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    A New Way to Reproduce

    Scientists are trying to manufacture eggs and sperm in the laboratory. Will it end reproduction as we know it?

    Let’s call him B.D., because that’s what his wife does on her infertility blog, Shooting Blanks. Several years ago, the 36-year-old learned he was azoospermatic. It means his body makes no sperm at all.

    During a recent phone interview, I could hear his wife in the background. She is 35 and facing what she describes as a terrifying countdown toward a life with no children. “Being childless can’t be my destiny, it just can’t be,” she wrote on her blog.

    So far, B.D.’s case of infertility has proved untreatable, despite years of pills, vitamins, and a major surgery. But he may still have a long-shot chance at being a father. In 2012, B.D. traveled to Stanford University, where a technician performed a skin punch, removing a small disk of tissue from his shoulder. With a technique called “reprogramming,” his skin cells were converted into stem cells that have the potential to mature into various types of human cells. These were then transplanted into the testicles of a mouse. Would the stem cells take cues from their environment and form sperm? Two years later, when the scientists announced what they had foundevidence of primitive human reproductive cellsthe provocative findings made the national news.

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    “I heard it on NPR. I was thinking, ‘Son of a bitchthat is me they are talking about,’” B.D. recalls.

    The experiment was an attempt to turn ordinary cells obtained from human adults into fully functional gametes—that is, sperm or egg cells. No one has done it yet, but scientists say they are on the cusp of proving it is possible. If they can develop a technology for manufacturing eggs and sperm in the lab, it could bring an end to the problem of infertility for many. But it would also present a fundamental and, to some, troubling advance toward reducing the creation of life to a procedure in a laboratory.

    It’s part of an explosion of research into how cells make decisions about their fate. To be a neuron or a beating heart cell? From the moment an egg is fertilized, a flurry of biochemical signals orchestrate its division, growth, and specialization as a complete new life is formed. The ambition of biologists who study development is to understand each step and, if they can, copy it in their laboratories.

    And no type of cell made in the laboratory would have a bigger scientific and social impact than a sperm or an egg. Re-creating these would give scientists access to the chamber of secrets where the links between the generations are forged. “Is there anything more interesting than that? It’s so amazing,” says Renee Reijo Pera, the scientist who carried out the experiment with B.D.’s cells. “I know people who study how did life begin on Earth, or work on finding the edges of the universe. And I think none of that beats the fact that the sperm and the egg come together and you get a human. And mostly we get two arms and two legs. It is amazingly accurate.”

    Progress toward making “artificial gametes” has been accelerating. In Japan, mice were born from eggs scientists had manufactured in a dish from a tail cell. Chinese scientists later claimed they had determined the exact sequence of molecular signals required to make mouse sperm. So far, the exact biochemical formula for prompting a stem cell to mature into functional human eggs or sperm remains out of reach. No human skin cell has been turned into a bona fide human reproductive cell. But many scientists believe it’s only a matter of time—maybe only a year or two—before they get the right recipe. Recent advances have been “absolutely clear, and breathtaking” says George Daley, a stem-cell biologist who recently became dean of Harvard’s medical school.

    As control over the fundamental units of reproduction advances, the work is drawing the attention of entrepreneurs, legal experts, bioethicists, and specialists in in vitro fertilization. Some believe that artificial gametes could be the biggest leap forward since IVF itself was first tried, in 1977. Many millions of people can’t reproduce, whether because of cancer, accidents, age, or genetics. “You’d be saying that if you have skin, which you do if you are even alive, then you can have sperm,” says B.D.

    The technology could carry socially disruptive consequences. Women might have children regardless of age. Just grab some skin and poof, young eggs. And if eggs and sperm can be produced in the lab, why not also make embryos by the dozens and test them to pick those with the least disease risk or the best chance of a high IQ? Henry Greely, a member of Stanford University’s law faculty and one of the most influential bioethical thinkers in the U.S., finds that scenario likely. Last year, in a book titled The End of Sex, he predicted half of couples would stop reproducing naturally by 2040, instead relying on synthetic reproduction using skin or blood as a starting point.

    Others say it’s possible, even probable, that lab-made gametes could be genetically engineered to remove disease risks. And still more speculative possibilities are on the horizon. For instance, scientists believe it will be possible to make eggs from a man’s skin cell and sperm from a woman’s skin cell, though the latter would be more difficult because women lack Y chromosomes. This process, termed “sex reversal,” in theory could allow reproduction between two people of the same sex. And then there is what Greely terms the “uni-­parent—his own sperm, his own egg, his own ‘unibaby.’” Such bizarre possibilities have dominated news coverage of recent advances. The episode of All Things Considered that B.D. heard on the radio asked whether it would be possible to steal a hair from George Clooney’s head and create a clandestine Hollywood sperm bank.

    Reijo Pera, now vice president for research at Montana State University, thinks such speculation is misleading and harmful. “I don’t view something like in vitro gametogenesis as something scary. I see a group of people that is hurting,” she says. She also doubts people will go out of their way to obtain a lab-made baby if they don’t need to. “I think that it would grieve people who are infertile to hear those questions,” she says. “Because people who can reproduce the natural way—well, that’s what they do. I might be naïve, but I think the way to have a healthy child is still two people get together and you have wine and dinner.”

    REPROGRAMMING CELLS

    As a postdoctoral fellow in the 1990s, Reijo Pera helped to identify genes that cause total loss of sperm in men. One no-sperm gene, called DAZ, was particularly interesting because it exists only in primates. It means that in addition to our thumbs and our intellect, there are details of human reproduction that are also unique.

    The problem for scientists is that many of these details are hidden from view. Scientists are allowed to keep embryos alive in the lab for only 14 days for research purposes. After that comes a crucial period when a few cells of the developing embryo—about 40—begin a mysterious trek toward what’s called the gonadal ridge, the future ovaries or testicles. During that journey, in ways still incompletely understood, the gametes gain the capacity to form a new being.

    Reijo Pera has a personal interest in deconstructing how that process works. Early in her career, she was diagnosed with ovarian cancer, a rare kind called a granulosa cell tumor. The disease left her infertile. “People said ‘Oh, it’s easy to adopt, it’s easy to do this, that, or the other.’ And I became concerned about a certain coarseness in health care about infertility,” she says. She and her husband eventually decided to adopt a child from Guatemala. By 2006, she was learning Spanish and telling Newsweek, in an item naming her that year as one of the 20 most influential women in America, that she was going to be a mother. But then Guatemala ceased allowing foreign adoptions. By that time she was 49.

    “So we just decided, we’ll make a life—me and you and a dog named Boo. And that is what we did,” she says.

    Despite giving up on motherhood, Reijo Pera did not let the scientific question drop. Instead, she seized on what could be the ultimate answer to infertility.

    In 2006, a Japanese scientist named Shinya Yamanaka reported that he’d hit on a formula for turning any adult cell, including skin and blood cells, into what’s called an induced pluripotent stem cell. These cells—iPS cells for short—had undergone a kind of molecular amnesia. Just like cells found in newly formed human embryos, they had no fixed identity but were capable of becoming bone, fat, or any other part of the body. The technique proved extraordinarily simple to use. Some compared it the fall of a biological Berlin Wall.

    Yamanaka was swiftly handed a Nobel Prize, just six years later. With the development of iPS cells, he had solved an ethical controversy. He’d found a way to explore the earliest stages of human development without using embryos discarded in IVF. What’s more, iPS cells came from specific people. That meant the resulting cells would be an exact match to a patient. Scientists began talking about making supplies of “personalized” neurons or heart cells for transplant procedures.

    Reijo Pera was among those who understood that genetically identical stem cells could be especially important in reproduction. How else to get a biologically related child from a skin cell? Yet as straightforward as “rewinding” cells with Yamanaka’s recipe quickly became, causing them to pursue a chosen fate has proved challenging. Scientists still don’t know the exact combination of chemicals that prompt a cell to develop into, say, a neuron rather than part of a toenail. Figuring out that recipe—the precise set of ingredients and steps needed to direct a cell’s development—has become one of biology’s most daunting puzzles.

    In June, 3,900 developmental biologists, biotech executives, and doctors converged at Boston’s cavernous convention center for the 15th annual meeting of the International Society for Stem Cell Research. Yamanaka was there, trailed by Japanese TV crews. Many of the scientists in attendance work on creating specific cell types. One, Douglas Melton of Harvard University, says he spent more than a decade determining how to turn stem cells into pancreas cells, the kind that respond to insulin, and finally managed it in 2014. He has two children with diabetes and hopes they could be cured with a cell transplant. “We want complete dominion and mastery over cell fate,” Melton told the convention crowd.

    RECIPE FOR LIFE

    During the meeting, I tracked down two Japanese scientists, Mitinori Saitou and Katsuhiko Hayashi, who last November reported they had turned mouse tail cells into iPS cells and then into eggs. It was a notable first—the first time in the history of life that artificial eggs had been created outside an animal. Using the synthetic eggs, they’d produced eight mouse pups. Not only had those mice been healthy, but they had gone on to reproduce. The discovery took more than five years to perfect and 17 pages to describe in the journal Nature. Yamanaka has called Saitou a “genius.”

    The two scientists now aim to make human reproductive cells the same way. Saitou told me that Yamanaka himself directed him to try to master the production of human gametes. “He asked me in person. He thought we should do it because it’s scientifically very, very interesting,” he says. “We are really interested in why these cells can make a new individual. It’s the ultimate way of controlling cell fate.”

    Teams led by Yamanaka have been sweating to prove that iPS cells will have practical applications: creating cures from Japan’s Nobel Prize discovery has become a national priority. In 2014, Japanese researchers carried out the first test of iPS-generated cells, for treating blindness. But Saitou says artificial gametes aren’t yet on the agenda. “It’s not low on the list—it’s outside the list. It can’t even be compared to replacement cell [therapy],” he says. “I think it’s very difficult to use in vitro germ cells to make humans. But not impossible.”

    It’s not just technically difficult: Saitou is nervous about the ethical implications. He’s been deluged with letters from infertile couples. Yet in Japan, research guidelines currently forbid scientists from trying to use such cells to build an embryo. The country’s cabinet is weighing whether to loosen the rules.

    The technical obstacles will probably be overcome before the legal ones. That’s because, Saitou’s misgivings notwithstanding, there is now a race on to perfect a laboratory method for making human eggs. Saitou admitted he’s now in a “not so enjoyable” competition with his old mentor, Azim Surani of the University of Cambridge, to be the first to work out the recipe. Hayashi, his former student, now at the University of Kyushu, is also in the race. If any of them do perfect it, other researchers might not be so hesitant to use it in an IVF clinic.

    When I asked Hayashi, the younger of the two Japanese scientists, how long it would take to master making human gametes, he said 10 or 20 years. “How soon is the most difficult question, because I am doing the experiments and they are not easy. I don’t want to be a liar and say five years,” he says. “Five years later someone might blame me.”

    Scientists can already coax iPS cells to form primitive reproductive cells, like those made from B.D.’s tissue inside a mouse. What’s still unsolved is how to take the final step of turning those cells into functional sperm or eggs. In humans, that process isn’t fully completed until puberty. With their mice, Saitou and Hayashi tricked the iPS cells by placing them inside a simulated ovary that they constructed out of tissue harvested from fetal mice. Crafting such an incubator out of human fetal cells isn’t practical because they are hard to obtain. Instead, Saitou believes, he will need to manufacture the supporting tissue from iPS cells as well. That additional challenge could delay conclusion of the experiment.

    If they do make human eggs or sperm, scientists would hit another roadblock. That is because the only way to prove these cells are the real thing would be to create a human offspring. Right now, that’s a step the Japanese scientists aren’t willing or ready to consider.

    Instead, to demonstrate this final step, Hayashi and Saitou are also working with monkeys. Closely related to humans, the animals will be a good model for demonstrating whether their technology “is safe in a primate,” according to Hayashi. “What we need to prove is that we can make nice, good-quality eggs. For that we need to demonstrate offspring,” he says.

    EMBRYO FARMING

    Commercial interest is starting to swirl around the scientists. During my conversation with Hayashi, we were joined by Hardy Kagimoto, the CEO of a Japanese biotech company called Healios that is seeking to turn iPS cells into a treatment for blindness. Kagimoto also hopes to team with Hayashi to explore lab-made human gametes. He said a group of IVF doctors who operate a global network of clinics was interested as well. “A big thing is happening, and society isn’t aware of it,” says Kagimoto. “Don’t get me wrong, though—if we do anything, we’ll do it with the consensus of society.”

    Although he has patented his inventions, Hayashi so far hasn’t been willing to join a company. He says that last November, Japanese venture capitalists asked him to start one to make human eggs. “I refused. I refused because I can’t do it yet. Mainly it’s because it’s technically difficult,” he says. “But it’s also too immature to contribute to society.” Surveys in Japan show about 30 percent of people accept the idea of children from lab-made gametes. Support is highest for use by couples who have tried IVF and failed.

    Some investors see far wider possibilities. If eggs could be made from human iPS cells, the supply would potentially be limitless, perhaps leading to what is sometimes called “embryo farming.” Kagimoto remarked on one of the images in Hayashi’s publications. It is a picture taken through a microscope of dozens of lab-made mouse eggs floating in a drop of water.

    In that case, genetic sequencing could be used to inspect each embryo, allowing people to choose the “best” ones—those with desirable genes or without undesirable ones, like those associated with a risk of schizophrenia. This is the scenario predicted by Greely, the legal scholar, who argues that parents would choose artificial reproduction over sexual reproduction if they had enough to gain. “If you have 1,000 eggs, then you can make choices,” Kagimoto says.

    BRAVE NEW WORLD

    During the Boston stem-cell meeting, students strained from the doorways to hear presentations on the ethical issues raised by new reproductive technologies. From the podium, Daley cited Aldous Huxley’s 1932 book Brave New World, which described a society that controlled reproduction and incubated children in centralized facilities. The picture ­Huxley drew was dystopian but also “prescient,” said Daley. It predicted IVF.

    Daley believes scientific advances will allow for scenarios not unlike the one Huxley described. In addition to the Japanese efforts to create gametes, some scientists have created “gastruloids”—self-assembling blobs of cells that look, and behave, much like human embryos. At the same time, researchers are pressing on nature from the other direction. In February, doctors in Philadelphia removed fetal lambs from their mothers and kept each alive until birth inside a transparent fluid-filled sac known as an artificial uterus. The combination of these technologies points to a day when the entire reproduction process, from conception to birth, can be done in the lab. “One only has to speculate how long it is going to be before we can gestate animals entirely ectogenetically, entirely ex utero,” Daley said. “So the question then becomes: Can you draw the line?”

    Daley has paid particular attention to progress toward turning iPS cells into eggs and sperm, which he terms “a disruptive technology.” One reason is that he thinks artificial gametes are likely to be combined with the gene-editing technology called CRISPR, which since it was developed four years ago has made it much easier to alter DNA inside a living cell.

    That links artificial gametes to the debate over designer children—what’s called “germ-line genetic modification.” The debate over that question was rekindled in 2015 after Chinese scientists reported they’d used CRISPR on an embryo in a lab dish to try to remove a gene that causes the blood disease beta thalassemia. The report was initially met with grave concern, in part because CRISPR is not error-free: the experiments suggested that embryos might be imperfectly edited, creating unknown and intolerable risks for any child born this way.

    While some critics say modifying the gene pool is a bright ethical line that should never be crossed, that has not been the view of the scientific community (see “Engineering the Perfect Baby”). A report from the National Academy of Sciences, issued this year, concluded that editing human embryos would be permissible if the technique were used to eliminate serious diseases such as Huntington’s, a fatal brain disorder. While the committee did oppose using genetic engineering for mere enhancements—blue eyes and intelligence, say—the report left the definition of a disease open to interpretation.

    The reason the report paid special attention to artificial gametes is that editing might be carried out with great precision in iPS cells. Once the perfect iPS cells were in hand, they could be induced to create gametes with the specified genetic improvement.

    The idea of using CRISPR in stem cells has already been successfully implemented in mice. In China, a scientist named Jinsong Li edited mouse stem cells and removed a gene that causes cataracts. When he generated sperm and later fertilized eggs, the resulting animals appeared to have been edited with “100 percent efficiency.” Such reports give scientists reason to think the best argument against germ-line modification—that it will never be reliable or safe enough—is quickly evaporating. “It’s no longer possible to say it will not be feasible,” says Richard Hynes, an MIT professor who is one of the two senior authors of the National Academy report.

    HUGE DEMAND

    At the Harvard Stem Cell Institute, an IVF doctor and scientist named Werner Neuhausser is among those exploring how genome sequencing, stem cells, and genome editing could all come together to change reproduction. Neuhausser spends one day a week at Boston IVF, a large fertility center where he meets with patients. The other four days a week he has spent verifying and trying to extend the discoveries being made in Japan and elsewhere.

    As an IVF doctor, Neuhausser told me, he would “absolutely” see demand for lab-made sperm and especially lab-made eggs. “This is a big deal if it becomes possible,” he says.

    Like Kagimoto, Neuhausser believes it’s likely that embryos will be measured and their attributes quantified: “We are going to end up for each embryo that it has this risk of heart disease and that risk of psychiatric disease compared to the general population, and then how do you choose?” Neuhausser thinks parents may not have to. Instead, he says, parents could opt to genetically improve their own reproductive cells. “You could sequence the prospective parents’ genomes and then you can ask, ‘Are there variants you could correct before you reproduce?’ This is something that we haven’t thought through. It would depend greatly on the risks, and there is a lot we don’t know,” he says. “No one wants to use this in a patient anytime soon.”

    Gene editing of gametes is already being explored in his Harvard University lab. The team is obtaining sperm from men who carry a gene that causes amyotrophic lateral sclerosis, or ALS, a devastating neurological disease, and plan to try to remove the mutation using CRISPR. After his lab corrects the error, it will sequence the sperm cells to see the results.

    But Neuhausser says the more precise approach would be to make genetic corrections in iPS cells instead. These cells grow and multiply vigorously in the lab. Once they were edited, then eggs or sperm could be created from them. “You would gain access to the genome; you could change the genome at will. It’s controversial, of course,” he says. “But we should definitely investigate whether it works or not.”

    The futuristic technology of gametes-in-a-dish can’t come soon enough for men like B.D. He told me that he holds out hope he’ll be “the first candidate or one of the first” if a treatment using lab-made sperm ever gets approved. But it’s not likely to happen in time for him. He says he and his wife recently set a date on which they’d give up trying to have children. It’s September 2019.

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