Synthetic embryos: a new venue in ethical research

The recent publication by Amadei et al. (2022), along with that of Tarazi et al. (2022), reveals the possibility of obtaining mouse embryos without eggs or sperm. Indeed, these so-called ‘artificial embryos’ can recapitulate some stages of development ex utero, without implantation, employing technology developed by Aguilera-Castrejon et al. (2021). This novel tool constitutes a milestone in the field of developmental and synthetic biology, allowing scientists to get new insights into both pregnancy and embryo development.

The creation of a method for mimicking mouse embryo development by surpassing utero implantation in vitro (Aguilera-Castrejon et al. 2021) is the first milestone grounding said tour de force in embryo modeling. The experimental setup consisted of a novel method based on the combination of static and rolling culture bottles, together with a novel culture medium composition, allowing ex utero development from pre-gastrulation to advanced organogenesis. However, this tool makes matter more complex when employed to grow embryos solely from stem cells, without the need for gametes to subsequently undergo fertilization. Independent research groups have been able to recreate mouse embryo development based on this novel culture technique, thus reaching mid-gestation stages from embryonic stem cells (ESCs) alone. In the case of Amadei et al. (2022), they mixed and aggregated three different mouse cell lines: naïve ESCs, trophoblast stem cells (TSCs), and extra-embryonic endoderm-like cells (XEN) genetically modified to transiently express Gata4 (a major driver in endoderm differentiation). Both TSC and XEN cell lines are extra-ESCs that interacted with naïve ESCs to promote the formation of synthetic embryos and their subsequent neurulation. Similarly, Tarazi et al. (2022) mixed naïve ESCs with two additional ESC lines expressing either Cdx2 or Gata4 (upon doxycycline treatment) to differentiate them into trophectoderm and primitive endoderm, respectively.

These new embryo models are thought to be useful for properly understanding the implantation process, a key stage in which most spontaneous abortions occur. The already proposed model is intended to provide new insights into early development processes. As decades of bioscience research have shown, what can be done in mice can often be done in humans. From blastoids (Kagawa et al. 2022) to gastruloids (Moris et al. 2020), previous embryo models that were originally proved with mouse cells have now been adapted to work with human samples. Thus, it is expected to deploy this novel strategy with human cells at some point.

These promising investigations, nevertheless, raise ethical issues – especially if used with human cells. On the one hand, there are ethical reasons for trying to create synthetic human embryos through stem-cell technologies. In addition to providing valuable knowledge in basic science, human synthetic embryos may lead to laudable applications in regenerative medicine, organ transplantation, or assisted reproduction.

However, this mid-gestation stage also raises some concerning ethical questions. What if functional primitive nerve structures were created in their ectogestation? Consider some parallels with the abortion debate. For many years, the gradual formation of specific neural structures in the fetus has been a key aspect of the ethical and legal debate (Derbyshire & Bockmann 2020). In most countries where abortion is legal, it is only so before a certain stage of fetal development, beyond which voluntary termination of pregnancy is usually prohibited. Similarly, should the destruction of synthetic embryos be avoided from any particular period of embryonic development? Additionally, if primordial germinal structures can develop into a complete human being, how would the reproductive freedom apply in this case? Without the need for eggs or sperm to undergo ex utero development, this process could be reached with single reproduction purposes and then the reproductive freedom of both the donor and the so-called artificial embryo could lead to inconsistencies.

There are other more ethically puzzling implications. These disruptive innovations decouple the notion of ‘embryo’ from the fertilization of an egg with sperm and its maternal gestation. The moral status of human artificial embryos may thus seem uncertain. To what extent should we consider them as ‘real embryos’? This question is hard to answer because the definition of a human embryo is highly controversial. Some nations, including Spain, believe that only fertilized eggs can be regarded as such. Others, such as the Netherlands and Belgium, believe that any cell or group of cells with the potential to develop into a human should be regarded as an embryo, regardless of how the fetus was generated. At the EU level, the Court of Justice for the European Union stated in 2011 (Case C-34/10, Oliver Brüstle v Greenpeace) that the concept of ‘human embryo’ shall be understood in a wide sense. Accordingly, it considered that every human ovum, once fertilized, shall be recognized as a ‘human embryo’ if that fertilization indeed initiates the process of human development. Both a non-fertilized human ovum into which the nucleus of a mature human cell was already transplanted and a non-fertilized human ovum whose division and further development were stimulated by parthenogenesis shall also be classified as ‘human embryos’. However, the same Court reversed its stance years later, adopting a somewhat narrower definition of what an embryo is: in Case C-364/13 (International Stem Cell Corporation v Comptroller General of Patents, Designs, and Trade Marks), it stated that human ova (irrespective of whether the egg was fertilized or ‘activated’ by techniques such as nuclear cell transfer) which were ‘capable of commencing the process of development of a human being just as an embryo created by fertilization of an ovum can do so’ should be considered human embryos (de Miguel Beriain 2017). Keeping this criterion in mind, should the embryos created by Amadei et al. (2022) be considered ‘real embryos’? This is hard to assess. Indeed, it is far from clear if these embryos could technically complete the gestation period through this method.

On the other hand, how should we consider such entities during the ex utero developmental process? Moreover, and more speculatively, if the future baby develops in an artificial womb from scratch, to whom does the moral responsibility belong about this human once they are born? It is not so obvious that any possible answer to this question would imply the donors of the genetic material, since in many countries, like Spain, the legal mother is the one giving birth independently of the genetic origin of the future child. Actually, this inconsistency still matters in current debates about in utero fetal development (Derbyshire & Bockmann 2020).

In both articles, the authors agreed that it could be technically possible to switch from in utero to ex utero development for ‘artificial embryos’, and vice versa (Amadei et al. 2022, Tarazi et al. 2022). Inferring this possibility to human cells, should we ban their implantation in a woman’s womb? These and many other ethical questions should receive greater attention as this fascinating research progresses in the future. And of note, in the light of novel applications with human cells that might give rise (or not) to human embryos or similar primitive structures, proper legislation should be discussed and proposed in advance to the recurrent application with samples from human sources.

Our conclusion is that this novel technique to develop ‘artificial embryos’ not only paves the way for the future of experimental embryology but also opens a completely new and unexpected venue in bioethics research. Much effort is needed and required to further explore the abovementioned questions, which might shift most of our current paradigms about reproductive ethics and become game-changing in our future understanding of human reproduction.