Event Review: ISSCR Embryo Models Working Group – Summary of findings and recommendations

Understanding the intricacies of human embryonic development is a longstanding aim of biological research. Advances in IVF have allowed closer observations of preimplantation human development – the progression from a single fertilised oocyte to a blastocyst that can potentially implant in the uterus.

However, much less is known about the next steps critical to the embryo's development – implantation, placenta formation and the physical reshaping of the blastocyst for onward growth into a healthy fetus. This is the stage at which high embryo losses are seen during pregnancies, and placental abnormalities and developmental defects can arise.

In part, this lack of knowledge is simply because developing embryos are obscured from observation by the uterine walls. However, this lack of knowledge is also because access to human embryos for research purposes is limited in general, and is subject to careful regulation (see BioNews 1219, 1220, 1243 and 1268).

For example, the culture of human embryos in the laboratory beyond 14 days of development is, in most countries, currently prohibited by the so-called '14-day rule' (see BioNews 885, 1086, 1213 and 1268). The pursuit of deeper knowledge of this peri-implantation stage of human development is one of the reasons why researchers have developed stem-cell based embryo models (SCBEMs) (see BioNews 1020, 1088, 1091, 1124, 1204 and 1219).

In 2021, the International Society for Stem Cell Research (ISSCR) addressed this rapidly growing area of research in an updated version of its Guidelines (see BioNews 1032, 1097 and 1098). Guided by work using mouse stem cells, the ISSCR distinguished between 'integrated' SCBEMs that contain extraembryonic cell types – meaning that there is a possibility they could implant and build a placenta – and 'non-integrated' SCBEMs, that do not contain (and cannot develop) extraembryonic cell types (see BioNews 1195 and 1216).

The 2021 guidelines suggested that research involving these different types of SCBEM should be governed differently, with integrated human SCBEMs subject to more stringent oversight than non-integrated human SCBEMs. However, as research in this fast-paced area has continued, the integrated/non-integrated distinction has become more difficult to sustain in light of the latest experimental evidence.

In April 2025, the ISSCR hosted a webinar to present the recommendations of its Embryo Models Working Group, which has been drafting a further update to ISSCR guidance on research involving SCBEMs. The session was hosted by the co-chairs of the Working Group, Professors Amander Clark and Janet Rossant.

Attendees were reminded that SCBEMs help researchers to experimentally probe the dynamics of critical developmental processes such as lineage segregation and germ cell specification in humans, rather than researchers having to rely on model organisms (see BioNews 1196 and 1200). In addition to deepening our fundamental understanding of early development, SCBEMs could also provide insights into early pregnancy loss due to implantation issues, help to improve IVF outcomes, and improve our understanding of stem cell culture in general.

The 2021 edition of the ISSCR Guidelines divides research into the following categories.

• Category 1A – Research activity determined (after an appropriate assessment) to be exempt from a specialised scientific and ethics oversight process by the appropriate existing mandates and committees.
• Category 1B – Research activity reportable to the body responsible for a specialised scientific and ethics oversight process, but not normally subject to further or ongoing review.
• Category 2 – Research activity that is permissible only after review and approval, through a specialised scientific and ethics review process.
• Category 3A – Research activity that should not be pursued at this time, because it is currently unsafe and/or because it raises unresolved ethical issues.
• Category 3B – Research activity that should not be pursued, because of broad international consensus that the activity lacks a compelling scientific rationale, and/or because the activity is widely considered to be unethical.

The Embryo Models Working Group was established following a number of publications reporting more complex human SCBEMs that mimic peri/post-implantation stages. Though not all of these SCBEMs formed extraembryonic cells, some of the research suggested – surprisingly – that extraembryonic cells develop quite differently in humans than they do in mice, and called into question the distinction between integrated and non-integrated SCBEMs.

The Working Group comprises researchers, bioethicists and clinicians from a wide range of jurisdictions. Some of the main changes that they have recommended are as follows.

• All 3D spatially organised SCBEMs – with or without extraembryonic cell types – to be included in Category 2, requiring specialised scientific and ethics review. The extent of the review should be appropriate to the complexity of the SCBEM, and the duration of culture should be defined.
• Bioprinted 2D differentiation models to be moved from category 1B into category 1A.
• Trophoblast and yolk sac organoids to be included explicitly in category 1A.
• In light of work on the interaction between SCBEMs and uterine cells, clarification of language in category 3B, to emphasise that a human SCBEM may not be transferred to the uterus of a living human or animal host.
• Prohibition of the culture of SCBEMs in artificial in vitro systems that are designed to develop to viability.

The webinar included a question and answer session, during which it was clarified that SCBEMs used solely as a platform for cell differentiation would nonetheless belong in Category 2 under the new proposals, and that an iterative process should be used to determine the duration of culture that is scientifically justifiable for SCBEMs. The ISSCR's Ethics Committee has recently published its own guidance on what 'scientific justification' means in these contexts.

One attendee asked what 'viability' means in the context of Category 3. It was explained that this would mean survival outside of the artificial structure that the investigator has created. Given recent advances in medical interventions enabling premature babies to survive, it will be interesting to see whether this prohibition is defined in greater detail in due course.