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Introduction

Progress in the in vitro derivation of human gametes (eggs and sperm) continues to advance. In vitro–derived gametes are generated using pluripotent stem cells (PSCs) through a process called “in vitro gametogenesis” (IVG). The stem cells used can be embryonic stem cells (ESCs) derived from preimplantation embryos or somatic cells that have been reprogrammed into induced PSCs (iPSCs). Although technical gaps remain to be overcome, partial reconstitution of human gamete production has been reported for both male and female pathways.

Reconstitution of gametogenesis has many potential uses and applications, including basic research into mammalian developmental biology and use in animal breeding. Were the in vitro reconstitution of human gametogenesis ever achieved and in vitro–derived gametes ever approved for human use, it could also serve as an assisted reproductive technology (ART) in the context of fertility treatments (see Figure 1-1). Somatic cells from parents could, theoretically, be converted to iPSCs, differentiated into functional gametes, and used to create an embryo through in vitro fertilization. By obviating the need for invasive, costly, and resource-intensive surgical procedures to extract eggs, this method could alleviate women¹ of the physiological, emotional, and economic burdens associated with conventional ART interventions. This technique

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¹ The terms “women” and “men” are used in some places in this proceedings. The National Academies recognize that these terms may not reflect how some individuals seeking reproductive health care may identify.

could allow prospective parents the choice of generating either egg or sperm from their own iPSCs—regardless of their sex assigned at birth. IVG could enable couples to produce embryos that are genetically related to both parents in situations where it would otherwise have been difficult or technically infeasible. Taken together, this could significantly alter the practice of reproductive medicine.

IVG could raise several important social, ethical, and legal repercussions for consideration. Novel reproductive technologies can have cascading effects on the social constructs of family, belonging, identity, disability, and justice. On a technical level, IVG could permit the creation of very large numbers of human embryos. With this increased capacity, prospective parents carrying disease-causing mutations could perform more efficient preimplantation genetic testing (PGT) on a larger cohort of embryos, and thus increase opportunities to establish a pregnancy only with an embryo that does not carry the mutation. On the other hand, the potential for greatly expanded embryo screening raises concerns about

the routinization of prenatal selection, the expansion of prenatal screening to include gene targets associated with complex conditions and traits, exacerbation of bias toward the disability community, and potential intersections with and proximity to embryo selection preferences associated with eugenics.

Full reconstitution of mature and viable human gametes has not been demonstrated, and the research faces many challenges. Were this technology to ever develop fully and become available for clinical practice, any use of in vitro–derived human gametes would raise important scientific, ethical, social, and regulatory questions that may not be answered by scientific, bioethics, and regulatory communities alone—they will likely require broader societal engagement. In anticipation that research development may continue, a workshop was convened to review the state of the science, understand what is driving progress, what is likely to be achievable versus unrealistic, and recognize the urgent issues that in vitro–derived gametes could raise. Such assessments may provide foundational analyses to inform future consultative social, legislative, and regulatory discussions.

BRIEF HISTORY OF IVG

Eli Y. Adashi of the Warren Albert Medical School of Brown University set the stage for the workshop by providing a high-level overview of the history of IVG. He began by saying, “Pluripotent stem cells, be they embryonic or induced, are revolutionizing medicine” and being explored as possible therapies for several diseases and conditions, including paralysis, blindness, and Parkinson’s disease. One potential application of PSCs involves guiding them toward a gametogenic fate that could be used as part of an ART. Pinpointing the beginning of research into IVG is difficult, Adashi said, but a key 2009 publication from Mitinori Saitou’s laboratory may serve as a starting point; Ohinata et al. (2009) identified signals required to specify the germ cell fate (i.e., BMP4) in mice with the goal of reconstituting germ cells in vitro. Adashi suggested that “the long road to define the multiple signaling systems involved” in germ cell development for IVG started around the time of the publication of this paper. Since then, scientists have successfully reconstituted in vitro the entire developmental cycle of both male and female mouse germ cells, including the fertilization of in vitro–derived gametes leading to the birth of progeny (Hikabe et al., 2016; Yoshino et al., 2021). Adashi also highlighted a very recent technical breakthrough from Katsuhiko Hayashi’s laboratory wherein functional oocytes were generated from male mouse–derived iPSCs through a process Adashi termed “germ cell interconversion” (Murakami et al., 2023). Despite the progress in mice, Adashi noted

that the in vitro reconstitution of human egg and sperm has proven more complicated. Although scientists have successfully generated oogonia and prospermatogonia from human iPSCs, the reconstitution of fully mature gametes has yet to be accomplished (Hwang et al., 2020; Yamashiro et al., 2018). “There is an unfinished agenda,” Adashi concluded, to reconstitute human eggs and sperm along with their supporting somatic cells.

Because of this “unfinished agenda” for developing in vitro–derived human gametes and the multiple social, ethical, and legal concerns, he said, it is timely and important to discuss the landscape of IVG research, scientific and technical barriers, legal and regulatory frameworks relevant to conducting and overseeing research, potential clinical impacts, and social and ethical concerns and considerations.

ORGANIZATION OF THE WORKSHOP

A planning committee of the National Academies of Sciences, Engineering, and Medicine (the National Academies) convened a 3-day public workshop² that explored the scientific, ethical, and regulatory implications associated with the research and development of in vitro–derived human gametes.

The hybrid in-person/virtual workshop, held on April 19–21, 2023, featured a combination of presentations, panels, general discussions, and breakout groups, during which speakers and participants offered a broad range of perspectives. An opening panel on the potential impacts for stakeholders and society anchored the workshop in the human considerations of this disruptive technology. Next, several sessions explored the state of the science, including research achievements in other mammalian species and roadblocks to achieving in vitro–derived human gametes. The first day closed with a session on potential clinical implications of IVG, with presentations and discussions from practicing clinician-scientists. On the second day, discussions centered on the social, ethical, and legal implications of IVG as well as the equity, access, and cost considerations raised by its development. The next session discussed what features could be included in any potential pathway for human IVG from the laboratory to clinical research. The second day closed with parallel breakout groups, during which participants discussed (1) the social, ethical, and legal

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² The planning committee’s role was limited to planning the workshop, and the Proceedings of a Workshop has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants and are not necessarily endorsed or verified by the National Academies of Sciences, Engineering, and Medicine, and they should not be construed as reflecting any group consensus.

implications of IVG; (2) the potential impact on the fertility enterprise; and (3) issues involved in translation from laboratory to market. On the final day, rapporteurs delivered summaries from workshop participants in their respective breakout groups; then a panel discussed community engagement around reproductive scientific advances, focusing on the value and importance of community and patient voices. The day closed with reflections on what was learned during the workshop and potential next steps.

ORGANIZATION OF THE PROCEEDINGS

Following this introductory chapter, Chapter 2 summarizes the state of the science for IVG in both animal models and humans. Speakers discussed achievements in the field, potential barriers to fully reconstituting human gametogenesis, and near-term prospects for overcoming these barriers. Chapter 3 explores potential clinical implications of IVG. It summarizes a panel discussion on the potential real-world impacts to stakeholders and society, along with presentations from reproductive endocrinologists on how IVG could potentially impact fertility care. Chapter 4 provides an overview of social, ethical, and legal implications, including intended and unintended consequences, that could arise from the development or potential use of human IVG. Chapter 5 summarizes a discussion on equity, access, and cost considerations raised by IVG. Panelists engaged in nuanced discussions about whether IVG ought to be pursued and for what aims, considered factors that could affect the cost and price if it were ever available clinically, and highlighted equity issues that extend beyond cost and access. Chapter 6 provides an overview of discussions that imagined what a potential clinical research pathway for human IVG would entail were it permitted and pursued. Speakers and participants shared perspectives on relevant legal and regulatory frameworks and what types of preclinical research and validation would be needed before considering any initial clinical trial. Chapter 7 summarizes the final panel, which focused on how scientists and clinicians can engage with members of the public on reproductive scientific advances, including IVG. Panelists discussed the importance of including and centering patient and public voices at every stage of technological development. Finally, Chapter 8 outlines key messages and potential next steps for activities related to reproductive health and the development of ART, such as IVG, identified by speakers and participants during the final session.

Appendix A provides the reference list for this proceedings while Appendix B includes the workshop statement of task and agenda, and Appendix C provides brief biographies of speakers and planning committee members.

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