Lab-grown embryos push scientific boundaries, ethical limits

Scientists are making significant strides in creating laboratory models that mimic human embryos, raising both excitement about potential medical breakthroughs and ethical concerns about the nature of these entities.

Recent advancements in stem cell research have allowed researchers to cultivate cell structures that closely resemble early-stage human embryos without using eggs, sperm, or a womb. These "embryo models" provide unprecedented insights into the earliest stages of human development, a period that has long been shrouded in mystery due to technical and ethical limitations.

At the Weizmann Institute of Science, Professor Jacob Hanna and his team have developed embryo models that display key features of natural embryos at around 14 days of development. These models include structures resembling a yolk sac and a proto-placenta and even produce hormones that can trigger a positive pregnancy test result.

These models are opening new doors to understanding crucial stages of human development. While they are not perfect replicas, they offer a valuable tool for studying processes that have been largely inaccessible until now.

The ability to create and study these models is particularly significant because the earliest stages of human embryonic development remain poorly understood. Traditional ultrasound technology cannot detect embryos at such an early stage, and keeping natural embryos alive outside the body for extended periods is challenging and ethically fraught.

For decades, scientific policy and regulation have maintained a 14-day limit on culturing human embryos in laboratories. This guideline, often called the "14-day rule," was established in the 1980s when in vitro fertilization (IVF) was still a new technology.

The 14-day mark is considered significant in embryonic development for several reasons. It marks the beginning of gastrulation, a key stage in which cells begin to organize into layers that eventually form organs. The primitive streak, a precursor to the spine, also appears around this time. Additionally, it is the point after which an embryo can no longer split to form twins.

Jeremy Sugarman, a professor of bioethics and medicine at the Johns Hopkins Berman Institute of Bioethics, explained the significance of this milestone. "You become an individual," he said. The U.K. committee that recommended the 14-day limit reasoned that "it was seen as the last point at which an embryo could definitively be considered no more than a collection of cells, without potential individual identity or rights."

However, the advent of advanced embryo models has led some groups to question the relevance of the 14-day limit. In 2021, the International Society for Stem Cell Research relaxed its 14-day guideline, suggesting that research could continue beyond 14 days, subject to ethical review and national regulations.

Different countries and organizations are taking varied approaches to regulating this emerging field. The United Kingdom has put out guidelines specifically for embryo models, while Australia's Embryo Research Licensing Committee has decided to treat more realistic models like natural embryos, prohibiting their development beyond 14 days.

In the United States, the situation is more complex. While federal funding for human embryo research has been prohibited since 1996, there are no federal laws governing experiments with either natural or model embryos.

Hank Greely, a law professor and the director of the Center for Law and the Biosciences at Stanford University, highlighted the fundamental questions raised by these models. "The preliminary question is, are they embryos at all?" he said. "Allow one to develop further, and maybe it grows a second head. We don't know."

Despite these uncertainties, researchers are pushing forward. Hanna's team is working to cultivate their models to the equivalent of 21 days, which would take them through the end of gastrulation. So far, they have managed to grow them to about 18 days.

While the potential for these models to develop into fully formed humans remains extremely low, the rapid progress in the field has surprised many. Both Hanna and Magdalena Żernicka-Goetz, a developmental and stem cell biologist at the California Institute of Technology and the University of Cambridge, have created mouse embryo models with brains and beating hearts.

These advancements underscore the need for scientists and ethicists to consider what qualifies as human before human embryo models reach similar milestones. Some ethicists argue that the most critical question 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.

Insoo Hyun, a bioethicist and the director of life sciences at Boston's Museum of Science, emphasized this shift in focus. "It's no longer so much about how embryos are made or where they come from, but more what they can possibly do," he said.

A recent experiment published last year demonstrated that seven-day-old model monkey embryos could be successfully implanted in the uteruses of three female monkeys. Although signs of pregnancy disappeared after about a week, the study raised the possibility — and ethical implications — of similar experiments with human models.

Despite the ethical challenges, proponents of embryo model research argue that it could yield enormous benefits. One of the primary advantages is the potential to enhance our understanding of early human development.

Much of our current knowledge about early embryonic development is based on the Carnegie stages, a series of 23 phases covering the first eight weeks of development. These stages were established nearly a century ago using thousands of collected embryo samples. However, as Hanna pointed out, "We don't know what happens in between. To study development, you need the living material. You have to watch it grow."

Until recently, scientists had rarely sustained embryos in the lab for the past seven days, leaving many questions about development beyond the first week unanswered. Most developmental defects occur in the first trimester of pregnancy, and the causes of many birth defects remain unknown. For instance, cleft palate, a potentially debilitating condition, occurs sometime before week nine of pregnancy for reasons that are not yet fully understood.

Greely suggested that more developmental research on embryo models could help solve such mysteries. "This research could provide crucial insights into why some developmental disorders occur and how we might prevent or treat them," he said.

The potential applications of this research extend far beyond developmental disorders. It could help reveal why some women experience recurrent miscarriages or have difficulty conceiving. Żernicka-Goetz has been using embryo models to study the formation of the amniotic cavity, suspecting that improper formation may lead to pregnancy failure.

Embryo models could also shed light on how various factors, including viruses, alcohol, and medications, affect prenatal development. This knowledge could be particularly valuable in prenatal medicine, where the testing of new treatments is severely limited due to the potential risks to the fetus.

Pregnant individuals are generally excluded from drug trials, which leaves them without access to treatments for new and chronic health conditions. Hanna has started a company aiming to test drug safety on embryo models, potentially opening new avenues for safe and effective prenatal care.

Looking further into the future, Hanna envisions even more revolutionary applications. He suggested the possibility of treating infertility by growing embryo models to 60 days, harvesting their ovaries, and then using the eggs for IVF. Because stem cells can be grown from skin cells, such a system could potentially solve infertility issues caused by older eggs without the more invasive aspects of traditional IVF.

However, not all research in this field requires hyper-realistic models of embryos. Aryeh Warmflash, a biosciences professor at Rice University, is studying gastrulation using simplified models that omit certain structures like those that form the placenta. "In some sense, the better your model goes, the more you have to worry," he said, referring to the ethical implications of increasingly realistic models.

Hyun advised scientists to be cautious about creating extremely complex models to avoid triggering heated debates, especially in countries already divided over when life begins. However, given the potential medical advances that could be achieved by studying realistic models, it seems unlikely that all researchers will heed this advice.

The story of embryo models is still in its early chapters, but it is already clear that this field of research has the potential to revolutionize our understanding of human development and transform many aspects of medical care.