The Agence de la biomédecine's Orientation Council publishes an opinion awaited by the international scientific community, framing research on embryonic models (embryoids).

The Agence de la biomédecine's Orientation Council has just adopted a framework opinion concerning research using embryoids[1], which are in vitro models of embryonic development designed exclusively from stem cells. The Conseil d'orientation considers that embryoids enable scientific and medical advances that justify their use in fundamental and applied research. However, it stresses the risks of abuse, and recommends that a specific framework be defined to prevent any risk of unethical behavior. These models were initially developed in mice in 2018, then in humans in 2021, and have since raised a number of ethical questions that are being debated within the international scientific community.

France is the only country to have adopted a provision in its law relating to this type of model. The 2021 bioethics law stipulates that research aimed at "obtaining in vitro embryonic development models" must be declared to the Agence de la biomédecine, which must seek the opinion of the Conseil d'orientation (articles L2151-6 and L2151-7 of the public health code).

Against this backdrop, the Conseil d'orientation wished to draw up a framework opinion covering all the ethical and scientific questions raised by these models, and attempting to provide some answers based on the current state of knowledge. This is the first document of its kind produced by an ethical body at national and international level.

1. The main points of this opinion

Embryoids are not embryosThe Policy Board considers that human embryonic models or embryoids cannot, in essence, be equivalent to embryos today, for two reasons:

The origin of the genesis of these structures: from stem cells (hESC or iPS), and not a natural conception: fertilization consisting in the union of two haploid genomes each carried by the parental gametes. The intentionality: initial parental project in the context of embryos donated to research, which is not the case for embryoids. There is currently an international consensus to prohibit the transfer of human embryoids into a human or animal uterus.

Interest in researchThe Policy Board considers that embryoids are particularly valuable study models for a wide range of biomedical applications: more efficient assisted reproduction techniques; pharmacological and toxicological testing; better understanding of developmental abnormalities and early abortions, with the possibility of developing preventive treatment; development of cell-based therapies. What's more, embryoids represent an interesting alternative from an ethical point of view, since as models they avoid the need for researchers to experiment on human embryos.

The opinion of the Conseil d'orientation proposes authorizing research on embryoids up to a stage of development equivalent to the 28th day of natural embryo development, with a complete halt to all experimentation beyond this stage. This would not call into question the current law, which sets a limit of 14 days on the cultivation of human embryos. Cultivating these embryonic models beyond 28 days would not be justified either, because in the current state of science, it is considered that these models drift away from physiological development and lose their scientific and medical relevance and usefulness. On the other hand, the study of these embryoids would make it possible to explore the period of embryonic development known as the "black box", which currently runs from day 14 to the beginning of the second month of embryo development. This period includes the gastrulation stage, during which the majority of congenital diseases appear, and is not accessible to research under current regulations.

Nevertheless, these considerations do not rule out the need for increased vigilance in the case of protocols proposing experiments on embryoids more than 14 days old, with the authors of such protocols having to provide a well-founded justification for this extension.

Inorderto enable scientific advances, while providing an ethical framework, the Policy Board proposes that the legislator consider research on these embryonic models in a specific third way, between that concerning hESCs and iPS cells, which would be too permissive, and that concerning embryos, which would be too restrictive.

The Conseil d'orientation considers that the risks of commercial exploitation of embryoids and their derivatives (cells, tissues or organs) should be a point of vigilance. Human embryoids must be used exclusively for scientific research purposes, with criteria of scientific relevance and medical purpose. Their in vivo implantation must be prohibited, in line with the recommendations of the International Society for Stem Cell Research (ISSCR).

Finally, the Policy Board believes that the issue of consent to research should be revisited, with a view to updating the information and consent forms given and completed by couples or single women wishing to donate their embryos to research, or by individuals agreeing to donate somatic cells with the aim of generating iPS cells.

2. Embryoids ?

"Embryoid" is a generic term. They are "embryonic development models", obtained from embryonic or induced stem cells, capable of reconstituting the first stages of embryonic development in vitro. They can be obtained from two types of cell:

from embryonic stem cells harvested from the trophoblast and/or the inner mass of the embryo at the blastocyst stage (d5 to d7 of development); or from induced pluripotent stem (iPS) cells. These are specialized adult cells that are genetically reprogrammed into undifferentiated cells capable of restoring any cell type in the body.

These models are capable of reconstituting in vitro either part of an embryo, or the entire embryo. They represent an alternative to the use of natural embryos for research. In the general press, they are sometimes misrepresented as "embryos conceived without gametes" or "synthetic embryos". However, they are not the equivalent of a natural embryo for two reasons:

mouse embryoids, when transferred to the female for gestation, implant in the uterus, but rapidly become disorganized and are unable to develop to full term and give birth to a mouse-baby; fine analysis of embryoids shows, in all species studied to date, the abnormal presence of over-developed or under-developed cells at the stage studied.

Given the current state of knowledge and technical developments, these models are therefore incapable of reconstructing the entirety of embryonic and fetal development in animals. They should not be considered as equivalent to embryos: they are not derived from gametes and are designed as research models.

Today, there is no consensus on the status of these models: are they to be considered as cell clusters? Should we anticipate improvements in protocols and techniques and consider them as equivalent to a natural embryo in ethical and regulatory terms? Or should they be considered as something in between?

3. A session on the subject at the Rencontres de l'Agence de la biomédecine

Friday, October 13, from 10:30 a.m. to 12:00 p.m. at the Cité Universitaire in Paris, a session entitled "The latest developments in embryonic stem cell / IPS research". Session program:

Current status of clinical trials using cells derived from pluripotent stem cells in France and worldwide. Pr John DE VOS, Unité de Thérapie Cellulaire, Hôpital Saint-Eloi, Montpellier and President of the French Society for Stem Cell Research (FSSCR) Self-organization of stem cells in human embryonic models - Blastoids, Gastruloids, etc. Nicolas RIVRON, Institute of Molecular Biotechnology, Austrian Acadmy of Sciences, Vienna, Austria New ethical issues raised by pluripotent stem cell research. Bernard BAERTSCHI, University of Geneva and Inserm Ethics Committee.

Free registration: www.rencontres-biomedecine.fr/session-13

Agence de la biomédecine press release: https://presse.agence-biomedecine.fr/rencontres-de-la-biomedecine-2023/

[1]

A generic term preferred by scientists to "in vitro embryonic development models".