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YUE SHAO wasn鈥檛 trying to create an embryo. But, a few years ago, working in a lab at the University of Michigan, he witnessed something mind-boggling. The cells he was working with seemed to assemble themselves into what looked just like an early-stage human.

鈥淲e were looking for something else,鈥� says Shao, a bioengineer now at the Massachusetts Institute of Technology 鈥� but 鈥渟erendipity hit鈥�.

The idea that scientists could create the first steps towards human life is astonishing, but Shao鈥檚 discovery wasn鈥檛 the first. A year before he published his results in 2017, research by a team in Japan led to the birth of live mouse pups using eggs the team made from adult skin cells.

Discoveries like these are bringing us closer to solving some of the most intractable problems in reproductive biology and medicine. By recreating these first days of development in the lab, researchers are breaking open the black box of early pregnancy, a poorly understood and fragile time at which most miscarriages happen and fertility treatments fail.

Now 40 years after the birth of the first test-tube baby, the potential of these breakthroughs is heralding a new biological revolution, one that forces us to rethink what it means to reproduce and make a baby. And there鈥檚 a lot to consider. Imagine being able to conceive a child from someone鈥檚 skin cells, for instance 鈥� with or without their consent. Given the ability to make a human artificially, we need to decide whether we want to.

Already, some 1.5 per cent of all babies born in western Europe, North America and Australia are conceived using in vitro fertilisation (IVF). So making the spark of life outside the body is routine. But it is also unpredictable. So much is still unknown about why some embryos don鈥檛 implant after transfer or, in both IVF and natural conceptions, what causes some to die while others keep growing. IVF also relies on prospective parents having viable sperm and eggs to work with in the first place.

Perhaps the boldest attempt so far at getting around that problem is to make sperm and eggs from totally unrelated cells in the body. Working with mice, Mitinori Saitou of Kyoto University in Japan and his collaborators took adult skin cells and reprogrammed them into stem cells, which have the potential to become any type of cell. They then turned these into either sperm or eggs. In 2016, they reported that they had fertilised some of these eggs with sperm from normal mice, and implanted the embryos into surrogates. Eight seemingly healthy pups were born. Then a year later, working with a team from the Crick Institute in London, they did the corresponding experiment using their lab-made sperm.

鈥淚t could lead to less invasive IVF or help women who are being treated for cancer鈥�

The potential for treating infertility is huge (see 鈥�Why make babies from skin cells?鈥�) but attempts at creating human sperm and eggs in the lab have so far produced only rudimentary precursors to these sex cells. For example, Azim Surani, a developmental biologist at the University of Cambridge鈥檚 Gurdon Institute, announced in late 2017 that his team had managed to grow 鈥減rimordial germ cells鈥� 鈥� precursors of sperm and eggs 鈥� to the four-week mark. Next, he hopes to nurture these cells to eight weeks, the point at which they either go on to form sperm or eggs.

It is possible that if these were transplanted into the body, they would mature and restore fertility in otherwise infertile individuals, says , a stem-cell biologist at Harvard University. But, he adds, 鈥渢here鈥檚 a whole other layer of safety issues that will have to be dealt with before this would ever enter clinical practice鈥�.

And we are still a long way from finishing the process in a lab dish.

One promising advance came earlier this year, when Evelyn Telfer at the University of Edinburgh, UK, and her colleagues cultured mature human eggs in the lab from a different type of stem cell found in ovaries. Telfer envisions using this technique to help women with cancer, where treatment can cause infertility. The idea would be to remove a piece of the ovaries before treatment, and to use it later on to make new eggs. It could also lead to 鈥渘ext-generation IVF鈥�, Telfer says, in which women would undergo a one-off surgical procedure to retrieve ovarian tissue, instead of successive cycles of hormones and invasive egg-harvesting.

Alternatively, we might not need to make eggs or sperm at all. Last year, a team led by Magdalena Zernicka-Goetz at the University of Cambridge coaxed two different kinds of mouse stem cells to that, after three or four days in a lab dish, looked and behaved the same way as a natural embryo. 鈥淪uperficially, they were very, very similar,鈥� says Sarah Harrison, who worked on the project as a PhD student.

Five months later, Shao鈥檚 group published its made entirely with human stem cells (see image, below).

In both cases, the impetus for the research was a desire to understand the early stages of embryo formation, which are difficult to study inside the body 鈥� specifically, what happens after an embryo implants in the uterus and starts organising its cells into layers. Shao also envisions his embryoids providing a platform for screening drugs and environmental toxins to see whether they cause birth defects. Neither team is trying to make viable embryos.

Besides, after four or five days these embryo-like structures already look more like two-week-old natural human embryos. That means they have effectively skipped the earliest steps of development and missed the stage at which implantation is feasible.

So the only shot at viability that these lab-grown embryoids might have would be outside the womb. Until recently, that prospect would have been unimaginable, because no one had succeeded in nurturing human embryos in a dish past the implantation stage. But two years ago, separate teams led by , an embryologist at Rockefeller University in New York, for up to two weeks after fertilisation. And they might have gone even longer were it not for the 鈥�14-day rule鈥�, a legal and regulatory line in the sand agreed by most countries engaged in research on human embryos.

That cut-off was chosen because it is the time at which a faint band of cells known as the primitive streak appears, a key developmental milestone for complex tissue formation. It is also when an embryo can no longer split into identical twins, and so it has been defined by some as the moment a distinct biological entity comes into being.

With that definition in mind, many scientists are now scrambling to figure out how best to apply the like the kind Shao鈥檚 team created 鈥� or even whether the rule applies at all. Last year, a team led by John Aach and George Church, geneticists at Harvard Medical School, 鈥搒ynthetic human entities with embryo-like features, or SHEEFs 鈥� and called for a broad international discussion of ethical issues raised by their creation.

As bioethicist Sarah Chan at the University of Edinburgh points out, a mass of self-assembling stem cells doesn鈥檛 have a clear day zero from which to start counting, so 14 days is meaningless. What鈥檚 more, because SHEEFs don鈥檛 develop along the conventional pathway, they may acquire morally concerning features long before the primitive streak is visible at 14 days. 鈥淲e need to have this wide-ranging debate,鈥� Chan says.

As developments like these push how long we can grow embryoids in the lab, others are working away at one of the most daunting challenges in reproductive medicine 鈥� how to keep babies alive when they enter the world too early. According to David Adamson, a reproductive endocrinologist who runs Advanced Reproductive Care, a US-wide network of fertility clinics, this 鈥渨ill be exceptionally difficult, and not achievable in this century鈥�.

There are good reasons to try, though. Neonatologists are advised against trying to save the lives of babies born before 22 weeks because of limitations with existing resuscitation technologies. An artificial womb could change that.

Last year, fetal surgeon Alan Flake and his colleagues at Children鈥檚 Hospital of Philadelphia described one such invention: a fluid-filled sac dubbed the Biobag. It kept lambs alive for about four weeks after they had been born at the equivalent of about 23 to 24 weeks in a human pregnancy, judged by lung development. Survival for premature babies is currently less than 50 per cent at that stage.

For the lambs, this and other systems, like the 鈥渁rtificial placenta鈥� developed by George Mychaliska鈥檚 team at the University of Michigan鈥檚 Extracorporeal Life Research Laboratory, can serve as a bridge until the lambs are ready for artificial ventilators and eventually to transition to breathing on their own.

The next generation

鈥淚t does appear that the lungs are continuing to develop over time, and they鈥檙e protected,鈥� Mychaliska says. In March, his team showed that , too. 鈥淭he goal is clinical translation in five years,鈥� he says. Human trials will initially include premature babies who have less than a 20 per cent chance of survival.

If one of these womb-like systems works for humans, it opens the door not just to sparking life in the lab, but keeping it alive entirely outside of the body. All these baby steps in our quest to improve the human condition could thus add up to the giant leap of making life from scratch. 鈥淢y guess is this would be a major way of having babies 100 years from now,鈥� says Hank Greely, a bioethicist and lawyer at Stanford University in California. 鈥淥nce you get 50 or 60 years out, the sky is the limit with biology.鈥�

Others are less bullish. 鈥淎 lot of things have to go very, very wrong 鈥� and have been very wrong for a while 鈥� before that would seem like a good idea,鈥� says Gigi Gronvall at the Johns Hopkins Bloomberg School of Public 91色情片 in Baltimore, Maryland.

And Jeantine Lunshof, a bioethicist at the University Medical Center Groningen in the Netherlands, says: 鈥淕iven the ease of making babies, in general, I do not see any need for it, nor arguments to support such an endeavour.鈥�

Yet similar things were once said about IVF: it was too dangerous, an unnatural and immoral abomination. Then came the birth of the first 鈥渢est-tube baby鈥� Louise Brown in 1978. An estimated 7 million have followed since. Now the fertility technique is practically routine, and few outside certain religious circles continue to debate its merit.

A similar acceptance could prevail for the next generation of assisted-reproductive treatments.

One reason to continue towards the goal of a complete from-scratch baby would be protection against some kind of environmental catastrophe or nuclear disaster. Think Children of Men or The Handmaid鈥檚 Tale. 鈥淚f the human race as a whole were seriously endangered, and if our reproductive abilities were seriously compromised, we might have to manufacture human beings,鈥� says Ronald Green, a retired ethicist from Dartmouth College in Hanover, New Hampshire.

More likely, says Anna Smajdor, a bioethicist and philosopher at the University of Oslo, Norway, the ability to build human life from scratch would occur more as an after-effect than as a deliberate goal of reproductive research. As new technologies develop for bona fide medical reasons 鈥� treating infertility, preventing the transmission of genetic disease, saving the lives of premature babies 鈥� 鈥測ou鈥檒l get this creep,鈥� she says.

Whatever the driver, it is undeniable that a huge biological shift is under way. Still, if experiments like Shao鈥檚 tell us anything, it鈥檚 that whether you are doing it in the lab or the old fashioned way, when it comes to the spark of life, you can never predict the outcome.

This article appears in print under the headline 鈥淣ew beginnings鈥�