The little clump of cells looked almost like a human embryo. Created from stem cells, without eggs, sperm, or a womb, the embryo model had a yolk sac and a proto-placenta, resembling a state that real human embryos reach after approximately 14 days of development. It even secreted hormones that turned a drugstore pregnancy test positive.
To Jacob Hanna’s expert eye, the model wasn’t perfect—more like a rough sketch. It had no chance of developing into an actual baby. But in 2022, when two students burst into his office and dragged him to a microscope to show him the cluster of cells, he knew his team had unlocked a door to understanding a crucial stage of human development. Hanna, a professor at the Weizmann Institute of Science in Israel, also knew that the model would raise some profound ethical questions.
You might recall images of embryonic development from your high-school biology textbook: In a predictable progression, a fertilized egg morphs into a ball of cells, then a bean-shaped blob, and then, ultimately, something that looks like a baby. The truth is, though, that the earliest stages of human development are still very much a mystery. Early-stage embryos are simply too small to observe with ultrasound; at 14 days, they are just barely perceptible to the naked eye. Keeping them alive outside the body for that long is difficult. Whether anyone should is another matter—for decades, scientific policy and regulation has held 14 days as the limit for how long embryos can be cultured in a lab.
Embryo models—that is, embryos created using stem cells—could provide a real alternative for studying some of the hardest problems in human development, unlocking crucial details about, say, what causes miscarriages and developmental disorders. In recent years, Hanna and other scientists have made remarkable progress in cultivating pluripotent stem cells to mimic the structure and function of a real, growing embryo. But as researchers solve technical problems, they are still left with moral ones. When is a copy so good that it’s equivalent to the real thing? And more to the point, when should the lab experiment be treated—legally and ethically—as human?
Around the 14th day of embryonic development, a key stage in human growth called gastrulation kicks off. Cells begin to organize into layers that form the early buds of organs. The primitive streak—a developmental precursor of the spine—shows up. It is also at that point that an embryo can no longer become a twin. “You become an individual,” Jeremy Sugarman, a professor of bioethics and medicine at the Johns Hopkins Berman Institute of Bioethics, told me.
The primitive streak is the main rationale behind what is often referred to as the “14-day rule.” Many countries limit the amount of time that a human embryo can be kept alive in a petri dish to 14 days. When a U.K. committee recommended the 14-day limit in the 1980s, IVF, which requires keeping embryos alive until they are either transferred or frozen around day five or six, was still brand-new. The committee reasoned that 14 days was the last point at which an embryo could definitively be considered no more than a collection of cells, without potential individual identity or individual rights; because the central nervous system is formed after the 14-day milestone, they reasoned, there was no chance it could feel pain.
But the recent rise of advanced embryo models has led some groups to start questioning the sanctity of the two-week mark. In 2021, the International Society for Stem Cell Research relaxed its 14-day guideline, saying that research could continue past 14 days depending on ethical review and national regulations. (The organization declined to set a new limit.) In July, U.K. researchers put out a similar set of guidelines specifically for models. Australia’s Embryo Research Licensing Committee, however, recently decided to treat more realistic models like the real deal, prohibiting them from developing past 14 days. In the United States, federal funding of human-embryo research has been prohibited since 1996, but no federal laws govern experiments with either real or model embryos. “The preliminary question is, are they embryos at all?” Hank Greely, a law professor and the director of the Center for Law and the Biosciences at Stanford University, told me. Allow one to develop further, and “maybe it grows a second head. We don’t know.” (Having a second head is not necessarily a reason to disqualify someone from being human.) In the absence of an ethical consensus, Hanna is at work trying to cultivate his models to the equivalent of day 21, roughly the end of gastrulation. So far, he said, he’s managed to grow them to about day 18.
Researchers generally agree that today’s models show little risk of one day becoming walking, talking human beings. Combining sperm and eggs the old-fashioned way is already no guarantee of creating new life; even women in their 20s have only about a 25 percent chance of getting pregnant each month. Making embryos in a lab, sans the usual source material, is considerably harder. Right now, only about 1 percent of embryo models actually become anything that resembles an embryo, according to Hanna. And because scientists don’t have a great idea of what a nine-day-old embryo looks like inside the body, Greely said, they don’t actually know for certain whether the models are developing similarly.
And yet, in the past few years, scientists have already accomplished what seemed impossible not so long ago. Both Hanna and Magdalena Żernicka-Goetz, a developmental and stem-cell biologist at the California Institute for Technology and the University of Cambridge, have created models for mice with brains and beating hearts. Scientists and ethicists would be wise to consider what qualifies as human before human embryo models have beating hearts, too. The most important question, some ethicists argue, is not whether researchers can achieve a heartbeat in a petri dish, but whether they can achieve one with a model embryo implanted in a human womb. “It’s no longer so much about how embryos are made or where they come from, but more what they can possibly do,” Insoo Hyun, a bioethicist and the director of life sciences at Boston’s Museum of Science told me. In an experiment published last year, seven-day-old model monkey embryos were successfully implanted in the uterus of three female monkeys. Signs of pregnancy disappeared about a week afterward, but the paper still raised the specter—or perhaps the promise—of a human version of the experiment.
Building more realistic embryo models could have enormous benefits—starting with basic understanding of how embryos grow. A century ago, scientists collected thousands of embryo samples, which were then organized into 23 phases covering the first eight weeks of development. Those snapshots of development, known as the Carnegie stages, still form much of the basis for how early life is described in scientific texts. The problem is, “we don’t know what happens in between,” Hanna said. “To study development, you need the living material. You have to watch it grow.” Until recently, scientists had rarely sustained embryos in the lab past day seven or so, leaving manifold questions about development beyond the first week. Most developmental defects happen in the first trimester of pregnancy; for example, cleft palate, a potentially debilitating birth defect, occurs sometime before week nine for reasons that scientists don’t yet understand. It’s a mystery that more developmental research performed on embryo models could solve, Greely said.
Better understanding the earliest stages of life could yield insights far beyond developmental disorders. It could help reveal why some women frequently miscarry, or have trouble getting pregnant at all. Żernicka-Goetz has grown models to study the amniotic cavity—when it forms improperly, she suspects, pregnancies may fail. Embryo models could also help explain how and why prenatal development is affected by viruses and alcohol—and, crucially, medications. Pregnant people are generally excluded from drug trials because of potential risks to the fetus, which leaves them without access to treatments for new and chronic health conditions. Hanna has started a company that aims, among other things, to test drug safety on embryo models. Hanna told me he also envisions an even more sci-fi future: treating infertility by growing embryo models to day 60, harvesting their ovaries, and then using the eggs for IVF. Because stem cells can be grown from skin cells, such a system could solve the problem of infertility caused by older eggs without the more invasive aspects of IVF, which requires revving the ovaries up with hormones and surgery to retrieve the resulting eggs.
Answering at least some of these questions may not require hyperrealistic models of an embryo. Aryeh Warmflash, a biosciences professor at Rice University, is studying gastrulation, but the cells that form the placenta aren’t relevant to his research questions, so his models leave them out, he told me. “In some sense, the better your model goes, the more you have to worry,” he said. Hyun told me he cautions scientists against making extremely complex models in order to avoid triggering debate, especially in a country already divided by ideas about when life begins. But given all the medical advances that could be achieved by studying realistic models—all the unknowns that are beginning to seem knowable—it’s hard to imagine that everyone will follow his advice.
