European scientists have created an artificial embryo from human stem cells that reproduces for the first time in the laboratory a crucial moment in human development: when the embryo first touches the mother’s uterus and begins to make room for a baby.

That first contact is called implantation and until now it has hardly been studied, which is a huge barrier to understanding why humans are so ineffective when it comes to reproducing, as the biologist Nicolas Rivron, lead author of this study, says. Rivron, a researcher at the Austrian Institute for Molecular Biotechnology, explains that only half of the eggs fertilized by a sperm eventually succeed and give rise to a new person. Of the other half, many of the frustrated pregnancies happen right during implantation. What decides that an embryo nests happily in the mother’s womb and that another seemingly the same disappears forever? Nobody knows.

Rivron’s team has devised a way to simulate what happens in a mother’s womb using stem cells grown in a laboratory. In a study published on December 2 in the scientific journal Nature, explains how by making three molecular modifications the stem cells are reprogrammed and begin to form spheres very similar to an embryo of about seven days of age, also known as a blastocyst. At this point the embryo is a ball of less than a millimeter and about 200 cells, but it already has all the genetic information necessary to generate a human being.

“These experiments show us that we can recreate the first contact between an embryo and the mother in a culture dish in the laboratory

Nicolas rivron

The next step was to put these pseudo-embryos together with endometrial cells, which are the cells that line the uterus. The results were “spectacular”, celebrates Rivron. If the scientists did nothing, nothing happened, but if they added estrogen and progesterone, hormones secreted by pregnant women, the pseudo-embryos would stick to the cells of the uterus, simulating the long-awaited implantation.

“These experiments show us that we can recreate the first contact between an embryo and the mother in a culture dish in the laboratory,” Rivron explained at a press conference to publicize his study. The team has analyzed the gene expression of their pseudo-embryos on a cell-by-cell basis and this matches that of real human zygotes by 97%. Another similarity: Only 50% of artificial embryos implant, a rate equal to that of humans.

This work opens the door to a much better control of the ability to generate or interrupt pregnancies in a few years. “The success rate of IVF is approximately 25%. There is a lot of room for improvement, ”says Rivron. One way to refine these techniques would be to analyze implantation with these embryo models. On the other hand, the researcher recalls that around the world thousands of very problematic unwanted pregnancies occur among very young women. “Most of the current contraceptives are based on hormones, which serve to prevent the formation of an embryo or its implantation. These treatments have many side effects and cannot be used by all women, for example they are prohibited for those who suffer from hormonal breast cancer ”, she details.

The study shows that a known molecule – SC144 – prevents pseudo embryos from sticking to endometrial cells, suggesting that it may function as a contraceptive.

Scientists have only allowed their artificial embryos to live for 13 days. They have done so in part because in many European countries, including Spain, a law prevents cultivating human embryos beyond 14 days. The reason is that it is thought that from that day it is impossible for the embryo to generate twins, so it is assumed that it is just two weeks later when a future individual appears. No law prevents growing artificial embryos beyond this red line. But Rivron argues that after 13 days something goes wrong. The growth of laboratory zygotes begins to be more disorderly and different from that of normal embryos. It is something that also happens with real human embryos grown in the laboratory and, again, no one knows why.

This research also opens up delusional possibilities, such as implanting one of these artificial embryos in the uterus of an animal or even a woman and trying to have a baby born. Rivron emphasizes that such a thing should “never” be done, adding that it will probably not be successful. His team has been trying for years to implant a mouse pseudo-embryo into the uterus of a mouse. On no occasion did they manage to generate newborn mice. “In all likelihood” it wouldn’t work in humans either, he notes.

“This is an important study”, highlights Alfonso Martínez-Arias, a researcher at the Pompeu Fabra University in Barcelona. “These are the first really reliable embryonic models. And this is important because it allows us to reduce and perhaps eventually avoid the use of human blastocysts derived from in vitro fertilization clinics to understand early human development and its pathologies without many ethical ties; although the ethical position of these blastoids is something that must be discussed ”, he highlights.

Of all the abortions that occur, only 10% are clinically recognized with an image and the verification that there is a heart that was beating and it no longer does. The rest are losses that happen a few days before. It’s the iceberg of embryo loss

Marta Shahbazi, biologist

Last year, Martínez-Arias created another embryo model that emulates the first stages of gastrulation, a phenomenon that begins when the embryo is 14 days old and that begins the process of forming the general plane of the human body. Until the appearance of these models, implantation and human gastrulation have been “black boxes” almost impossible to investigate and understand, he highlights.

“This study improves the technique of creating pseudo-embryos much more similar to real embryos and also shows that they simulate implantation, that is, they teach how cells talk to each other”, explains Marta Shahbazi, who researches human development at the University of Cambridge .

The study also points to mind-boggling avenues, such as generating mini-uteri from the cells of a patient who is having trouble having children, implanting a pseudo-embryo in them, and finding out where the problem lies. There is a theory that the uterus does not allow embryos that are not perfect to implant.

This foundational moment in human life is a violent battle. The embryo slits the wall of the uterus and digs a very deep hole to implant itself. It must be camouflaged with biochemical signals so that the mother’s immune system does not annihilate it like the strange being that it is. “Of all the abortions that happen, only 10% are clinically recognized with an image and the verification that there is a heart that was beating and it no longer does. The rest are losses that happen a few days before. It is the iceberg of embryo loss. The woman many times does not even know that she is pregnant. The fertilized egg is there and three days later it has disappeared. Why? We don’t know, ”concludes Shahbazi.

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