degree of functional integration of human cells is considerable enough to raise concerns that the nature of the animal host may be significantly altered." These best practices include: "(a)
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From page 80... ...
process.b These entities vary substantially in whether they look only at research involving embryonic stem cells (ESCs) or also consider iPSCs and if so, in which projects -- usually those that involve the generation of human gametes that will be fertilized.
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From page 81... ...
The oversight of organoids addresses only the ethical concerns regarding the human donors of the cells from which they are developed. Scenario 2: Human Neural Cell Transplant into an Animal A researcher at an American university wants to transplant human neural stem cells derived from patients with early-onset schizophrenia and from neurotypical individuals into the brains of neonatal mice.
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From page 82... ...
However, several countries have policies that include provisions for the transplantation of human stem cells into nonhuman animals, and these policies show a range of approaches. The ISSCR guidelines, described above, are influential in much of the world and provide additional relevant guidance for scientists and institutions.
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From page 83... ...
macaque such that integration into circuits might lead to altered behavior Red Level of Scrutiny: Research That Should Not Proceed at This Time Neural Organoids Neural Cell Transplants Neural Chimeras Experiments using iPSCs to Studies where human stem Transplantation of human generate neural organoids that cells introduced into nonhuman cells into blastocysts of violate the terms of the human primate embryos with the aim nonhuman primates followed donor's consent of populating the developing by implantation into the uterus neural tube could result in of a host generation of donor-derived gametes in the host common in the developed world, as discussed above, and add another layer of oversight for this type of research. Several countries have developed official policy or guidance on the transfer of human cells into nonhuman animals that follows the three-tiered approach to oversight described in the preceding section, identifying research that can proceed under existing oversight mechanisms; research that may require additional review; and research that should be prohibited.
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From page 84... ...
Studies involving transplantation of human stem cells into the brains of great apes fall into the third tier and should be prohibited. The Embryo Protection Act of 1990 had essentially already placed fusion of nonhuman animal embryos with human embryos into the third tier by prohibiting this research.36 The United Kingdom Home Office adopted guidance of this type in 2016 in response to a report from the UK Academy of Medical Sciences (Academy of Medical Sciences, 2011)
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From page 85... ...
they are designed to reconstitute a specific tissue or organ to derive a preclinical model or to demonstrate that the cells are pluripotent, and (2) these nonhuman animals grafted with human stem cells will not be used for reproductive purposes.
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From page 86... ...
Oversight of research involving neural cell transplants and human neural chimeras in China is unclear. In 2003, the Ministry of Science and Technology and the Ministry of Health enacted the Ethical Guidelines for Research on Human Embryonic Stem Cells, which includes some oversight at the national and institutional levels for these cells (Liao et al., 2007)
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From page 87... ...
Rather than creating an exhaustive list of potential future uses (such as the use of tissues to create neural organoids) , participants consent to donating tissue to a biobank with an explicitly described governance model.
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From page 88... ...
Research on neural organoids or transplantation of human cells into nonhuman animals was not specifically discussed in this workshop. Animal Welfare If the acquisition of new capacities is suspected in animals used in research involving neural transplants or chimeras, additional training may be needed for 44 NRC and IOM, 2010, §§ 3.6 and 7.1.
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From page 89... ...
As research involving human neural organoids, transplants, and chimeras advances, there may be additional opportunities at the national level for discussion of ethical issues and oversight. For example, the Novel and Exceptional Technology and Research Advisory Committee (NExTRAC)
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From page 90... ...
released reports on such issues as stem cell research (PCB, 2004) , human cloning (PCB, 2002)
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