Science Is Getting Us Closer to the End of Infertility

About 40 years ago, Louise Brown, the first human created using in vitro fertilization, was conceived in a petri dish. Not long after her birth, Leon Kass, a prominent biologist and ethicist at the University of Chicago, wrung his hands about the then-­revolutionary technology of joining sperm and egg outside the body. The mere existence of the baby girl, he wrote in an article, called into question “the idea of the humanness of our human life and the meaning of our embodiment, our sexual being, and our relation to ancestors and descendants.” The editors of Nova magazine suggested in vitro fertilization was “the biggest threat since the atom bomb.” The American Medical Association wanted to halt research altogether.

Yet a funny thing happened, or didn’t, in the decades that followed: Millions of babies were conceived using IVF. They were born healthy and perfectly normal babies, and they grew to become healthy and perfectly normal adults. Brown is one of them. She lives in Bristol, England, and works as a clerk for a sea freight company. She’s married and has two healthy boys. Everyone is doing fine.

Nothing so excites the forces of reaction and revolution like changes in human reproduction. When our ideas of sex are nudged aside by technologies, we become especially agitated. Some loathe the new possibilities and call for restrictions or bans; others claim untrammeled rights to the new thing. Eventually, almost everyone settles down, and the changes, no matter how implausible they once seemed, become part of who we are.

We are now on the brink of another revolution in reproduction, one that could make IVF look quaint. Through an emerging technology called in vitro gametogenesis (or IVG), scientists are learning how to convert adult human cells—taken perhaps from the inside of a cheek or from a piece of skin on the arm—into artificial gametes, lab-made eggs and sperm, that could be combined to create an embryo and then be implanted in a womb. For the infertile or people having trouble conceiving, it would be a huge breakthrough. Even adults with no sperm or eggs could conceivably become biological parents.

In the future, new kinds of families might become possible: a child could have a single biological parent because an individual could theoretically make both their own eggs and sperm; a same-sex couple could have a child who is biologically related to both of them; or a grieving widow might use fresh hair follicles from a dead spouse’s brush to have a child her late husband didn’t live to see.

At the same time, modern gene-editing technologies such as Crispr-Cas9 would make it relatively easy to repair, add, or remove genes during the IVG process, eliminating diseases or conferring advantages that would ripple through a child’s genome. This all may sound like science fiction, but to those following the research, the combination of IVG and gene editing appears highly likely, if not inevitable. Eli Adashi, who was dean of medicine at Brown University and has written about the policy challenges of IVG, is astounded by what researchers have achieved so far. “It’s mind-boggling,” he says, although he cautions that popular understanding of the technology has not kept pace with the speed of the advances: “The public is almost entirely unaware of these technologies, and before they become broadly feasible, a conversation needs to begin.”

The story of artificial gametes truly begins in 2006, when a Japanese researcher named Shinya Yamanaka reported that he had induced adult mouse cells into becoming pluripotent stem cells. A year later, he demonstrated that he could do the same with human cells. Unlike most other cells, which are coded to perform specific, dedicated tasks, pluripotent stem cells can develop into any type of cell at all, making them invaluable for researchers studying human development and the origins of diseases. (They are also invaluable to humans: Embryos are composed of stem cells, and babies are the products of their maturation.) Before Yamanaka’s breakthrough, researchers who wanted to work with stem cells had to extract them from embryos discarded during IVF or from eggs that had been harvested from women and later fertilized; in both cases, the embryos were destroyed in the process of isolating the stem cells. The process was expensive, controversial, and subject to intense government oversight in the United States. After Yamanaka’s discovery, scientists possessed a virtually inexhaustible supply of these so-called induced pluripotent stem cells (or iPSCs), and all over the world, they have since been trying to replicate each stage of cellular development, refining the recipes that can coax stem cells to become one cell or another.

In 2014, as a consequence of Yamanaka’s work, a Stanford researcher named Renee Reijo Pera cut skin from infertile men’s forearms, reprogrammed the skin cells to become iPSCs, and transplanted them into the testicles of mice to create human germ cells, the primitive precursors to eggs and sperm. (No embryos were created using these germ cells.) Two years later, in a paper published in Nature, two scientists in Japan, Mitinori Saitou and Katsuhiko Hayashi, described how they had turned cells from a mouse’s tail into iPSCs and from there into eggs. It was the first time that artificial eggs had been made outside of an organism’s body, and there was even more extraordinary news: Using the synthetic eggs, Saitou and Hayashi created eight healthy, fertile pups.

But baby mice do not a human make, and Saitou and another scientist, Azim Surani, are each working directly with human cells, trying to understand the differences between how mice and human iPSCs become primordial germ cells. In December 2017, Surani announced a crucial milestone concerning the eight-week cycle, after which germ cells begin the process of transforming into gametes. His lab had successfully nudged the development of stem cells to around week three of that cycle, inching closer to the development of a human gamete. Once adult human cells can be made into gametes, editing the stem cells will be relatively easy.

How soon before humans have children using IVG? Hayashi, one of the Japanese scientists, guesses it will take five years to produce egg-like cells from other human cells, with another 10 to 20 years of testing before doctors and regulators feel the process is safe enough to use in a clinic. Eli Adashi is less sure of the timing than he is of the outcome. “I don’t think any of us can say how long,” he says. “But the progress in rodents was remarkable: In six years, we went from nothing to everything. To suggest that this won’t be possible in humans is naive.”

Some cautiousness about IVG and gene editing is appropriate. Most medicines that succeed in so-called mouse models never find a clinical use. Yet IVG and gene editing are different from, say, cancer drugs: IVG induces cells to develop along certain pathways, which nature does all the time. As for gene editing, we are already beginning to use that in non-germ-line cells, where such changes are not heritable, in order to treat blood, neurological, and other types of diseases. Once scientists and regulators are confident they have minimized the potential risks of IVG, we could easily make heritable changes to germ cells like eggs, sperm, or early-stage embryos, and with those changes, we’d be altering the germ line, our shared human inheritance.

Used together, we can imagine would-be parents who have genetic diseases, or are infertile, or want to confer various genetic advantages on their children going to a clinic and swabbing their cheeks or losing a little piece of skin. Some 40 weeks later, they’ll have a healthy baby.

The demand for IVG coupled with gene editing would be significant. Around 7 percent of men and 11 percent of women of reproductive age in the US have reported problems with fertility, according to the National Institutes of Health. And IVF, which is typically the last, best hope for those struggling to conceive, is invasive, often doesn’t work, and can’t work for women who have no eggs at all.

Then there is genetic disease. Of the more than 130 million children who will be born next year, around 7 million will have serious genetic disorders. Today, parents who don’t want to pass on genetic abnormalities (and who have the thousands of dollars often required) might resort to IVF with preimplantation genetic diagnosis, where embryos are genetically tested before they are transferred to a woman’s uterus. But that process necessarily involves the same invasive process of IVF, and it entails rejecting and often destroying embryos with the unwanted genes, an act that some parents find morally impermissible. With IVG and gene editing, prospective parents would think it unremarkable to give doctors permission to test or alter stem cells or gametes. A doctor might say, “Your child will have a higher chance of developing X. Would you like us to fix that for you?”

Proving that IVG and gene editing are broadly safe and reliable will be necessary before regulatory agencies around the world relax the laws that currently preclude creating a human being from sythnetic gametes or tinkering with the human germ line. Although IVF was greeted with alarm by many mainstream physicians and scientists, it nonetheless was subject to little regulation; it slipped through the federal regulatory machinery charged with overseeing drugs or medical devices, as it was neither. Because IVG and gene editing are so strange, there may be popular and expert demand for their oversight. But in what form? Richard Hynes, a professor of cancer research at MIT, helped oversee a landmark 2017 report on the science and ethics of human genome editing. “We set out a long list of criteria,” Hynes says, “including only changing a defect to a gene that was common in the population. In other words, no enhancements; just back to normal.”

Critics imagine other ethical quandaries. Parents with undesirable traits might be coerced by laws—or, more likely, preferential insurance rates—to use the technologies. Or parents might choose traits in their children that others might consider disabilities. “Everyone thinks about parents eliminating disease or [about] augmentation, but it’s a big world,” says Hank Greely, a professor of law at Stanford University and the author of The End of Sex and the Future of Human Reproduction. “What if there are parents who wanted to select for Tay-Sachs disease? There are plenty of people in Silicon Valley who are somewhere on the spectrum, and some of them will want children who are neuro-atypical.”

And what of unknown risks? Even if Saitou, Hayashi, and their peers can prove that their techniques don’t create immediate genetic abnormalities, how can we know for sure that children born using IVG and gene editing won’t get sick later in life, or that their descendants won’t lack an important adaptation? Carriers of the gene for sickle cell, for example, enjoy a protective advantage against malaria. How can we know if we are shortsightedly eliminating a disorder whose genes confer some sort of protection?

George Daley, the dean of Harvard Medical School, has a simple answer to that question: We can’t. “There are always unknowns. No innovative therapy, whether it is a drug for a disease or something so bold and disruptive as germ line intervention, can ever remove all possible risk. Fear of the unknown and unquantifiable risks shouldn’t absolutely prohibit us from making interventions that could have great benefits. The risks of a genetic, inherited disease are quantifiable, known, and in many cases devastating. So we go forward, accepting the risks.”

Among the current unknowns are the name and sex of the first child who will be born using IVG. But somewhere there might be two people who will become her parents. They may not know each other yet or the difficulties with fertility or genetic disease that will prompt their physician to suggest IVG and gene editing. But sometime before the end of the century, their child will have her picture taken for a birthday profile in whatever media exists. In the likeness, her smile, like Louise Brown’s today, will be radiant with the joy of being here.

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Jason Pontin (@jason_pontin) is the former editor in chief and publisher of MIT Technology Review.

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