Introduction
From the very beginning, the creation of increasingly realistic models of human embryos has raised significant bioethical questions, which have intensified as the “humanization” of these synthetic models adopts a configuration closer to that of true embryos obtained by fertilization, as reported in a recent article published in the journal Nature [1].
Although scientists have been working on these models for more than a decade, it was in 2021 when they managed to create two embryonic models that resembled the human blastocyst at the stage when the embryos are transferred to the uterus during in vitro fertilization.
These models, called blastoids, contained extraembryonic cells, making them the first “complete” or “integrated” models of the human embryo.
Since then, ethicists have sought to address the bioethical dilemmas they pose. In 2021, the International Society for Stem Cell Research (ISSCR) developed guidelines prohibiting the transfer of human embryo models to the uterus.
More recently, in June 2024, the ISSCR announced that it had created a working group to assess the state of the science and revise previous guidelines regarding human embryoids.
Background
The technique of in vitro fertilization has a huge problem: its efficacy ceiling is only around 30%. The embryos obtained in the laboratory are transferred to the maternal uterus when they reach the blastocyst stage a few days after fertilization, when the embryo has about 100 cells. Their morphology is very simple: a hollow sphere of cells, at one of whose poles the “embryoblast” is concentrated; and an outer cell layer or “trophoblast”, which is the one that is contact with the uterine wall and is internalized in the endometrium.
Once implanted, the embryoblast differentiates into two cell layers, the epiblast and the hypoblast, which form the bilaminar embryonic disc. The cells of the epiblast then generate three cell layers, the ectoderm, mesoderm and endoderm, from which all the tissues and organs of the developing human being will be derived. Under normal conditions, “gastrulation” takes place by the third week. This is characterized by the appearance of the so-called primitive streak, a thickened cell band located in the central posterior region of the embryoblast overlying the aforementioned three cell layers, and organogenesis begins.
Credit: Monash University
Thus, the most critical period of human embryonic development takes place from the third week after implantation, when organization of the tissues and organs of the human being begins and the activities of most genes of the genome — necessary for cell differentiation and organogenesis —- are activated. Only 30% of embryos produced by IVF and artificially implanted in the uterus successfully overcome this stage, which will bring the pregnancy to term. Many embryos are expelled or their development collapses without a known cause.
Just after gastrulation, the critical stage begins in which the fate of the implanted embryos is consolidated or fails and, understandably, there is a great interest in determining the causes of so much failure. In the uterus, however, newly implanted embryos are too small to be observed by ultrasound or other methods, and there are technical, ethical — and in many countries legal — limitations to studying the development of human embryos beyond 14 days post-fertilization.
For a few years now, the great development of synthetic biology has facilitated the production of so-called “organoids”, cellular aggregates that mimic human structures or organs through artificial cell fusion. Thus, in order to circumvent the 14-day rule, work has been carried out in different laboratories with the synthesis of structures resulting from cell fusion, which are described as “synthetic embryos”, “embryonic models”, “artificial embryos” or “pseudoembryos”. The aim for researchers is that they resemble an embryo enough to provide a real glimpse into human development, while at the same time maintaining that they are synthetic products and not embryos in themselves, to avoid restrictions in their work.
The first of these “synthetic embryos” emerged in 2021 and was called a “blastoid”, due to its blastocyst-like appearance [2]. Several research teams from different countries would continue in the same line of producing “embryonic models”, which are said not to raise the issue of study beyond day 14 because they do not come from the in-vitro fertilization of an egg by a sperm. Later we shall see that this is unclear.
The first of these studies was carried out by a team led by Dr. Magdalena Żernicka-Goetz (b.1963), associated with the University of Cambridge and the Salk Institute of Cell Technology in California. In mid-2023, she announced that human “synthetic embryos” had been obtained, which she claimed did not come from in vitro fertilization. Indeed, they are not directly obtained from this method, but indirectly, if we take into account the origin of the cells used in their synthesis, which are embryonic stem cells that have been genetically modified to express different differentiation factors and limit possible organ development. These cells are added with others that simulate the placenta and yolk sac, developed using “genetic reprogramming” technology (induced pluripotent stem cells, iPSCs). That is, the cells of the synthetic embryoblast are genetically modified so that certain organs do not develop from these pseudoembryos. The research was reported at a World Stem Cell Congress held in Boston, and later published in Nature [3].
Assuming that these are synthetic products comparable to embryos, these types of structures open the possibility of investigating beyond the 14-day limit permitted by law. However, the first doubt about their usefulness arises precisely from their biological nature: to what degree can it be said that these synthetic organoids are comparable to or representative of natural human embryos? Strictly speaking, they do not seem comparable, but rather similar or embryo-like. These are synthetic cell aggregates created for research purposes and, although they have the capacity to follow a growth and development process and even reach stages after the blastocyst stage, they are incomplete structures. Those of Zernicka-Goetz’s group do not have cells that behave like trophoblasts, which provide nutrition for the embryo, while Hanna’s contain a trophoblast-like layer, but not organized like a trophoblast of a natural embryo.
Furthermore, genetic modifications have been introduced in Zernicka-Goetz’s models so that certain organs are not formed, which from the outset invalidates them to specifically investigate failures in early embryonic development. For his part, Hanna works with models in which the genes involved in brain and heart development are inactivated, and according to his own statements, he has consulted with Christian and Jewish leaders in his community on whether or not an embryonic model that lacks brain or heart tissue should be considered a person. It is a point that does not seem to be included among the arguments that justify his work.
Other research groups have obtained similar embryonic models, most of which have genetic alterations that aim to prevent the development of some organ, although they can provide information on the partial development of other organs. Some even form repetitive segments known as somites, which give rise to vertebrae, and others generate models of the neural tube, progenitor of the nervous system [5].
The cellular organization of these embryonic models is similar to that of real embryos, but to be considered equivalent to them it would be necessary to demonstrate that they are capable of continuing development through the embryonic and fetal stages, until delivery, which would obviously be an act of recklessness that goes beyond the ethically acceptable. From the biological perspective, we must conclude that this is a trompe l’oeil of embryos. In fact, most researchers agree that current human embryo models are nowhere near reality. Nevertheless, they allow us to investigate some key questions regarding post-implantation human development that may offer some insights into the causes of the considerable pregnancy failures after the application of IVF.
Bioethical considerations
In addition to this biological objection, there are two sides that must be taken into account when assessing the ethical aspects of this technology.
In the first place — and it is not the fault of those who design embryonic models — there is the false limit of 14 days as a criterion for deciding on the lowest moral value of human life. Furthermore, the origin of the cells used to obtain them and whether there is any negative ethical aspect implicit in this needs to be clarified.
Regarding the first point, as we shall see later, the law in the United Kingdom, the United States, and many other countries sets the limit for research with human embryos within the first 14 days after fertilization. It is considered that, based on the myth of the “pre-embryo”, the product of in vitro fertilization is not an embryo, but a cell cluster with no biological or moral entity until day 14, so that up to that time limit it can be used in research, its stem cells extracted, or it may be donated, selected or eliminated based on its genes after pre-implantation genetic testing, etc. However, human life is a reality beginning at fertilization, not at nesting or gastrulation, and an embryo of 1, 5, 10, 12 or less than 14 days of life is as human as the one that has gone beyond that limit, whether it has nested or not. Life is a continuous process and its beginning is fertilization, when the genetic identity of the new being of the human species is constituted.
The early embryo is an organism in its initial stage of development, which obeys a genetic program established with fertilization, the true beginning of life, regardless of what legal norms or agreements tainted with utilitarianism say. The term “pre-embryo” is legislative or legal in nature, but has no entity in the scientific literature. It is a contradiction to say, as stated in the Spanish Law on Biomedical Research, that a pre-embryo is an embryo obtained by in vitro fertilization of less than 14 days. In this regard, the European Court of Justice based in Luxembourg ruled in the case Oliver Brüstle v. Greenpeace e.V., in October 2011 (case C–34/10), which established the exclusion of human embryos as a source of stem cells for commercial, industrial, patent or scientific research uses, on moral and public order grounds.
Secondly, there is the question of the origin of the cells that are used to model these synthetic embryos. The reality is that these are structures or artifacts produced using cells that come from real embryos, which in turn come from in vitro fertilization, and, although it is stressed in these studies that no gametes have been used, nothing is further from the truth. Thus, Zernicka-Goetz’s embryonic models use two types of extraembryonic cells generated by the overexpression of transcription factors with wild-type embryonic stem cells. Similarly, Hanna’s synthetic embryos combine two types of extraembryonic cells generated by the overexpression of transcription factors with wild-type embryonic stem cells. Accordingly, in both types of synthetic embryos, cells are used that come from embryos obtained by in vitro fertilization, so the ethical problem is transferred to the human embryos that donate their stem cells, the use of which requires their destruction, i.e., the destruction of human lives.
Finally, there is another critical aspect that must also be considered from an ethical point of view. And, it is that, although the causes of infertility should be investigated and attempts should be made to unravel the difficulties of human embryonic development after implantation, it does not have to be done with human embryos. This type of research can also be carried out in animal models, macaques, mice or others, such as those commonly used in laboratories and in which artificial fertilization can be carried out. Mammals conserve in their genome the same types of orthologous genes involved in the phases of development that they wish to investigate, and there are no legal obstacles or regulations that hinder their use, provided that it is done in accordance with the ethical standards established for the use of laboratory animals.
Nicolás Jouve
Professor Emeritus of Genetics at the University of Alcalá
Member of the Bioethics Observatory
Former member of the Spanish Bioethics Committee
References
- Mallapaty, S. Human embryo models are getting more realistic-raising ethical questions. Nature 2024; 633(8029):268-71.
- Yu, L., Wei, Y., Duan, J. et al.Blastocyst-like structures generated from human pluripotent stem cells. Nature 591, (2021) 620–626.
- Weatherbee, B.A.T., Gantner, C.W., Iwamoto-Stohl, L.K. et al.Pluripotent stem cell-derived model of the post-implantation human embryo. Nature 622 (2023) 584–593.
- Oldak, B., Wildschutz, E., Bondarenko, V. et al.Complete human day 14 post-implantation embryo models from naive ES cells. Nature 622 (2023) 562–573.
- Xue, X., Kim, Y,S,, Ponce-Arias, A.I. et al. patterned human neural tube model using microfluidic gradients. Nature. 628 (8007) (2024) 391-399.
