A rendering of emerging medical technology.
Ethics needs context. So does science – specifically, science that aims to create bioengineered models of early human embryo development in a dish (hereafter synthetic embryos). Even the term "synthetic embryos" begs for an explanation. What are these? And why would anyone want to create them?
"This knowledge may help scientists understand how certain birth defects are formed and why miscarriages often occur."
First the research context. Synthetic embryos are stem cell-derived simulations of human post-implantation embryos that are designed to mimic a stage of early development called gastrulation. That's the stage—around 14-15 days after fertilization – when embryos begin to form a very primitive body plan (basic dorsal-ventral and anterior-posterior axes, and distinct cell lineages). Researchers are starting to create synthetic embryos in the lab – albeit imperfect and incomplete versions – to learn how gastrulation might unfold in real human embryos embedded unseen in the womb. This knowledge may help scientists understand how certain birth defects are formed and why miscarriages often occur soon after implantation. As such, synthetic embryos are meant to be models of human embryo development, not themselves actually embryos. But will synthetic embryos ever get to the point where they are practically the same thing as "natural" human embryos? That is my concern and why I think researchers should avoid creating synthetic embryos capable of doing everything natural embryos can do.
It may not be too difficult to prevent this slide from synthetic to real. Synthetic embryos must be created using sophisticated 3D culture systems that mimic the complex architecture of human embryos. These complex culture systems also have to incorporate precise microinjection systems to chemically trigger the symmetry-breaking events involved in early body plan formation. In short, synthetic embryos need a heavy dose of engineering to get their biological processes going and to help keep them going. And like most engineered entities, designs can be built into the system early to serve well-considered goals – in our case, the goal of not wanting to create synthetic embryos that are too realistic.
"If one wants to study how car engines work, one can model an engine without also modeling the wheels, transmission, and every other car part together."
A good example of this point is found a report published in Nature Communications where scientists created a human stem cell-based 3D model that faithfully recapitulates the biological events around post-implantation amniotic sac development. Importantly, however, the embryo model they developed lacked several key structures and therefore – despite its partial resemblance to an early human embryo – did not have complete human form and potential. While fulfilling their model's aim of revealing a previously inaccessible early developmental event, the team intentionally did not recreate the entire post-implantation human embryo because they did not want to provoke any ethical concerns, as the lead author told me personally. Besides, creating a complete synthetic embryo was not necessary or scientifically justified for the research question they were pursuing. This example goes to show that researchers can create a synthetic embryo to model specific developmental events they want to study without modeling every aspect of a developing embryo. Likewise – to use a somewhat imprecise but instructive analogy – if one wants to study how car engines work, one can model an engine without also modeling the wheels, transmission, and every other car part together.
A representative "synthetic embryo," which in some ways resembles a post-implantation embryo around 14 days after fertilization.
(Courtesy of Yue Shao)
But why should researchers resist creating complete synthetic embryos? To answer this, we need some policy context. Currently there is an embryo research rule in place – a law in many nations, in others a culturally accepted agreement – that intact human embryos must not be grown for research in the lab for longer than 14 consecutive days after fertilization or the formation of the primitive streak (a faint embryonic band that signals the start of gastrulation). This is commonly referred to as the 14-day rule. It was established in the UK decades ago to carve out a space for meritorious human embryo research while simultaneously assuring the public that researchers won't go too far in cultivating embryos to later developmental stages before destroying them at the end of their studies. Many citizens accepting of pre-implantation stage human embryo research would not have tolerated post-implantation stage embryo use. The 14-day rule was a line in the sand, drawn to protect the advancement of embryo research, which otherwise might have been stifled without this clear stopping point. To date, the 14-day rule has not been revoked anywhere in the world, although new research in extended natural embryo cultivation is starting to put some pressure on it.
"Perhaps the day will come when scientists don't have to apply for research funding under such a dark cloud of anti-science sentiment."
Why does this policy context matter? The creation of complete synthetic embryos could raise serious questions (some of them legal) about whether the 14-day rule applies to these lab entities. Although they can be constructed in far fewer than 14 days, they would, at least in theory, be capable of recapitulating all of a natural embryo's developmental events at the gastrulation stage, thus possibly violating the spirit of the 14-day rule. Embryo research laws and policies worldwide are not ready yet to tackle this issue. Furthermore, professional guidelines issued by the International Society for Stem Cell Research prohibit the culture of any "organized embryo-like cellular structures with human organismal potential" to be cultured past the formation of the primitive streak. Thus, researchers should wait until there is greater clarity on this point, or until the 14-day rule is revised through proper policy-making channels to explicitly exclude complete synthetic embryos from its reach.
I should be clear that I am not basing my recommendations on any anti-embryo-research position per se, or on any metaphysical position regarding the positive moral status of synthetic embryos. Rather, I am concerned about the potential backlash that research on complete synthetic embryos might bring to embryo research in general. I began this essay by saying that ethics needs context. The ethics of synthetic embryo research needs to be considered within the context of today's fraught political environment. Perhaps the day will come when scientists don't have to apply for research funding under such a dark cloud of anti-science sentiment. Until then, however, it is my hope that scientists can fulfill their research aims by working on an array of different but each purposefully incomplete synthetic embryo models to generate, in the aggregate of their published work, a unified portrait of human development such that biologically complete synthetic embryo models will not be necessary.
Editor's Note: Read a different viewpoint here written by a leading New York fertility doctor/researcher.
Paul Alexander spent more than 70 years confined to an iron lung after a polio infection left him paralyzed at age 6. Here, Alexander uses a mirror attached to the top of his iron lung to view his surroundings.
Paul Alexander was one of several thousand who were infected and paralyzed by polio in 1952. That year, a polio epidemic swept the United States, forcing businesses to close and polio wards in hospitals all over the country to fill up with sick children. When Paul caught polio in the summer of 1952, doctors urged his parents to let him rest and recover at home, since the hospital in his home suburb of Dallas, Texas was already overrun with polio patients.
Paul rested in bed for a few days with aching limbs and a fever. But his condition quickly got worse. Within a week, Paul could no longer speak or swallow, and his parents rushed him to the local hospital where the doctors performed an emergency procedure to help him breathe. Paul woke from the surgery three days later, and found himself unable to move and lying inside an iron lung in the polio ward, surrounded by rows of other paralyzed children.
Hospitals were commonly filled with polio patients who had been paralyzed by the virus before a vaccine became widely available in 1955. Associated Press
But against all odds, Paul lived. And with help from a physical therapist, Paul was able to thrive—sometimes for small periods outside the iron lung.
The way Paul did this was to practice glossopharyngeal breathing (or as Paul called it, “frog breathing”), where he would trap air in his mouth and force it down his throat and into his lungs by flattening his tongue. This breathing technique, taught to him by his physical therapist, would allow Paul to leave the iron lung for increasing periods of time.
With help from his iron lung (and for small periods of time without it), Paul managed to live a full, happy, and sometimes record-breaking life. At 21, Paul became the first person in Dallas, Texas to graduate high school without attending class in person, owing his success to memorization rather than taking notes. After high school, Paul received a scholarship to Southern Methodist University and pursued his dream of becoming a trial lawyer and successfully represented clients in court.
Paul Alexander, pictured here in his early 20s, mastered a type of breathing technique that allowed him to spend short amounts of time outside his iron lung. Paul Alexander
Throughout his long life, Paul was also able to fly on a plane, visit the beach, adopt a dog, fall in love, and write a memoir using a plastic stick to tap out a draft on a keyboard. In recent years, Paul joined TikTok and became a viral sensation with more than 330,000 followers. In one of his first videos, Paul advocated for vaccination and warned against another polio epidemic.
Paul was reportedly hospitalized with COVID-19 at the end of February and died on March 11th, 2024. He currently holds the Guiness World Record for longest survival inside an iron lung—71 years.
Polio thankfully no longer circulates in the United States, or in most of the world, thanks to vaccines. But Paul continues to serve as a reminder of the importance of vaccination—and the power of the human spirit.
““I’ve got some big dreams. I’m not going to accept from anybody their limitations,” he said in a 2022 interview with CNN. “My life is incredible.”
