Attempts to produce “embryo models” manufactured artificially ?


What are we actually talking about ?

“Synthetic embryos”, “embryoids”, “synthetic human embryos”, “imitation embryos”, “embryo models”, “embryos derived from stem cells”, “laboratory  copy of human embryos”, “blastoids” etc. these are the convoluted designations which the press has used to relay the announcements by two teams of research scientists. They were made during the yearly meeting of the International Society for Stem Cell Research (ISSCR) held in Boston, on 14th June 2023.

The two teams are  the one led by professor Magdalena Zernicka-Goetz from the University of Cambridge and the California Institute of Technology and  the other led by Jacob Hanna, from the Weizmann Institute in Israel.

It is complex, in fact, to accurately describe the results of the experiments in question. They involve attempts to aggregate stem cells together. In simple terms: this work aims to artificially create biological models by combining different types of stem cells. These cells exhibit particular properties: they are termed pluripotent as they have the property of being able to differentiate indefinitely to form most of the tissues of the human organism. The stem cells may be obtained in several ways: either drawn from embryos (these cells are from a lineage established from human embryos, from In Vitro Fertilisation (IVF) which have been abandoned and donated for research), or drawn from particular tissues (bone marrow, fatty tissues, umbilical cord blood) or even generated artificially by the so-called IPS (Induced Pluripotent Stem cell) technique from already differentiated cell types  (for example, skin cells).

In this type of experiment, the research scientist cultivates one or other of several types of these cells together, in order to observe them organising themselves into a structure which may have similarities with embryos.

These structures are therefore not obtained naturally like those of embryos: i.e. by fertilisation, by the fusion of a sperm with an ovocyte.

They are therefore not “embryos” strictly speaking, to use the embryo terminology is therefore not accurate. An embryo which is allowed to develop ends up as an individual, whereas these models cannot.

Neither is the term “synthetic” very appropriate, inasmuch as the cells used have been drawn from “true” embryos or from other living sources.

What are the teams in fact claiming ?

It is important to note that their work has not yet been submitted to validation committees.

The Magdalena Zernicka-Goetz team claims to have constructed its models using reprogrammed human embryonic stem cells (cells taken from human embryos, at an early stage of their development, and subjected to a reprogramming technique).

The Jacob Hanna team has not used genetic modifications, merely embryo stem cells. According to the team, their model was able to achieve a highly complex organisation and began to exhibit a degree of differentiation of tissues.

What is the purpose of such research ?

They are essentially research models, aimed at acquiring new knowledge. The prospects of therapeutic progress and profits are also considered. Early embryonic development fascinates research scientists. “We do not have a full understanding of the human embryo. It constructs all its organs between the seventh and the twenty-eighth days of pregnancy. After that, they merely grow during the next eight months. There are therefore three weeks of rapid and critical development at the beginning where everything is decided, but there is a black box“,  explained  Jacob Hanna in  Israel Time. The research scientists mention in fact what they call among themselves a “black box”. This corresponds to a moment in the development when the embryos are little or not “available” for research.

In vitro research on the human embryo is currently possible up to the 14th day. Subsequently, the data can only come later from analyses performed on pregnancies or on miscarriage embryos donated for research.

The motivations for this race of announcements and research are multiple, more or less official, realistic or adventurous, and with an obvious limitation: they are not “normal” embryos and they are cultivated in test tubes.

Acquisition of new knowledge on in vitro embryo development

The teams hope that these models will provide further information on the embryo development stages, and therefore help the understanding of the possible causes of malfunctions, and provide better understanding of the events during early embryo development which are involved in miscarriages.

Use of the models to test the toxicity of certain molecules

These structures could be useful models for testing the toxicity of certain molecules, for understanding the malformations caused by certain toxins, medicines or pollutants.

Proposing an alternative to research on the human embryo

These models are presented as a possible alternative to the use of research on so-called supernumerary embryos, particularly for the models which merely use reprogrammed adult cells.

However, the theories which are expounded based on these models “must then be validated using human embryos, and are not therefore a replacement for research on donated embryos“, as already declared in 2021 by Teresa Rayon, a biologist at the Francis Crick Institute (London).

Exceeding the time limits for in vitro cultivation of embryos

The time limit for the cultivation of human embryos currently in force in many states is 14 days (this includes France, since the law dated 2nd August 2021). This limit complies with a widely accepted international consensus as it corresponds to the moment when the individuality of the embryo occurs. At that stage, it can no longer split into twins. This is also the stage of the formation of the primitive line, which begins to distinguish the head of the embryo from its tail and briefly precedes the appearance of the first signs of the formation of the central nervous system.

Concerning the artificial models which we are discussing, this rule does not apply, and the possibility of “going further” is one of the research motivations. A work theme which is already familiar to the Magdalena Zernicka-Goetz team, in particular, which has been aiming at this research slot on human embryos for several years. (Refer to In vitro embryos: ever further ? May 2016)

Bypassing the prohibition from creating embryos specifically for research

These models also make it possible to bypass the prohibition from creating embryos for research.

Prior to the 2021 French law, article L2151-2 of the public health code mentioned that “The in vitro fertilisation of embryos or their elaboration by human embryo cloning for research purposes is prohibited.” The term embryo was later supplemented with the following 5 words: “human by the fusion of gametes”, thus opening the legal doorway to the creation, for research purposes, of these gametes so-called “without fusion of gametes”.

Is such research totally new ?

The artificial manufacture, in test tubes, of this type of model without the use of fertilisation, without an ovule or sperm, has already been the subject of research for several years, in particular on animal models.

Experiments using human cells have also already been conducted. In 2018, a team in Cambridge published its work. In 2021, two other laboratories described in Nature magazine their development tests on these organised structures then described as “blastoids”, in reference to the term “blastocysts”, the scientific term given to the human embryo aged about 5 days. Which is what these artificially manufactured structures are already claimed to “imitate”.

Two different paths have already been followed by two teams, one in America and one in Australia. The team led by José Polo, professor at the university of Monash in Australia, has been working with fibroblasts, which are adult skin cells. These cells were reprogrammed, by the so-called IPS technique in order to reacquire their original pluripotent capability. The other team, led by Jun Wu at the university of Texas, also used this type of induced pluripotent cells as well as human embryo stem cells.

When cultivated in a favourable medium, these cells multiplied and self-organised to form complex cell structures. For the 3-dimensional cell organisation, supports were used: plastic plates featuring “micro wells” which enable the aggregation of cells by sedimentation, whilst controlling their number.

These studies confirmed that the cells “communicate” between one another since they self-organised into cell structures consisting of different cells: a layer of external cells (which appear on the future placenta, in the event of fertilisation and “normal” development) surrounding a cavity filled with a liquid containing a mass of “embryo” cells.

But these artificial structures exhibit notable differences compared with their natural models. For example, they contain cells which are absent from true blastocysts. In 2018, a French research scientist, Nicolas Rivron, in charge of a laboratory at the Austrian Academy of Science, managed to create the first models of blastocysts of a mammal (mouse). However, he then considered that it would take another “ten years to create blastoids which strongly resemble human blastocysts”.

These structures cannot develop for long and it seems highly implausible that at the current stage of research, they are capable of being implanted in the uterus of a woman, if the experiment ever reached that stage. With the animal model, the experiment has already been performed. Animal blastoids were implanted in the uterus of a mouse, vessels connected themselves to these pseudo-embryonic structures, and the immunity system of the mouse interacted with them. But, a mere four days after being implanted, anomalies were observed in the structures.

Regarding the failures observed on the animal models, it is not known whether there is a fundamental biological cause for such non-viability, or whether it was the result of some technical problem, according to Robin Lovell-Badge, at the Francis Crick Institute in London.

What then becomes of these models ?

Either their development ends spontaneously – nothing guarantees that these structures will never be capable of continuing to mature beyond the earliest stages of development – or they are intentionally destroyed.

Their implantation in a woman’s uterus is obviously currently prohibited, in France as in the other states where this research is being undertaken.

What is the status of such cellular organisations?

At the international level, the question remains open. No legal standard controls them. Facing the novelty which the biotechnologies are making possible, there is total chaos. Concerning the legal status of this “new category of living objects created by mankind, we are in a grey area, according to Hervé Chneiweiss, president of the Ethics Committee at Inserm.

What are the moral and ethical stakes?

The vertiginous evolutions made possible by the biotechnologies are modifying our relationships with life itself. “Life” which for a long time has been in the domain of the “given” is becoming, more and more, through technique, the domain of manufacturing, of construction. Engineering of living matter leads to the migration from a natural order to an artificial order.

The question of the “moral status” of these models is in debate, i.e. what are the moral obligations concerning these models elaborated using human cells ? These questions are becoming more pressing as the development stages become technically capable of extension, even leading to actual cardiac or cerebral activity, which the current state of  Science cannot yet achieve.

There is the ethical and moral issue of the risks linked to the “ideology of promise”, false promises, as soon as these experiments appear as multiple sources for therapeutic progress, at the risk of nourishing false hopes.

There is also the question of consent and information to donors of embryos or cells subsequently used for experiments or as IPS stem cells. The protection of genetic data, of the health data of donors and of any profits generated by these models also represent major challenges.

As of now, these experiments pose serious ethical questions as they induce, involve, feed the exploitation of human life at its very beginning (through the use of embryo stem cells) and lead to the destruction of human embryos.

According to Robin Lovell-Badge, in charge of cellular biology and the genetics of development at the Francis Crick Institute : “If the intention is for these models to closely resemble normal embryos, then, in a certain manner, they should be treated in the same way”.

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