This page assembles the sections of the Guidelines that specifically address research involving the transfer of human stem cells into animals. Other sections of the Guidelines may be relevant to such research (e.g., Section 2.1 Review Process and Section 2.3 Procurement and Informed Consent of Human Biological Materials).
2.2.1 Category 1
2.2.1A: Category 1A. Research determined to be exempt from a specialized scientific and ethics oversight process after being assessed by the appropriate existing mandates and committees for laboratory research. Category 1A research includes the following activities:
- The transplantation of human stem cells, their derivatives, or other human cells into postnatal animal hosts (see Recommendation 126.96.36.199).
2.2.1B: Category 1B. Research that is reportable to the entity or body responsible for the specialized scientific and ethics oversight process, but not normally subject to further or ongoing review, at the discretion of the entity responsible for the oversight process and subject to regulations and policies in the jurisdiction. Category 1B research includes the following activities:
- Chimeric embryo research in which human pluripotent stem cells are transferred into non-human, mammalian embryos and cultured in vitro for the minimum time necessary to achieve the scientific objective without gestation.
Scientists pursuing Category 1A and B research are recommended to consult with appropriate institutional review committees or the committee or body responsible for the specialized scientific and ethics review process (see Recommendation 2.1.3) to determine the categorization of new research proposals. Committees with the jurisdiction over the relevant research should oversee the provenance of cells, tissues and derived human pluripotent stem cell lines to ensure that procurement and derivation is deemed acceptable according to the principles outlined in this document (see section 2.3.5) and is in compliance with rigorous scientific, legal, and ethical standards.
Category 1B covers in vitro chimeric embryo research and in vitro gametogenesis for which there is no intent to generate a human embryo or fetus. Researchers are encouraged when possible to report on existing or planned in vitro experiments to the committee responsible for the specialized scientific and ethics oversight process to help identify cases that may warrant full review in the future.
Studies Transplanting Human Stem Cells or Their Direct Derivatives into the Central Nervous Systems of Animals
Recommendation 188.8.131.52: Research involving the transfer of human stem cells or their direct neural and/or glial derivatives into the central nervous systems of postnatal animal hosts requires review by institutional animal research oversight committees supplemented by reviewer expertise in stem cell or developmental biology. (ISSCR Guidelines, 2006; Academy of Medical Sciences, 2011). Such oversight should weigh the potential benefits of the research and should utilize available baseline non-human animal data grounded in rigorous scientific knowledge or reasonable inferences and involve a diligent application of animal welfare principles.
Institutions should determine whether research involving human cells that have the capacity to integrate into the nervous systems of laboratory animals requires supplementation of the pre-existing animal research review process with scientists and ethicists that have relevant topic-specific expertise.
To assist review and oversight of stem cell-based human-to-non-human animal research, the ISSCR has provided an advisory report that guides reviewers through a series of considerations not typically covered by institutional animal research committees, but that are relevant for review (Hyun et al., 2021). Past experiences with genetically altered laboratory animals have shown that reasonable caution might be warranted if changes carry the potential to produce new defects and deficits. Current best practices dictate that research involving modified animals must involve the following:
- the establishment of baseline animal data;
- ongoing data collection during research concerning any deviation from the norms of species-typical animals;
- the use of small pilot studies to ascertain any changes in the welfare of modified animals; and
- ongoing monitoring and reporting to animal research oversight committees authorized to decide the need for real-time changes in protocols and, if necessary, the withdrawal of animal subjects.
Research that may result in the presence of human gametes and their precursors in the gonads of laboratory animals is of not of significant ethical concern per se, as long as the animals are not allowed to breed (see Category 3 below).
Reviewers and investigators should follow the proposed ethical standards presented in the 2020 white paper and Appendix 1, while exercising appropriate judgment in individual situations. Research involving animals should also generally comply with the principles of the 3Rs (see: www.nc3rs.org.uk) and follow the ‘ARRIVE guidelines’ (Percie du Sert et. al 2020).
2.2.2 Category 2
2.2.2 Category 2. Forms of research with embryos, certain chimeras, and stem cell-based embryo models that are permissible only after review and approval through a specialized scientific and ethics review process. A comprehensive review should be coordinated with other relevant oversight, such as that provided by human subjects review committees, in vitro fertilization (IVF) clinic oversight bodies, and animal research review processes (see 2.2.1), and the research should comply with local law and policy. All such research should have a compelling scientific rationale and necessitate the use of these materials rather than employ alternative models. The research should use the minimum number of embryos necessary to achieve the scientific objective. Forms of research requiring comprehensive review by a specialized review process encompass the following activities:
- Chimera research in which human pluripotent stem cells or their derivatives with broad potential are introduced into a) a non-human embryo or fetus in utero or b) a non-human embryo in vitro followed by transfer into a non-human uterus. Such experiments – if they are scientifically justified for the use of non-human primates above all other laboratory species – must exclude great and lesser ape species hosts (i.e., chimpanzees, gorillas, orangutans, bonobos, gibbons, and siamangs), as apes are prohibited from being used for invasive research in most parts of the world.
Human-Animal Chimeric Embryo Research
Recommendation 184.108.40.206: Chimeric embryo and in utero research described in ‘Category 2, i’ (see above) should proceed for the minimum time necessary to achieve the scientific aim. This research must proceed incrementally, stopping at well-defined timepoints to assess the degree and scope of chimerism during development before proceeding to full gestation, if full gestation is among the well-justified goals of the research. To avoid unpredictable and widespread chimerism, researchers should endeavor to use targeted chimerism strategies to limit chimerism to a particular organ system or region of the gestating chimeric animal.
Techniques such as blastocyst complementation, whereby a specific cell type or organ is effectively deleted as the host embryo develops, can lead to a specific cell type or organ being replaced entirely by derivatives from the donor-derived pluripotent stem cells. By itself this targeted chimerism may not prevent contributions elsewhere in the chimera, thus the need for an incremental approach. Nonetheless, if the host cells have an advantage over the donor cells, such as even a slightly faster rate of cell replication, then the donor cells will be disadvantaged and effectively selected against, leading to a little or no contribution outside the organ of choice.
As a general principle, non-human primate species should only be used when all other species, more distant in evolution from humans, are inadequate for the scientifically well justified research question being pursued. Appropriate research aims include understanding human development, understanding species barriers to chimerism, and treating disease. Any research involving non-human primates must utilize common laboratory species that are widely used in biomedical research (which excludes apes). Trained veterinary staff specializing in the care of non-human primates must be closely involved in the review and oversight of studies involving the transfer of human stem cells and their derivatives into nonhuman primate hosts.
2.2.3 Category 3
2.2.3B Category 3B: Prohibited research activities. Research under this category should not be pursued because of broad international consensus that such experiments lack a compelling scientific rationale or are widely considered to be unethical. Such research includes:
- Research in which animal chimeras incorporating human cells with the potential to form human gametes are bred to each other.
- Transfer of chimeric embryos mixing animal and human cells (whether predominantly animal or human) to the uterus of a human or great or lesser ape (i.e., chimpanzees, gorillas, orangutans, bonobos, gibbons, and siamangs).
Public Representation of Science
Recommendation 4.1: The stem cell research community should promote accurate, current, balanced, and responsive public representations of stem cell research.
The high level of public and media interest in the field provides stem cell scientists with ample opportunities to communicate their findings through a variety of popular and social media channels. The research community is encouraged to responsibly engage interactively with the public through outreach and communications and by providing opportunities for public comment and feedback on scientific advances.
While such opportunities may allow scientists to gain recognition and understanding for their work among non-specialists, they also have the potential to fuel inaccurate public perceptions about the current state of scientific progress, potential for application, and associated risks and uncertainties (Kamenova and Caulfield, 2015). Scientists, clinicians, bioethicists, science communications professionals at academic and research institutions, and industry spokespersons should strive to ensure that benefits, risks, and uncertainties of stem cell science are not understated, misrepresented or overstated (see Recommendation 220.127.116.11). Additionally, due to public interest and concern in the ethics of human pluripotent stem cell research, and in order to ensure complete transparency of research and translational activities, the origin of stem cell materials should be clearly specified in all communications.
Care should be exercised throughout the science communication process, including in the promotion of research and translation activities, as well as in the presentation of scientific results, the use of social media, and in any communication with print and broadcast media. Particular caution should be exercised when preparing press releases and other types of promotional material. Researchers should make efforts to seek timely corrections of inaccurate or misleading public representations of research projects, achievements, or goals. Scientists should also be particularly careful about disclosing research findings that have not passed peer review, as premature reporting can undermine public confidence if findings are subsequently disproven. For example, if researchers post online preprints that have not been peer-reviewed, readers should be informed of the preliminary nature of such manuscripts.
Researchers must unintentionally avoid and correct inaccurate misconceptions in any communications regarding chimeras, genome editing, and other issues with a long history in the public imagination. While organoids, chimeras, embryo models, and other stem cell-based models are useful research tools offering possibilities for further scientific progress, limitations on the current state of scientific knowledge and regulatory constraints must be clearly explained in any communications with the public or media. Suggestions that any of the current in vitro models can recapitulate an intact embryo, human sentience or integrated brain function are unfounded overstatements that should be avoided and contradicted with more precise characterizations of current understanding. This is particularly relevant to brain organoids and human-animal chimeras, where any statements implying human cognitive abilities, human consciousness or self-awareness, as well as phrases or graphical representations suggesting human-like cognitive abilities risks misleading the public and sowing doubts about the legitimate nature of such research. Likewise, forward-looking statements on inherently uncertain developments, such as predictions on time required until clinical application, the likelihood of product approval, or speculation on the potential economic impact of currently unrealized technologies, must be accurate, circumspect, and restrained.
The stem cell community should work closely with communications professionals at their institution to create information resources that are easy to understand without oversimplifying, and that do not underplay risks and uncertainties or exaggerate potential benefits. Similarly, research-sponsoring institutions and communications professionals have a responsibility to ensure that any informational materials referring to research achievements adhere to these principles. Additionally, the scientists in charge of the research findings that are featured in informational materials should review and agree to the content prior to release. For potentially sensitive or high-profile cases, it is advisable to seek additional comments from independent experts to ensure objectivity and balance, place research in context of existing body of evidence, and help identify study limitations and alternative interpretations of key findings.