Lab-grown embryo models increasingly resemble the real thing

“Fetuses”, as such creations are called, can help in the study of embryology and pregnancy, and how they can go wrong. Some replicas look surprisingly realistic. In 2022 two teams, one led by Magdalena Zernicka-Goetz, who works at the California Institute of Technology and Cambridge University, and another by Jacob Hanna at the Weizmann Institute of Science in Israel, published a paper in which Rat embryos with rudimentary guts, brain, and beating heart were described. In June Dr. Zernika-Goetz published a paper describing a human embryo designed to mimic the early stages of development, shortly after implanting a real embryo into its mother’s womb Will go.

However, that study was controversial, with some other scientists doubting that it was as advanced as its authors claimed. But the state of the art is advancing so rapidly that some think it will soon become difficult to distinguish embryos from the embryos they want to model. In many ways, this would be a good thing: the more accurate the model, the more useful it will be. Can shed light on diseases such as human embryo developmental heart defects or spina bifida, and increase the success rates of in-vitro fertilization (IVF).

But research on embryos – which, after all, have the potential to develop into humans – is strictly regulated. Many countries prohibit the use in research of human embryos older than 14 days, and researchers in countries without such laws usually voluntarily follow the same standard. The more embryos become like the real thing, the harder it becomes to avoid the question of whether they should be subject to the same rules.

A natural embryo begins with a fertilized egg. To create an embryo, scientists grow a mixture of different stem cells obtained from embryos or sometimes from adult organisms. They can change molecular signals between cells and which of their genes are active. Within a few days, embryo-like structures become visible.

Embryos are desirable partly because actual embryos are rare: the main source is leftovers from IVF treatments. These are also difficult to develop. This makes it difficult to run experiments on a large scale. Embryos offer a less morally risky alternative.

A rose by any other name

An example of their benefits is the study of implantation, the process by which an embryo implants into the womb. This is where most of the pregnancy losses occur. But it was almost impossible to study the causes in detail before the advent of embryos. “You can’t go into the mother’s body to see this fetal development,” says Dr. Zernika-Goetz.

Embryos – specifically, a type called a blastoid – provide the next best thing. First created by Nikolaus Rivron at the Austrian Academy of Sciences, they resemble an embryo at the blastocyst stage just before implantation. In humans, implantation occurs around the seventh day and in rats, around the fourth day. Each blastoid consists of a hollow ball of cells which, in a true embryo, becomes part of the placenta. A small ball is attached to the inner wall, which under other circumstances develops into an embryo. By rolling blastoids in uterine tissue in a dish, Dr. Rivron’s team found that they stuck only when they were oriented so that this inner mass was closest to the womb tissue.

This means that the inner mass sends signals to the outer cells, instructing them to stick to the womb. Dr. Rivron believes he has identified those signals and plans to publish his results soon. They are hoped to help explain why so many embryos fail to attach. This, in turn, could improve the success rate of IVF, which is only about 35% in the US. Dr. Rivron says blastoids have made such discoveries much easier. He has started a company called Dawn Bio, which uses blastoids to screen drugs that may be useful in fertility treatments.

Other embryologists try to figure out what the embryo looks like after implantation. The most advanced are made from mouse stem cells, such as the brain and heart models described above, which represent day eight in mouse development. Dr. Hanna holds the record for human embryo testing. In a paper published in September, he and his colleagues describe embryos that mimic human fetal development between days 8 and 14. He wants to try to take things further, maybe until Day 35. At that time, their embryos, like those of mice, will begin to develop organs.

Dr Hanna believes this could make them a source of medically useful cells. For example, they can provide stem cells that can be transformed into bone marrow for transplantation into leukemia patients. If the stem cells used to create the embryo were taken from the patient, the marrow would be genetically identical to the patient. This will remove the risk of immune rejection, and eliminate the need for immune-suppressing drugs.

Coaxing embryos to develop further could open up truly mind-bending possibilities. By day 50 or so, the embryo will have gonads. This could mean that one day, women struggling to get pregnant could be given a new, freshly baked set of their own eggs. (Dr. Hanna’s company, Renewal Bio, is pursuing such goals.)

No one knows when or if these goals will be achieved. Naomi Morris, a developmental biologist at the Francis Crick Institute in London, agrees that Dr. Hannah’s 14-day-old fetus looks the part. But he doesn’t think they’re worthy of a full replacement yet. For one thing, Dr. Hanna’s embryos never go through a blastocyst-like stage. That missing link prevents them from attaching to the natural womb, and may put a limit on how long they can grow in a dish.

Nevertheless, the fact that such goals are being pursued has led some scientists to believe that now is the time to think about regulation. Dr. Morris has proposed a new legal definition for embryos that would be based on their ability to develop into a fetus, a developmental stage that begins eight weeks after fertilization and lasts until birth. Human embryos are legally ill-defined in many countries. Dr Morris hopes his proposal will make it clear that an embryo can qualify as a fetus – if it has the same developmental potential.

However, if they do, it may become difficult to get things done. The only way to know for sure whether an embryo can develop into a fetus would be to try it and see – although such an experiment might risk violating the law if it were successful. Instead Dr. Morris and his colleagues, including Dr. Rivron, have suggested a two-part test that would at least make a solid argument that the embryo has closed the gap.

A first step will be to test how closely human embryos track the developmental path of real embryos. Second, animal embryos must be carried forward as far as possible, ideally to the point of producing live, fertile offspring. Such a process may have started with rats before reaching pigs or monkeys. If such long-developing embryos appear biochemically similar to a modern-day human, caution would be warranted.

Dr. Morris believes that, within two to five years, one will be able to produce animal embryos that can reach the embryonic stage. In April, Chinese researchers implanted monkey blastoids into surrogate animals, causing pregnancies that lasted 20 days. And there is always a possibility that someone may turn evil. In 2018, He Jiankui, a Chinese researcher, announced that he had created gene-edited human babies. He was jailed and widely condemned. But it is not unimaginable that someone might try to push the boundaries in a similar way in the case of embryos.

pushing the limits

Amanda Clarke, president of the International Society for Stem Cell Research, highlights another irony that could make regulation difficult. Because human embryos cannot be cultured for more than 14 days, scientists do not have a detailed picture of how they develop later on. This will make it very difficult to tell whether fetuses older than 14 days are behaving as they should. The only comparisons are animal fetuses and dissections of surgically removed uteruses from pregnant women. In other words, rules designed to protect embryos mean that researchers may struggle to tell whether their choices were good enough – or good enough that they should be given legal protection in return.

Explanation (1 November 2023): An earlier version of this piece gave the impression that Dr. Zernika-Goetz was the first to publish work on advanced mouse embryos. Actually, Dr. Hanna’s team reached there first. We regret the error.

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© 2023, The Economist Newspaper Limited. All rights reserved. From The Economist, published under license. Original content can be found at www.economist.com

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Published: 03 January 2024, 01:25 PM IST