Forty years ago, couples suffering from infertility were given hope by the birth of Louise Brown, the first “test-tube baby”. But although millions of babies have now been born by IVF, the technique can offer no help to couples eager to have a child that is genetically theirs but who lack the eggs or sperm to make it: men whose testes produce no sperm, say, or women who have undergone surgery for ovarian cancer. Some opt for donor eggs or sperm, but an alternative may be on the way. Scientists are making steady progress towards creating human eggs and sperm – the so-called gametes that combine in fertilisation – artificially in a petri dish.

The idea is to make them from the ordinary “somatic” cells of the body, such as skin. The feasibility of such an extraordinary transformation of our flesh has only been recognised for 11 years. But already it is revolutionising medicine and assisted reproductive technologies may eventually feel the benefits too. If gametes grown in vitro prove safe for reproduction, the possibilities are dramatic – but could also be disconcerting, and might go well beyond providing eggs and sperm for those who lack them. Instead of having to undergo a painful egg-production and extraction procedure involving doses of hormones with uncertain long-term effects, a woman could have an almost limitless supply of eggs made from a scrap of skin. Huge numbers of embryos could be created easily and painlessly. What might we do with such a choice?

In 2007, Japanese biologists Shinya Yamanaka and Kazutoshi Takahashi showed that a human somatic cell like a skin cell can be turned into a stem cell, the kind of cell in an early embryo that can grow into every tissue type in the body. These artificially manipulated cells are called induced pluripotent stem cells (iPSCs) and they are now being studied for growing human organs such as pancreases and kidneys outside the body for surgical transplantation. In principle, they should also be able to form eggs and sperm.

This transformation of somatic cells is induced by injecting them with a cocktail of genes that generate proteins called transcription factors. In normal embryo growth, such proteins control gene activity and thereby guide cells towards their “fate” – what kind of specialised cells they become in the body. By adding the right factors artificially, a cell of one type can be tricked into thinking it is a different type. Yamanaka and Takahashi found that just four particular transcription factors were enough to persuade a skin cell to revert to acting like a stem cell. Once converted to an iPSC, a cell can then be directed by other factors towards a different fate.

Facebook Twitter Pinterest A microscopic view of a colony of induced pluripotent stem cells (iPSCs). Photograph: UCLA Broad Stem Cell Research Center/Plath Lab

But to make gametes, there’s a catch. While all our other cells contain two copies of all our genes, packaged on to 46 molecular fibres called chromosomes, eggs and sperm have only one copy: 23 chromosomes in all. When an egg and sperm merge in fertilisation, the full complement of 46 is then restored. So to produce viable germ cells from stem cells, the cells have to undergo a special process called meiosis that halves their number of chromosomes.

It’s not at all easy to recapitulate that process in a petri dish and until recently researchers have only managed to transform iPSCs into precursors of gametes, called primordial germ cells (PGCs), which haven’t yet undergone chromosome-halving meiosis and can’t be fertilised. But last month, a group at Kyoto University in Japan led by Mitinori Saitou reported a big step forward. They have cajoled human PGCs on to the next stage of development, called oogonia cells. It now remains to advance these further to the form called oocytes, which are ready to begin meiosis and become genuine egg cells.

To develop into oogonia, the PGCs need to receive chemical signals from tissues in the ovaries. The Japanese group supplied those signals by culturing the iPSCs alongside cells taken from mouse ovaries. Despite being of a different species, the ovarian cells were able to supply the right prompts. “We did not expect this,” says Saitou, “but tried anyway and were surprised to find it worked.”

Making fully functional eggs from iPSCs is already far more advanced in mice. Saitou’s team have made mouse PGCs in vitro, matured them using ovarian tissue and transplanted them back into the ovaries of live mice, where the cells completed their development into mature eggs. And two years ago they showed that they could carry out the entire reproductive cycle in vitro. They used cultures of ovary tissue to mature the “artificial” eggs, which they fertilised by IVF and grew into mouse embryos. They then harvested the embryonic stem cells and turned them into PGCs for a new cycle.

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Whether all this can work for human cells is another matter. Stem cell biologist Werner Neuhausser of Harvard University in Cambridge, Massachusetts, doubts that the mouse ovarian cells will be capable of guiding human oogonia cells all the way to bona fide eggs, although he admits that no one really knows. “We think that we need to use human ovarian cells to mature oogonia into oocytes and then to eggs,” agrees Saitou. “We are working on it now.”

What about artificial sperm? In 2011, Saitou and his colleagues reported that they had used the same strategy to make artificial mouse sperm from the skin cells of adult mice. They first reprogrammed the cells into iPSCs, induced them to become PGCs and then transplanted them into the testes of mice to complete their development into sperm. The researchers used some of this sperm to fertilise mouse eggs, which developed into apparently healthy mouse pups.

Mitinori Saitou of Kyoto University. Photograph: Kyoto University

Neuhausser thinks that Saitou’s approach might also work for advancing human PGCs towards sperm in vitro, by culturing them among mouse testicular cells. But again, whether fully mature sperm could be produced this way isn’t clear. Neuhausser says that it may not prove necessary, though, as even somewhat immature sperm, lacking the swimming “tail”, might be capable of fertilising an egg if injected into it. In 2016, a Chinese team claimed to have made artificial mouse sperm wholly in vitro and used it to fertilise eggs, transferring them into female mice for gestation. But some other scientists working in the field remain sceptical of those claims, which have not been repeated.

“In my view, regeneration of human gametes from somatic cells in the lab is probably just a question of time and effort,” says Neuhausser. “The clinical need for such a technology is of course tremendous, as it would replace donor egg treatments.”

He cautions that extensive testing will be necessary to establish the safety of such a method of assisted conception and that embryos made this way would need to be genetically tested before being implanted in the womb to check for abnormalities. “Even with these safeguards in place we would have to accept some residual risk,” he says. “Ultimately, some patients would have to make a leap of faith if this technology enters clinical trials.” All the same, says bioethicist Henry Greely of Stanford University in California, “I don’t see any show stopper that will keep what is feasible in mice from working in humans.”

The ability to make gametes from any bodily residue we leave lying around opens up alarming scenarios

If eggs and thus IVF embryos could be produced easily and in large numbers, says Greely, that could change the landscape of assisted conception when combined with the option of genetic screening. This can be done ever more cheaply and quickly for embryos and is currently permitted in the UK for identifying those carrying certain genetic disease mutations.

With such technologies in place, says Greely, “the stage is set for very, very widespread use of embryo selection”.

He foresees a day when IVF clients are presented with lists of characteristics for dozens, perhaps hundreds, of their embryos: this one a male with dark eyes and light brown hair and slightly above average risk of prostate cancer, that one a tall, dark-haired girl with a 55% chance of being in the top half in Sats tests. Given that option of choice, Greely suspects that IVF might eventually become the default method of human reproduction. “I expect that, some time in the next 20 to 40 years… sex [for reproduction] will largely disappear,” he writes in his 2016 book The End of Sex.

The advent of the precision gene-editing tool Crispr-Cas9 in the past five years makes it possible that embryos’ genetic profiles could be further tweaked and refined. Crispr has already been used on human embryos for research purposes, although there remain questions about how safe it is. “The generation of gametes and embryos from somatic cells would really open the door to efficient [gene] editing,” says Neuhausser. “Pretty much any genetic modification could be introduced in iPSC lines derived from somatic cells using Crispr.”

Facebook Twitter Pinterest A PGC-derived oogonium. Photograph: Mitinori Saitou/Kyoto University

That conjures up scary images of a genetic elite being bred by those who can afford it, as in the film Gattaca. “But,” says Neuhausser, “the feasibility and cost of embryo screening will largely depend on the efficiency of generation of healthy human embryos from in vitro-derived eggs and sperm. If only one in 1,000 embryos is ‘normal’, this may prove to be too difficult and expensive for routine IVF.”

Making artificial gametes could introduce new permutations into how we reproduce. The somatic cells of both men and women could in principle be transformed into eggs and sperm. So gay couples of both sexes could have babies that were genetically related to both parents, although male couples would need a surrogate mother. Rather more challenging is the notion of a single individual conceiving a child from eggs and sperm both made from his or her cells, what Greely calls the “unibaby” of a “uniparent”, which could become some grotesque vanity project. Equally disturbing is the prospect that genetic parents could include, say, the very elderly, children or even foetuses. The ability to make gametes from any bodily residue we leave lying around – “like cells you leave on beer bottles and wine glasses,” says Greely – opens up other alarming scenarios. You can imagine the celebrity paternity suits already.

We don’t have to worry about it quite yet, though. “I get lots of emails from people saying, ‘My husband is infertile, he’s desperate to have kids,’” says Azim Surani, a developmental biologist at the University of Cambridge University and leading specialist on artificial gametes. “Well, nothing is impossible, but this is very complex if you’re going to think about clinical applications.” He says that to establish feasibility and safety for human reproduction, there would have to be some work first on non-human primates, which is slow. “It probably won’t happen here, but there are facilities in China and Japan that might do it,” he says, adding: “I don’t think it will happen within 10 years.”

But it all comes from a revolution in our understanding of what cells can do. “When I think about it, it is quite astonishing,” says Surani. “Each cell in your body is a potential gamete. This is a profound change in the way we think about cells.”