The year is 2069, and you and your partner are ready to become parents. But like millions of others, you need reproductive technology to help make it happen. So you head to your local fertility clinic to drop off some samples. After a long wait in reception, a technician calls you into a private room. She asks you to roll up your sleeve, and after a quick procession of disinfectants and local anesthesia near your biceps, she punches out a piece of skin about the size of a pencil eraser and drops it into a tube of clear liquid.
“Remind me,” she says, “did you want sperm or eggs?”
This is the promise of in vitro gametogenesis (IVG), a technology that one day could allow scientists to turn any cell in the body — from skin, hair, and more — into a sex cell, and subsequently an embryo. It could be the future of assisted baby-making if you do some creative hand-waving at the long list of technical, safety, legal, financial, and ethical caveats.
IVG uses stem cells — the biological clay that can form every body part — to build sex cells, which in humans are sperm and eggs. If successful, the technique could solve infertility due to age, cancer, or various disorders, which today affects tens of millions of people. It could also stretch the possibilities for genetic kinship and nudge biology to match the ever-evolving concept of a nuclear family. Same-sex partners could both be genetically related to their children — a woman could make sperm, a man an egg. People who are transgender could make sex cells that match their identity, rather than their biology. A single woman could have a child with herself. The science is still in early stages, but so far the basic concept has worked, more or less, in live mice and in human cells in a petri dish. A handful of labs across the world hope it’ll also work in people.
But for Mitinori Saitou, a cell biologist at Kyoto University in Japan and one of the field’s top researchers, futuristic fertility clinics aren’t the point. “Possibly I don’t have an interest,” he says.
On a mild December day in Kyoto, Saitou, wearing a tailored monogrammed dress shirt and a grape-hued sweater vest, explains he’s more interested in how things work than how they might be used. But despite his demurring, Saitou has been forced to consider the future if he or his competitors turn the promise of IVG into a reality. Thanks to a series of high-profile papers from his lab, Saitou says he has already received about a hundred emails from hopeful people who want to use the tech now.
“It’s still a fantasy. You can just imagine whatever you would like to imagine.”
As he mulls over the possibilities, the deep smile lines in the corners of his eyes soften. “For people who are seriously suffering from getting their own kids,” Saitou says, “then maybe that will be [an] option.”
Whether or not Saitou wants to consider what his research might unleash, his work is catching the attention of bioethicists, who are trained to contemplate the possible futures and consequences, as well as legal scholars and curious journalists. The technology raises the question: How far should humanity go to chase genetic family ties?
“It’s still a fantasy,” Saitou says of the predictions, the crinkles around his eyes deepening. “You can just imagine whatever you would like to imagine.”
In a tidy room in Saitou’s lab filled with metal racks and a row of microscopes, graduate student Chika Yamashiro pulls a small, clear dish from a tray. At the center is a cloudy blob, one of a hundred reconstructed ovaries, each of which were growing — she hoped — a single human egg. “She’s really making a lot of these,” Saitou says.
In the latest IVG achievement from Saitou’s lab, Yamashiro led researchers in a study that used the technique to grow a very early stage version of a human egg — called an oogonia — from human stem cells derived from blood. The success, a historic first, was published in the journal Science in September 2018.
Now Yamashiro wants to see if she can nudge the cells to grow a little more. If she does, this dish under the microscope — or one of the dozens more on the racks — could be the first time anyone has made a full human egg outside the body. Like her mentor, she doesn’t have much use for pondering the implications. “I’m not interested,” says Yamashiro, laughing. As for other people’s curiosity, “I expected the reaction,” she says. She has friends who are infertile, which is hard. They wish she could fix their problems. But like Saitou, she just wants to know how sex cells form.
Saitou didn’t set out to solve anyone’s fertility woes. When he was selecting a research topic as a graduate student more than 20 years ago, he kept considering heavy philosophical questions about what it means to be human: How does our mind work? What is the meaning of life? Why do we have to die? But these questions weren’t objective enough and “were too difficult to answer,” he says. So he started thinking about human legacy in a different sense: How we are connected through the germ line, the genetic thread that ties one generation to the next ad infinitum. Saitou decided to “try to understand why only this certain lineage can do this kind of incredible task.”
Scientists have long labored to stitch together the basic story: An egg and sperm fertilize to form a single cell, where the genetic material from a male and female mix. The cell then furiously divides to make more cells, eventually forming stem cells, the foundation for an entire body. These stem cells can then evolve into any other cell, including sex cells. To reach the point where a fertility technician can punch out a piece of skin and transform it into sperm or eggs, scientists need to understand every key step in how a person is made, from how early sex cells develop in an embryo to what happens during puberty about 13 years later — and shrink the complexity and timeline of that development into a petri dish.
Saitou set out to understand these processes in mice in 1999, when he joined the lab of Azim Surani, a developmental biologist at the University of Cambridge. Then, in 2003, Saitou moved back to Japan to lead his own teams, eventually landing at Kyoto University.
In 2011, everything changed. Saitou’s colleague Katsuhiko Hayashi, another former student of Surani’s who was then an associate professor at Kyoto, was trying to decipher how early stage sperm forms in mice embryos. To do this, Hayashi was working with a relatively new type of stem cells called induced pluripotent stem cells (iPSCs), which another lab at Kyoto University discovered, winning the lab’s head scientist the Nobel Prize. These iPSCs behave like regular stem cells, but rather than plucking them from an embryo — which is politically fraught — scientists nudge adult cells back into an embryonic-like state.
Hayashi reasoned that he could use iPSCs to reverse engineer how real sperm is built in the body. So he set to work stripping skin from dozens of mouse tails, dicing it up, and transforming it into stem cells. But his research question had an intriguing side effect: He was making sperm from skin. No one in the world had done that before. And it worked.
When the research was published in 2011, it made headlines in most major newspapers in Japan. “I was so surprised,” Hayashi says from his new lab at Kyushu University in Fukuoka, about 400 miles southwest from Kyoto. “It kind of changed my work, actually.”
After the paper’s success, Hayashi and Saitou veered into unplanned territory to make early stage mouse eggs from mouse skin. In 2012, when the results were published, the reaction was even bigger, Hayashi says, in part because when it comes to fertility, eggs are the limited resource. Fertile women have about 300,000 eggs by puberty, only a few hundred of which have the chance to be fertilized. Men can make around 1,500 sperm every second.
The duo continued moving forward, and in 2016, they reported yet another historic first: From mouse skin, their team made full eggs in a dish. Not only that, but using in vitro fertilization (IVF), they transplanted embryos from the artificial eggs into a live mouse. The process was inefficient: Only 3.5 percent of the embryos were viable. Still, the mouse gave birth to eight pups. The mouse pups appeared healthy, although the researchers didn’t do a formal study to be sure. (Hayashi plans such studies in the future.) Though the mother ate two pups, as mice will do, the other six survived and had their own litters.
The 2016 paper was impressive in part because mature eggs are so complex. Sperm is just a sack of genetic programming; the egg holds not only DNA but also a nutrient-rich gel that is necessary for cell development. As Hiyashi puts it, the egg is “the nature of life.” But in order to get an egg to develop in a dish, the Japanese scientists had to recreate the way it works in an embryo, which isn’t fully understood.
In the embryo, sex cells develop at the same time as the organs that will hold them — the ovaries or testes — which in turn provide vital signals that tell the sex cells how to grow. So, to make the egg, the scientists needed to provide at least the semblance of a developing ovary. To do this, they used embryonic ovarian cells from a mouse to grow a miniature version in the dish, like the ones Yamashiro is now testing. (Because it is difficult to get human fetal tissue, she is growing the human egg cells in fetal mouse ovaries.)
Creating a makeshift ovary from fetal tissues may work for mice or human cells in a lab, but it won’t likely be accepted by society when it comes to people. “Where are those fetal cells going to come from?” asks Amander Clark, a stem cell biologist at the University of California, Los Angeles. “Are they going to be human in nature? If they are, will human fetal tissue need to be used? Or could they be made from another species?” Hayashi hopes the answer will lie in using iPSCs to grow an embryonic-like human ovary, although it’s a work in progress.
“At some point, it’s going to be — with reviews from about a million different committees — a leap into the unknown.”
Then there is the matter of translating the rest of the work to people. “A mouse isn’t a human” is a common refrain in biomedical research. While mice may hint at how human biology works, the biological signals in a developing embryo — and the timeline — are different from one species to another. Both Hayashi and Saitou are taking an intermediate step by translating the work to monkeys, which, they hope, will give more clues to how it might work in humans. Today, the pair aren’t exactly competitors, but there’s delicate maneuvering between them. Whereas they worked together in the past, Hayashi’s new lab focuses on areas that don’t directly conflict with Saitou’s research. Saitou, for example, is using macaques for his monkey studies, so Hayashi chose marmosets.
Despite the unknowns, Hayashi and Saitou receive regular emails, as do others in the field, from infertile people from all over the world asking whether they could try the technology or donate cells for research. The scientists have mixed feelings. “It’s complicated, actually,” Hayashi says. “On this side, I really want to help them. But on that side, it is actually too preliminary to adapt.”
Ready or not, those emails won’t stop. A global figure on infertility is hard to tally, but one comprehensive study from the World Health Organization (WHO) puts the estimate at 48.5 million couples. Whether these couples turn to reproductive technology varies depending on their country, class, health insurance, religion, and more. In the United States, the Centers for Disease Control and Prevention (CDC) estimates it’s that fertility treatments have been used by at least 7.3 million women.
Modern fertility treatments date to 1978, when the first IVF baby, Louise Brown, was born. The basics of the procedure have remained mostly the same: Women take large amounts of fertility drugs before their eggs are harvested and fertilized with sperm from their partner or a donor. Then doctors implant the most promising embryos in the woman’s uterus — or that of a surrogate — and hope for the best. The odds aren’t great. According to the most recent U.S. statistics from the CDC,in 2016 there were 263,577 infertility cycles. Less than a third resulted in a live birth. IVF also isn’t cheap: One cycle can cost between $10,000 and $20,000, and many women have to try more than once to get pregnant. Insurance doesn’t always cover it.
With IVG, this could all change. Plucking a few skin cells to create eggs would mean skipping the painful, often risky process of harvesting them from ovaries. IVG could also provide a big supply of eggs, meaning better odds of having a healthy embryo. (The current IVF process yields, in an ideal case, about a dozen.) Everyone has skin, so most people wouldn’t need a donor. Women may not have to freeze their eggs or ovaries when they are young as insurance against age or infertility from cancer treatments. Large supplies of IVG-derived eggs and the resulting embryos — which aren’t easy to get otherwise — could also help scientists understand the genetics of infertility.
Society may broadly accept such uses — at least for some couples, and in particular those who are wealthy, white, and straight. “I actually don’t think IVG for heterosexual infertility caused by lack of gametes is likely to be controversial,” says Henry Greely, a law professor at Stanford University and author of The End of Sex and the Future of Human Reproduction.
But same-sex couples are already starting families with IVF, and many bioethicists argue that if society accepts IVG for straight couples, it would be unethical to prevent same-sex couples from doing the same. Still, from a technical perspective, it may not work: Women and men don’t have the genetic equipment to build a sex cell of the opposite sex, and scientists are wondering whether they will be able to trick a cell into doing it. Several teams are trying in mice, including Hayashi and researchers at the University of Hawaii and the Weizmann Institute of Science in Israel.
Where some folks may get squeamish, Greely predicts, are the cases outside society’s current reproductive norms. What if a 90-year-old wants to use the technology? What about using preserved tissues from people who are dead, or bits of skin stolen from celebrities or other unwitting partners? What if more than two people want to have one baby together — which, with some manipulations in the lab, might be possible with IVG?
“Technology is always technology. How you use it? I think society probably decides.”
Some ethicists also bring up the specter of eugenics — the controversial and flawed idea that society could improve the gene pool. IVG could be combined with increasingly sophisticated genetic screening, which, as Greely argues in his book, may mean more than weeding out deadly genetic disorders and may, for example, focus on increasing the probability that a child will have blue eyes or a better chance of excelling at math or sports. Add a new gene editing tool called CRISPR — which, in December, Chinese scientists revealed they had used on babies for the first time, amid an ethical uproar — and parents may have the power to not only choose traits but also customize them.
As with existing reproductive technology, IVG will also heighten “genetic connectedness over the social creation of families,” as through adoption, says Sonia Suter, a law professor and bioethicist at George Washington University. “I’m not saying it’s bad that people want to do it, but there is a worry for me that it devalues other kinds of connections that, frankly, I think are probably more important. How much care did you give to a child? How much time did you spend with the child?”
It’s also fair to wonder how empowering millions more people to reproduce will affect a planet stricken with climate change. According to a 2018 paper in Reproductive Biomedicine, existing technologies could add 157 million people to the world by the end of the century. That’s a drop compared to global projections — 11.2 billion people by 2100 — but the distribution won’t be even. “Some of the wealthiest people in the world are the ones that use this technology,” says Travis Rieder, a bioethicist at Johns Hopkins University. Even if IVG is eventually affordable, it’ll likely be expensive at first. If only the rich make more babies this way, Rieder adds, those babies would likely have a heavy carbon footprint.
But before society faces these what-ifs, the most pressing ethical concern is “safety first, second, and third,” Greely says. “Safety for the babies. Both figuring out what kinds of testing would give us confidence about safety, and then how safe we would require it to be — that is going to take time and work.”
Ensuring safety won’t be easy. Some proof may come from research in monkeys in Japan and elsewhere. And, as Clark from UCLA and others point out, there are many tests that could be done on an early stage embryo, such as scanning for known genetic disorders. But the true test proving that IVG works will be to make a viable human embryo from iPSC-derived sperm and eggs.
For Saitou and Hayashi, this final test will be a particular challenge. At the moment, it’s illegal in Japan to create human embryos from reprogrammed stem cells. And most countries follow an international policy that limits keeping embryos for research beyond 14 days. There is a push to make it 28 days, but even that is only a fraction of the time needed for embryonic development.
Still, the field has been at this crossroads before with pretty much every other fertility treatment, including IVF, which to date has been used successfully in an estimated 8 million births, says Sherman Silber, director of the Infertility Center at St. Luke’s Hospital in St. Louis. “At some point,” he says, “it’s going to be — with reviews from about a million different committees — a leap into the unknown.”
Back in the lab, Saitou and graduate student Yamashiro huddle around a microscope. Yamashiro slips a dish holding one of her reconstructed mouse ovaries under the lens. The last time she did this experiment — when she grew the early stage human eggs in mouse ovary cells — the results were a happy accident. She left the cells growing for two months—twice as long as she meant to. When she remembered them, Yamashiro was surprised to find that the cells had matured to form the first stage of an egg. They just needed some extra time.
Up close in the glowing light of the microscope, the new cells in the dish form a compact white pancake — flatter than a real mouse ovary, which would puff out like a ball. If the scientists are patient, the dish could grow a full human egg.
Even if they succeed, there are many more steps to get to the futuristic fertility clinic. None of the researchers studying IVG want to make an exact prediction for when that may happen, although Saitou suspects he’ll have a clearer answer in the next few years. After that, humanity will face some interesting choices. “Technology is always technology,” Saitou says. “How you use it? I think society probably decides.”