Human embryo models are created from stem cells and provide opportunities to study early embryo development in ways that would generally be impermissible if real human embryos were used. Here, Dr Jonathan Lewis and Professor Soren Holm argue that with human embryo models becoming more advanced, regulations governing human embryo research need to be established to allow regulators, researchers, and funders to assess whether certain models should be considered as human embryos.

• Human embryo models have the potential to improve our understanding of various hereditary diseases, early miscarriages, and IVF outcomes.
• However, they are not currently captured by regulations governing in vitro embryo research and are not subject to the same legal norms.
• With human embryo models becoming more advanced, there are concerns about whether certain human embryo models would be deemed to be legally comparable to real human embryos.
• A regulatory definition of a human embryo is needed against which a human embryo model can be assessed.

The regulatory climate

Human stem cells have been used to develop in vitro models of early human embryo development. These “human embryo models” have also been referred to as artificial embryos, synthetic embryos, synthetic human entities with embryo-like features, and embryoids.

Studies with human embryo models could allow us to better understand the mechanisms behind, and factors that contribute to, various hereditary diseases, early miscarriages, and IVF outcomes. Importantly, such studies are made possible, in part, because human embryo models are not subject to the same regulatory standards as human embryos. For instance, in many countries, including the UK, in vitro research with human embryos is restricted to the first 14 days of development (or the appearance of early body plan structures – the ‘primitive streak’). In Europe, the standards for in vitro human embryo research are determined by individual jurisdictions. However, the European Commission explicitly excludes from funding all research activities that intend to create human embryos solely for research.

In most countries, including the UK, human embryo models are not formally defined in legislation, and are therefore not captured by regulations governing in vitro embryo research. While creating opportunities to explore aspects of embryo development that would generally be impermissible were real human embryos to be used, this regulatory climate has also attracted concern from stakeholders involved in human embryo model research. The HYBRIDA project—a 3-year project funded by the European Commission aiming to investigate the uncertainties within organoid research—found that researchers were concerned about whether certain types of human embryo model research would be deemed to be creating human embryos, and thereby excluded from EU funding programmes as well as potentially running afoul of local laws and guidelines governing human embryo research.

Defining the human embryo

As part of the HYBRIDA project, Dr Lewis and Professor Holm have identified the regulatory uncertainties related to human embryo model research. During this time, there have been substantial developments in human embryo model research, particularly relating to the complexity and developmental capacities of these models and the associated narrowing of the conceptual and biological gaps between human embryo models and real human embryos.

With the narrowing of these gaps, human embryo models have increasingly challenged legal definitions of the human embryo, which, including in the UK, often refer to fertilisation of an ovum by sperm and/or to cloning. Embryos used for IVF satisfy this condition and tend to be protected with a prohibition on research beyond 14 days development (or the appearance of the primitive streak). However, these definitions would exclude human embryo models formed from human stem cells, meaning that they are not subject to the legal protections afforded human embryos.

Defining the human embryo for the purposes of human embryo model research is no easy task. First, there is a lack of consensus regarding what a human embryo is in terms of its defining properties and determining conditions. An alternative approach involves focusing on the typical functional capabilities of a human embryo (e.g., the capacity to form a human being). This would entail testing a human embryo model to see whether it possessed the relevant functional capabilities. The problem is that such tests would undoubtedly be held to be unethical because they would require implantation in a uterus. It is not clear that testing animal embryo models, similar to a given human embryo model would get round this problem either, not least because we have no reason to believe that the developmental processes of animal and human embryo models are fully comparable.

Individual countries are responsible for setting their own regulatory standards for in vitro embryo research. At the same time, researchers in the UK and Europe rely on the ability to collaborate, and, in some cases, on EU funding. Collaboration relies on the efficient transfer of stem cells, embryo models, and their associated data across borders.

In light of the advances in human embryo model research and the gaps in their regulation, a regulatory definition of a human embryo is needed such that—at the point at which the relevant gap to real human embryos disappears—a human embryo model can be captured by regulatory frameworks for in vitro embryo research. This would not only ensure that sufficiently advanced human embryo models are, from a legal point of view, treated comparably to IVF embryos, cloned embryos, and other human embryos intended for research, but it would also allow researchers to develop and study human embryo models with a greater level of certainty as to what legislators and funders require of those models.

As a result, and as captured within their final report for the HYBRIDA project, Dr Lewis and Professor Holm argue that two things are required at this stage.

Firstly, individual countries and the EU Commission should develop a regulatory definition of a human embryo to provide certainty to researchers concerning whether their models are captured by legislation or guidelines for embryo research. This presents an excellent opportunity for the UK to be a global forerunner in developing such a regulatory definition for the purposes of human embryo model research and enshrining it in relevant legislation.

Additionally, the UK and the EU must develop agreed standard clauses for collaborative agreements, to ensure that a commitment not to generate human embryos is recognised as valid in all countries participating in the collaboration.

Failing to respond urgently to these calls for regulatory reform could not only lead to potential legal challenges to the research being undertaken by those currently developing increasingly advanced and complex human embryo models, but also severely impede cross-border collaboration on which human embryo model research and its claimed downstream healthcare advances rely.