The news on 14 June that scientists had made “synthetic human embryos” caused widespread surprise and alarm. Sounds scary, right? Perhaps even, as an editorial in the Guardian suggested, like “playing God” and paving the way towards a dystopian “brave new world”.
The reality is different. For one thing, calling these “synthetic embryos” is rather misleading, even prejudicial – most scientists prefer the term “embryo models”, and they are made from ordinary human cells. And they are not new – the earliest ones were made years ago, although the scientists behind the latest work say they have been able to grow them for longer than before. What’s more, these embryo models are not being created out of Frankenstein-like hubris just to see if it’s possible, but could offer valuable new insights into embryology, disease and pregnancy. None has the potential to grow into a human being, nor is there any reason why scientists would want them to.
All the same, the work raises urgent ethical questions. In nearly all countries, embryo models are not covered (or not obviously) by existing regulations on embryo research. However, far from exploiting this regulatory gap, most scientists are keen to see it filled with new guidelines and laws about what is and isn’t permissible.
To do that, however, may mean confronting some of the profound questions that embryo models raise. What qualifies as an embryo? Or as a human organism? Or indeed, as a human?
The latest embryo models were made by two groups – that of Jacob Hanna at the Weizmann Institute of Science in Israel and of Magdalena Zernicka-Goetz of Cambridge University. The media frenzy started when Zernicka-Goetz spoke about her work at a meeting of the International Society for Stem Cell Research (ISSCR) in Boston, Massachusetts.
Embryo models are created from embryonic stem cells (ESCs), produced from cells taken from embryos before the different tissue types have started developing. They can grow into any tissue type in the body, a property called pluripotency.
In 2018, Zernicka-Goetz and colleagues showed that clumps of ESCs could organise themselves into hollow structures resembling an early embryo, shaped a little like a peanut shell, if they were grown in a culture dish along with the two cell types that make the structures that support the embryo: the yolk sac and placenta. It is as if the stem cells “know” what they should become, even outside the womb.
What’s more, the cells showed signs of preparing to develop into the distinct layers that eventually become the tissues and organs of the body. This stage, called gastrulation, starts to occur in normal human embryos in the womb about 14 days after fertilisation.
It marks the point where an embryo can no longer split into identical twins, and has therefore been regarded as a crude marker of the onset of true “personhood”. From 1990 it was adopted in the UK (and several other countries) as the limiting point to which human embryos from IVF could be legally grown outside the womb for research.
This limit means that human embryology can’t easily be studied beyond 14 days. Much of what we know about it relies on studies of other organisms, such as mice – which might or might not apply to humans. If human embryos could be studied for longer, we could explore questions such as why so many pregnancies – estimated to be about one in four – result in miscarriage.
Because they seem to mirror embryo development without being formally classed as embryos themselves, embryo models aren’t subject to that limit. They “allow us to carry out experiments that would be otherwise impossible on natural human embryos,” says Zernicka-Goetz. “Thirty to 40% of natural miscarriages occur around this developmental stage, [so] we hope that by understanding human development at this stage we might be able to do something to prevent this loss of life.”
In their new work, Zernicka-Goetz and Hanna report human embryo models that they say resemble the natural embryo around the 14-day mark, as gastrulation begins. “This is the stage when cells within the embryo decide what to become in the future adult body,” says developmental biologist Berna Sozen of Yale University in Connecticut. Being able to study it could help us understand basic aspects of human biology as well as the origins of some diseases, she says.
Could embryo models be grown to even later stages of development? Sozen says it might be exceedingly difficult to get beyond 21 days. But last year, both Hanna’s and Zernicka-Goetz’s groups reported mouse embryo models grown to a later equivalent point, where the head and organs such as a primitive heart begin to appear. “I imagine the same thing will eventually be possible with human cells,” says developmental biologist Marta Shahbazi of Cambridge University.
Hanna believes it should eventually be possible to grow embryo models to the equivalent stage of a 40-day human embryo. Aside from understanding early pregnancy, he believes that these embryo models could be useful for drug testing and as a source of mature cells for transplantation to address disease, such as blood-producing stem cells found in the foetal liver. “The field is still in its infancy,” says Sozen, “and it’s hard to predict what the future may hold.”
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Sozen regrets that the work was covered before being peer-reviewed: “So, the information that was presented by the media to the public could be potentially misleading.” Bailey Weatherbee, a PhD student in Zernicka-Goetz’s lab and the first author on their paper, says they felt compelled to release their preprint after the coverage of the Boston talk because of “mischaracterisation and overstatements” in the media. She says that that initial version was substantially improved by peer review before being published last week in Nature.
Developmental biologist Alfonso Martínez Arias of the Universitat Pompeu Fabra in Barcelona has some serious criticisms. While he thinks Hanna’s work is “a superb technical tour de force with many surprises”, he says the results that Zernicka-Goetz has presented so far are hard to interpret: “They are conglomerates of different cells which are difficult to relate to normal embryos, or to decide their developmental stage – but it’s certainly not day 14. I cannot find any of the features described in the original media coverage.” He adds that he doesn’t see the work as an advance on what has been published previously.
Hanna too says that Zernicka-Goetz’s results “are not qualified to be called embryo-like”. A true embryo model, he says, can’t be just a clump of cells that does embryo-like things. It must have all the right structures in the right place and so have the potential to develop further.
Weatherbee is impressed by the embryo-like structures reported by Hanna’s team, and agrees that their own don’t have these structures. But, she adds: “We have tried to be very measured and honest in how this is presented within the manuscript.”
Zernicka-Goetz pushes back against the criticism: “We have seen social media being used by competitors to criticise in the absence of full knowledge, and a personalisation of unjustifiable criticism.” Shahbazi, who worked as a postdoctoral student with Zernicka-Goetz and now runs her own lab, defends her as “one of the pioneers in the field”.
The media hype has stoked the tensions, and Sozen worries that competition and rancour could mar the field. She dislikes the way it is often presented as rivalry. “Such a combative mindset can create a closed community that lacks transparency and the diverse perspectives that drive innovation,” she says. “I particularly worry for trainees in the field. It can be very off-putting for newcomers and limits their opportunities.”
Despite these criticisms and controversies, this is by no means a two-horse race. Several other labs have also developed embryo models made from human stem cells; for example, in 2021 researchers found that ESCs could organise into embryo-like structures resembling those at an earlier developmental stage called the blastocyst, which appears around five to six days after fertilisation, before implantation has occurred in the uterus wall. They were dubbed blastoids, and this May biologist Ali Brivanlou of the Rockefeller University in New York and his team reported that human blastoids could be made to mimic implantation in plastic surfaces and then to begin gastrulation. Sozen’s own group as well as teams at the University of Pittsburgh and the Kunming University of Science and Technology in China have also reported embryo models that mimic some aspects of post-implantation and gastrulating embryos. Competition aside, this wealth of approaches could be a boon, because different model systems are likely to be good for studying different questions.
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This diversity of embryo models also says something profound about human development: it’s not really about the early embryo being “genetically programmed” to make a human being. Rather, pluripotent cells have capabilities for growth and development with many possible end results; it’s only in the undisturbed environment of pregnancy that the outcome is generally a baby.
That’s why embryo models pose challenging philosophical questions, destabilising the whole notion of what a “human” is or can be – and making it tricky to decide how best to regulate the research.
Because the embryo models reported by Hanna and Zernicka-Goetz mimic the stage after implantation would normally have occurred, they couldn’t even in principle produce a pregnancy. But human blastoids, which resemble the pre-implantation embryo, might do so. “Hypothetically, human blastoid models may show the capability of full-term development if implanted in a womb,” says Sozen. Currently such an experiment would be illegal for humans – but in April, researchers in Shanghai reported the equivalent for monkeys. In that work, a few of the embryo models did implant and begin pregnancies, but these quickly aborted spontaneously.
“Even in experimental animals, there is no evidence yet that embryo models can develop into live young,” says stem-cell biologist Martin Pera of the Jackson Laboratory, a nonprofit biomedical research institution in Maine. Sozen adds that this potential could be designed out of embryo models anyway, so that the issue of being a “potential human being” would be moot. For such reasons, she considers the term “synthetic embryo” misleading.
Weatherbee stresses that “the goal of the field has always been to develop tools to aid in understanding development and elucidating potential drivers of pregnancy loss – it’s not to simply build ‘embryos’.” And researchers are by no means ignoring the ethical issues. “The ISSCR makes enormous efforts to provide an appropriate ethical framework for this kind of research,” says Sozen.
Because embryo models don’t meet formal definitions of an embryo, it is not yet clear quite how they should be regulated, beyond existing rules about the use of ESCs. The ISSCR updated its guidelines in 2021 to recommend ethics reviews for research on embryo models that have significant potential to develop further. These guidelines “are widely recognised throughout the research community, and stem-cell scientists adhere to them,” says Pera.
But researchers themselves want to see more clarity about what is and isn’t permitted. According to Cambridge Reproduction, an initiative that aims to promote the university’s research on reproductive technologies, “the absence of clear, transparent guidance in this area hinders research and risks damaging public confidence.” It has launched a project called Governance of Stem Cell-Based Embryo Models (G-SCBEM) to produce a “comprehensive governance framework” for research using embryo models. There are challenges as well as opportunities to making embryo-like structures without eggs or sperm – but it needn’t set us on the perilous road to that brave new world.
