New guidelines for stem cell and embryo research from the ISSCR.

Abstract

The guidelines from the International Society for Stem Cell Research (ISSCR) provide regulators and research funders with a framework for the regulatory oversight of stem cell research and clinical translation, including recent advances related to embryo models, chimeric embryos, and mitochondrial replacement. The creation of embryos for research is not permitted in many countries. However, in vitro fertilization (IVF) is practiced widely and commonly leads to the creation of embryos that are not suitable for clinical use or that are in excess of the clinical need. Embryos that would otherwise be discarded can be donated, with informed consent, for research that could improve fertility treatment and reduce congenital disease, such as through mitochondrial replacement techniques (MRTs). Recent advances in stem cell and embryo research have shown that MRTs can be performed successfully and have enabled the generation of embryo-like structures from pluripotent human cell lines in culture, offering opportunities to use these, instead of human embryos, to study early human development. There have also been advances related to the capacity to generate chimeric animal embryos containing human cells that may someday offer the possibility of generating human organs for transplantation. However, new guidelines are required to validate these models and to determine the circumstances under which such research can proceed ethically. The ISSCR Guidelines for Stem Cell Research and Clinical Translation (https://www.isscr.org/guidelines), including the updates published on May 26, 2021, provide scientifically and ethically rigorous guidance for this research. The guidelines were written by a task force that included scientists, clinicians, bioethicists, and regulatory experts. They address the recent advances involving organoids, embryos, stem cell-based embryo models, chimeric embryos, and genome editing (Lovell-Badge et al., 2021Lovell-Badge L. Anthony E. Barker R. Bubela T. Brivanlou A. Carpenter M. Charo R.A. Clark A. Clayton E. Cong Y. et al.ISSCR Guidelines for Stem Cell Research and Clinical Translation: The 2021 Update.Stem Cell Reports. 2021; 16 (in press. Published online May 27, 2021)https://doi.org/10.1016/j.stemcr.2021.05.012Abstract Full Text Full Text PDF Scopus (34) Google Scholar) by weighing the scientific benefits of the research against unique issues posed by such research. The guidelines establish clear boundaries for permissible research and provide a basis for a rigorous oversight process to evaluate scientific and ethical issues. We discuss areas where regulators and research funders should consider the ISSCR Guidelines as a basis for revising policies that hinder promising research involving stem cell-based embryo models, chimeric embryos, and MRTs. Stem cell-based embryo models are created by using pluripotent cell lines to generate clusters of cells in culture that resemble embryos. Importantly, these models offer the opportunity to reduce the use of human embryos in research. Research using these embryo models has the potential to improve assisted reproduction and advance our understanding of early human development (Hyun et al., 2020Hyun I. Munsie M. Pera M.F. Rivron N.C. Rossant J. Toward Guidelines for Research on Human Embryo Models Formed from Stem Cells.Stem Cell Reports. 2020; 14: 169-174Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). Previous versions of the ISSCR Guidelines precluded research for more than 14 days on stem cell-based embryo models that had the potential to develop into viable organisms. The updated Guidelines drop that concept because it is an ambiguous threshold: it is unknown which cell clusters would be viable if transplanted in vivo. Instead, the updated Guidelines categorize all stem cell-based embryo models as permissible, with the exception that no such model can be transferred to the uterus of a human or animal, establishing a clear standard for research review committees that will prevent attempts to establish pregnancies from embryo models (Lovell-Badge et al., 2021Lovell-Badge L. Anthony E. Barker R. Bubela T. Brivanlou A. Carpenter M. Charo R.A. Clark A. Clayton E. Cong Y. et al.ISSCR Guidelines for Stem Cell Research and Clinical Translation: The 2021 Update.Stem Cell Reports. 2021; 16 (in press. Published online May 27, 2021)https://doi.org/10.1016/j.stemcr.2021.05.012Abstract Full Text Full Text PDF Scopus (34) Google Scholar). The updated Guidelines describe an oversight process that categorizes embryo models according to their complexity and anticipated ability to undergo further development. Models containing the relevant embryonic and extraembryonic cell types to sustain development (e.g., blastoids) must be reviewed through a specialized oversight process (Lovell-Badge et al., 2021Lovell-Badge L. Anthony E. Barker R. Bubela T. Brivanlou A. Carpenter M. Charo R.A. Clark A. Clayton E. Cong Y. et al.ISSCR Guidelines for Stem Cell Research and Clinical Translation: The 2021 Update.Stem Cell Reports. 2021; 16 (in press. Published online May 27, 2021)https://doi.org/10.1016/j.stemcr.2021.05.012Abstract Full Text Full Text PDF Scopus (34) Google Scholar). Several of the world’s leading research funders have ambiguous policies or categorial restrictions that may hinder research using stem cell-based embryo models (Matthews and Moralí, 2020Matthews K.R. Moralí D. National human embryo and embryoid research policies: a survey of 22 top research-intensive countries.Regen. Med. 2020; 15: 1905-1917Crossref PubMed Scopus (28) Google Scholar). For example, this year the US National Institutes of Health (NIH) has sent mixed messages about whether they can support this research. They are concerned that the developmental potential of some stem cell-based embryo models may cause them to fall under the “Dickey-Wicker Amendment,” an annual spending rider that prohibits using federal funds for research that involves the creation or destruction of human embryos (Public Law No: 116-260). Similarly, Australia’s National Health and Medical Research Council interpreted a 2002 law regarding embryo research to restrict the culture of embryo models beyond 14 days. Given the potential of this research to allow scientists to study periods of human development without using human embryos, research funding agencies should support this research when it falls within the parameters outlined in the updated guidelines. The stated goal of many that supported the Dickey-Wicker Amendment, to reduce the use of embryos created from human gametes in research, is enabled by embryo models derived from pluripotent cell lines in culture. The creation of chimeric embryos by transferring human stem cells to animal embryos is an area of research that can advance our understanding of human development and may lead to the production of human organs for transplantation (Masaki and Nakauchi, 2017Masaki H. Nakauchi H. Interspecies chimeras for human stem cell research.Development. 2017; 144: 2544-2547Crossref PubMed Scopus (19) Google Scholar). However, this area of research also poses unique oversight challenges. The oversight process described in the Guidelines enables this research to proceed incrementally, while imposing guardrails that would prevent it from crossing ethical boundaries (Lovell-Badge et al., 2021Lovell-Badge L. Anthony E. Barker R. Bubela T. Brivanlou A. Carpenter M. Charo R.A. Clark A. Clayton E. Cong Y. et al.ISSCR Guidelines for Stem Cell Research and Clinical Translation: The 2021 Update.Stem Cell Reports. 2021; 16 (in press. Published online May 27, 2021)https://doi.org/10.1016/j.stemcr.2021.05.012Abstract Full Text Full Text PDF Scopus (34) Google Scholar). The Guidelines are sensitive to the need to avoid high levels of chimerism by human cells in certain animal tissues after birth, including the nervous system and germline. Depending on the research goals, these concerns can be managed by not allowing chimeric animals to be born, by restricting the developmental potential of the human cells, or by preventing chimeric animals from breeding. The Guidelines are consistent with regulations in countries such as the UK that allow important chimeric embryo research to proceed with restrictions. Japan also allowed such research to proceed after updating their regulations in 2019 to enable research aimed at generating human organs in animals (Sawai et al., 2019Sawai T. Hatta T. Fujita M. Japan Significantly Relaxes Its Human-Animal Chimeric Embryo Research Regulations.Cell Stem Cell. 2019; 24: 513-514Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). Unfortunately, in the US, the NIH has restricted chimeric embryo research since 2015, despite considering, but never finalizing, a new policy that would have enabled such research. Instead of the current moratorium, the NIH and other policymakers should consider the oversight framework proposed in the Guidelines. Mitochondria are structures within cells that produce much of the energy required by cells through oxidative metabolism. While the vast majority of genes are encoded in the nuclear genome, mitochondria have their own genome that encodes some proteins that are essential for oxidative metabolism. Consequently, people can have normal nuclear genomes but severe defects in mitochondrial function. Mitochondrial DNA is uniquely inherited from the mother. Some women carry a high proportion of abnormal mitochondria in their oocytes and cannot have biologically related children that do not suffer from severe mitochondrial diseases marked by a wide range of health problems including muscle weakness, developmental delays, and neurological and respiratory problems. MRTs can enable these families to have healthy, biologically related children with nuclear DNA from the biological parents and normal (unmutated) mitochondrial DNA from an oocyte donor. While MRTs have resulted in successful pregnancies, this technology should continue to be refined and closely overseen by regulators. The Guidelines recommend limiting the initial uses of MRTs to cases with a high probability of transmitting mitochondrial disease, consistent with UK regulations. Unfortunately, some countries, including the US and Canada, do not allow MRTs due to broad restrictions on heritable genome editing that do not distinguish between the editing of nuclear and mitochondrial DNA (Cohen et al., 2020Cohen I.G. Adashi E.Y. Gerke S. Palacios-González C. Ravitsky V. The Regulation of Mitochondrial Replacement Techniques Around the World.Annu. Rev. Genomics Hum. Genet. 2020; 21: 565-586Crossref Scopus (11) Google Scholar). Policymakers should revise these restrictions to advance MRT research while continuing to prohibit the editing of germline nuclear DNA for reproductive purposes in humans. More research is required to determine whether it would be safe or ethically appropriate to perform heritable genome editing in humans. The recent advances involving embryo models, chimeric embryos, and MRTs hold great potential for improving our understanding of human development and advancing assisted reproduction; however, the research oversight policies in many countries must be reformed to enable such research. The ISSCR Guidelines provide a scientifically rigorous and ethically justifiable way forward. R.L.-B. serves on a number of advisory boards that are concerned with some of the issues covered in the manuscript. The positions are listed as follows, and all of the positions are unpaid: co-opted member of the Scientific and Clinical Advances Advisory Committee of the Human Fertility and Embryo Authority (HFEA), 2006–present; Sense About Science, Member of Board of Trustees, March 2014–present; Public Library of Science (PLOS), Board Member (and Chair of Audit Committee, Chair of Remunerations Committee, and member of Scientific Advisory Board), February 2012–present; Royal Society, Chair of “Genetic Technologies Programme,” April 2017–present; Progress Educational Trust, Chair of the Board of Trustees, January 2019–present; Member of the WHO Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing, February 2019–present; Chair of ISSCR Guidelines Working Group, May 2019–present; and Member of External Advisory Board, “Cambridge Reproduction Strategic Research Initiative,” University of Cambridge, UK, February 2021–present. S.M. is a member of the advisory board of Cell Stem Cell and chairs the Public Policy Committee for the ISSCR. R.L.-B. is a member of the Public Policy Committee for the ISSCR. E.A. is the manager of public policy for the ISSCR. National Health and Medical Research Council, https://www.nhmrc.gov.au/about-us/news-centre/nhmrc-statementNational Institutes of Health, https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-158.htmlNational Institutes of Health, https://grants.nih.gov/grants/guide/notice-files/not-od-16-128.htmlNational Institutes of Health, https://osp.od.nih.gov/2021/03/11/human-embryo-development/Public Law No: 116-260: Consolidated Appropriations Act (2020), https://www.congress.gov/bill/116th-congress/house-bill/133/text