Developing an international framework for stem-cell-based embryo models

The ability of pluripotent stem cells to differentiate into different cell types has enabled the creation of stem-cell-based embryo models (SCBEMs), which have the potential to illuminate the early stages of embryo development and implantation. SCBEMs hold promise as an avenue to address global health challenges including infertility, pregnancy loss and the need for organ transplants, as well as congenital, neonatal and adult health conditions.

In addition to answering existing scientific questions and raising new scientific questions, SCBEMs pose practical, ethical and legal questions that also need to be addressed. Following a meeting of researchers at the Institut Pasteur in Paris in November 2024, we have been working with colleagues around the world to develop a foundational framework for research, technological development and regulation in relation to SCBEMs.

Some of our key recommendations are set out below, grouped into three sections – 'Science and standards', 'Technologies and applications' and 'Ethics and law'. These matters are explored at greater length in our full white paper, and we have also set out proposals for how to approach the concluding recommendation below – the identification of developmental features of ethical concern – in a separate paper.

Science and standards

The enormous diversity of SCBEMs has great advantages but it complicates reproducibility, regulatory oversight and progress towards translational goals. The following strategies are needed to ensure that the scientific and medical potential of SCBEM-related research can be fulfilled responsibly.

• Community-driven standardisation and transparency. Protocols with detailed reagent lists, cell line specifications and success metrics should be published, emulating the organoid community's best practices. Open databases for SCBEM transcriptomic profiles, protocols and troubleshooting tips should be developed. There should be rigorous comparison of human SCBEM data to data concerning preimplantation IVF human embryos and nonhuman primate embryos.
• Focused research and development to improve fidelity. Better in vitro environments that recapitulate uterine cues or maternal factors – potentially via microfluidics, or co-culture with endometrial cells or organoids (see BioNews 1321a and 1321b) – should be developed.
• Creation of biobanks. Biobanks should be created, to distribute high-quality stem cell lines and organoids to researchers.

Technologies and applications

SCBEMs can potentially advance our understanding of reproductive biology, and lead to advances in associated technologies. The following recommendations concern the technological development of the field.

• Design specialised SCBEM platforms for infertility research. This will require optimising IVF protocols, understanding implantation failures and testing for teratogenicity (screening pharmaceuticals or environmental agents).
• Promote interactions between SCBEM-related researchers and the assisted conception community. Clinical needs will strengthen the research field, and will focus the resulting applications. For example, researchers should investigate whether SCBEMs are sensitive to conditions such as quality of culture media, or teratogens that affect embryo development.
• Develop high-standard, clinical-grade SCBEMs. This should serve as a basis for practical applications of SCBEMs, particularly applications associated with teratology and regenerative medicine.
• Build bridges to clinical applications. Promote interactions between the private and academic sectors in the design of specialised SCBEM platforms in order to optimise IVF protocols, understand implantation failures and test for teratogenicity. Integrate patient-specific induced pluripotent stem cell lines, to identify individual genetic or epigenetic risk factors for congenital anomalies and early pregnancy loss.
• Develop and support training workshops. This will encourage the uptake of SCBEMs in applied research, in IVF and teratology.

Ethics and law

Several groups have discussed ethical and legal considerations surrounding SCBEMs in recent years. International guidance and recommendations have been published by major scientific societies including the International Society for Stem Cell Research (ISSCR) and the European Society for Human Reproduction and Embryology (ESHRE) (see BioNews 1289, 1293 and 1302).

Such work has also been pursued at a national level. The UK has seen the creation of a SCBEM Code of Practice published jointly by Cambridge Reproduction and PET – the Progress Educational Trust – (see BioNews 1194, 1246a, 1246b and 1247), and a review of ethical and governance questions published by the Nuffield Council on Bioethics (see BioNews 1267a and 1267b). Meanwhile, ISSCR recommendations have been adapted and implemented nationally in France, and related policy work has been undertaken in countries including Sweden and the Netherlands (see BioNews 1214 and 1218).

Our own recommendations in this area include the following.

Establish a distinct legal and ethical status for SCBEMs.

• Due to their limited developmental potential, current SCBEMs should not be considered human embryos in either a biological or a legal sense (see BioNews 1203, 1273 and 1292).
• The transfer of human SCBEMs to the uterus of a living human, or to the uterus of a living nonhuman animal, should be explicitly prohibited.
• Attempts to achieve ectogenesis – that is, the development of an organism to term outside a biological womb – should be explicitly prohibited.

Address key ethical and regulatory challenges.

• International ethical guidance, such as has been developed by the ISSCR and ESHRE, should be implemented across the world.
• There should be oversight of SCBEM-related research, particularly regarding the formation of features of ethical concern.
• An open-access register of relevant decisions taken by different ethics committees should be created, and an international group of advisory ethicists – who can then assist other committees – should be established.
• It should be mandatory to obtain informed consent from donors of biological material used in SCBEM-related research.

Adopt guidelines and oversight adapted to complexity.

• Incremental research approaches should be encouraged, with limits on culture durations and proportional justification for more complex SCBEM models.
• Oversight mechanisms should be designed, that can adapt to the increasing sophistication of SCBEMs and to advances in science.
• Specific boundaries – including time limits on culture – should be identified, introduced and monitored, while maintaining alignment with international standards.

Foster public trust through transparency and communication.

• Transparent and accurate communication about the limitations, purposes, and safeguards of SCBEM-related research should be promoted.
• Citizens and stakeholders should be engaged in ongoing dialogue concerning acceptable ethical boundaries, thereby building public trust in the governance of SCBEM-related research (see BioNews 1234).
• Academic institutions should be encouraged to promote discussion of ethics and regulation, whenever SCBEMs are the subject of lessons or lectures.

Implement dynamic governance frameworks.

• Regular updates to SCBEM guidance should be required, as scientific capabilities evolve.
• Developmental features of ethical concern should be identified, and should remain at the core of public accountability strategies.