Lab-grown models of embryos increasingly resemble the real thing

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THe is traditional The way to create an embryo is to combine a sperm cell with an egg, often over dinner and a bottle of wine. But a new way may be around the corner. In recent years scientists have discovered that they can induce stem cells – which have the ability to transform into many other types of cells – to create structures that look and behave like embryos.

“Fetuses,” as the creation is called, can help with the study of embryology and pregnancy and how they can go wrong. Some facsimiles look strikingly real. In 2022 two teams, one led by Magdalena Zernica-Goetz, who works at the California Institute of Technology and the University of Cambridge, and the other led by Jacob Hanna at the Weizmann Institute of Science in Israel, published research papers describing mouse embryos with initial boldness, brains and beating hearts. In June, Dr. Zernica-Goetz published a paper describing a human embryo designed to mimic the early stages of development, immediately after a real embryo is implanted in its mother’s womb.

This second study was controversial, with some other scientists doubting that it represented as much progress as its authors claimed. But the state of the art is advancing fast enough that some think it may soon become difficult to distinguish embryos from their models. In many ways, this would be a good thing: the more accurate a model is, the more effective it is. Human embryos can shed light on developmental heart defects or diseases such as spina bifida and increase the success rate 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 of human embryos older than 14 days in research, and researchers in countries without such laws generally adhere to the same standards voluntarily. The more similar embryos are to real things, the harder it becomes to avoid the question of whether they should be subject to similar rules.

A natural embryo begins with a single fertilized egg. To create an embryo, scientists mix together different stem cells obtained from an embryo or sometimes from an adult organism. They can change molecular signals within cells and which genes are activated. Within a few days, embryo-like structures appear.

Embryos are desirable in part because actual embryos are scarce: the main source is leftovers IVF Treatment is also difficult to increase them. This makes it difficult to run large-scale experiments. Fetuses offer a less ethically viable option.

A rose by any other name

An example of their utility is the study of implantation, the process by which an embryo is implanted in the womb. This is where most pregnancy losses occur. But it was almost impossible to study the causes in detail before the appearance of the fetus. “You can’t go through the mother’s body to see this developing fetus,” says Dr. Zernica-Goetz.

Embryos—specifically, a type called a blastoid—offer the next best thing. First created by Nicolas Rivron at the Austrian Academy of Sciences, they resemble an embryo at the blastocyst stage just before implantation. In humans, implantation occurs around day seven and in mice around day four. Each blastoid consists of a hollow ball of cells that, in the true embryo, becomes part of the placenta. A small ball attached to the inner wall that would otherwise develop into an embryo. By rolling the blastoids across the uterine tissue in a dish, Dr. Rivron’s team found that they adhered only when they were oriented so that this internal mass was closest to the uterine tissue.

The inner mass sends signals to the outer cells, instructing them to adhere to the uterus. Dr. Rivron thinks he has identified these signals and plans to publish his findings soon. He hopes to help explain why so many embryos fail to attach. That, in turn, can improve success rates IVF, which is only 35% in America. Blastoids make such discoveries much easier, Dr. Rivron said. He started a company, Dawn Bio, that uses blastoids to screen drug candidates that might be effective in fertility treatments.

Other embryos attempt to capture what embryos look like after implantation. Most advanced mice are made of stem cells, such as the brain-and-heart model described above, which represent eight days of mouse development. Dr. Hanna holds the record for human embryos. In a paper published in September, he and his colleagues described embryos that mimic human fetal development between 8 and 14 days. He is interested in trying to push things further, perhaps on day 35 At that time, its embryos, like rats More, organs will begin to develop.

Dr Hanna believes this could make them a source of clinically useful cells. For example, they can provide stem cells that can become bone marrow for transplants in leukemia patients. If the stem cells used to create the embryo are taken from the patient, the marrow will be genetically identical to the patient’s own. This would eliminate the risk of immune rejection and the need for immune-suppressing drugs.

Persuading embryos to develop further could open up truly mind-bending possibilities. From day 50 onwards, the embryo will have gonads. This could mean eggs that, one day, could give women struggling to conceive a brand new, freshly baked set of their own. (Dr. Hanna’s company, Renewal Bio, is pursuing such goals.)

No one knows when these goals can be achieved. Naomi Morris, a developmental biologist at the Francis Crick Institute in London, agreed to let Dr. Hanna see part of a 14-day-old fetus. But he doesn’t think they qualify as full replacements just yet. For one thing, Dr. Hanna’s embryos never progress to the blastocyst-like stage. That missing link prevents them from attaching to the natural womb and can impose limitations on how long they can continue to develop in a dish.

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

If they do, it can be difficult to work. The only way to know for sure whether an embryo can develop into an embryo is to try and see it – although such experiments can risk breaking the law if successful. Instead Dr. Morris and his colleagues, including Dr. Revron, suggested a two-part test that would at least make a compelling argument that the fetus had closed the gap.

The first step is to examine how closely human embryos track the developmental trajectory of real embryos. The second is to push the animal’s embryo as far as possible, ideally to the point of producing live, fertile offspring. Such processes may begin with mice before moving on to pigs or monkeys. If such long-developing embryos biochemically look like human state-of-the-art, caution will be warranted.

Dr. Morris thinks that, within two to five years, someone will create animal embryos that can reach the embryonic stage. In April, Chinese researchers transplanted monkey blastoids into surrogate animals, incubating for up to 20 days. And there is always a chance that someone is rogue. In 2018, Chinese researcher He Jiankui announced that he had created a gene-edited human baby. He was jailed, and widely condemned. But it’s not inconceivable that someone might try to push the boundaries in a similar way with embryos.

border crossing

Amanda Clarke, president of the International Society for Stem Cell Research, points out 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 after that. This would make it very difficult to tell whether embryos older than 14 days were as they were supposed to be. The only comparators are animal embryos and surgical dissection of pregnant women. In other words, the rule, which is meant to protect fetuses, means researchers may struggle to know whether their alternatives were good enough—or so good they should in turn be given legal protection.

Clarification (November 1st 2023): An earlier version of this piece suggested that Dr. Zernica-Goetz was the first to publish work on cultured mouse embryos. Actually Dr. Hanna’s team went there first. We regret the mistake.

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