The pregnancy was completely normal. In the spring of 2003, Danielle Messer was about to bring her second child into the world—a world that seemed more stable, more settled, more planned than when, as a teenager, she had given birth to her son, Taylor. After years as a single mom, Messer, now 25, had a steady partner, a well-paying job as a cosmetologist, and plans to pursue a college degree she had long deferred. Then the baby arrived.
“It was immediate that something was not right,” Messer said. Ari (short for Aristotle) was “floppy-ish,” in her words. “He wouldn’t eat. He wouldn’t wake up really at all, even after the first few days. He wasn’t alert. His muscle tone was pretty weak.” The doctors in Louisville, Kentucky—where Messer and Ray, now her husband, lived—ran tests but could offer only a diagnosis of “failure to thrive.” Messer understood the catchall phrase to mean “We don’t know.”
Ari’s parents brought him home, but as the months went by, the baby’s condition worsened. On the rare occasions when Messer could get him to breastfeed, he would vomit soon after. When he was 7 months old, his doctors performed a surgical procedure in which his esophagus was wrapped around the top of his stomach to prevent regurgitation; at the same time, they inserted a feeding tube. For a while, Ari gained weight, began to burble proto-words, played patty-cake. In their continuing quest to understand his condition, his doctors sent a biopsy of his muscle tissue to a laboratory in Atlanta. That’s around the time that Messer encountered a new word in an expanding vocabulary of dread: mitochondria. The doctors were beginning to think Ari’s failure to thrive was a symptom of mitochondrial disease.
Mitochondria are tiny satellite organs that float around in the jelly, or cytoplasm, of the cell—hundreds of thousands of them in virtually every cell in the human body. They are a bit like independent duchies within the greater kingdom of the cell: Mitochondria have their own DNA, their own proteins, their own metabolic pathways for manufacturing energy. Because they play a critical role in orchestrating the body’s biochemical conversion of nourishment into energy, they are popularly known as the cell’s power plants. And when they malfunction, very bad things can happen.
Mitochondrial diseases represent a rare but devastating constellation of illnesses that typically derive from a single misplaced letter of DNA, usually in the mitochondria but sometimes in the cell nucleus. Almost from the moment of birth, many children with mitochondrial disease (at least 1,000 each year in the US) struggle to move, breathe, or develop normally. There are a number of mitochondrial diseases, but among the most feared is Leigh’s syndrome. Infants born with Leigh’s rarely survive to their second birthday. As Messer scoured the internet for any tidbit of information that might help Ari, she thought, “Please don’t be this one.”
Ari’s improvement after the operation was short-lived. His breathing grew progressively weaker. He developed a cough that sounded like the croup, Messer recalls, and in October 2004, when he was 18 months old, his parents had to rush him to the emergency room, where doctors decided Ari needed a tracheotomy so that he could remain, indefinitely, on a ventilator. A postoperative MRI revealed severe brain atrophy. “They came in and told me, basically, he would never be the same again,” Messer recalls, “and that they were really sorry.”
Ari’s brain scans and another muscle biopsy were sent to Juan Pascual, an expert in mitochondrial disease then at Columbia University. There was finally diagnostic clarity, though not of the kind Messer and her husband had hoped for. Pascual diagnosed Ari with Leigh’s syndrome. “Once we got our diagnosis,” Messer says, the Louisville doctors “kind of said that they didn’t expect him to be alive much longer.”
Danielle and Ray took Ari home, awaiting the inevitable. The circumstances were already daunting, with 8-year-old Taylor and now the demands of caring for Ari, who was tethered to a ventilator, unable to speak or interact, much of his brain function eroded. Messer had nursing help part of the time, but her Medicaid coverage didn’t extend to 24-hour-a-day assistance. She postponed her college plans. “I don’t know how I made it work,” Messer said, “but I did.” Despite the prognosis, Ari did not die. When he was 8, his parents moved him to the Home for the Innocents, a special pediatric care facility in Louisville, where he received round-the-clock attention. He was on life support and slept as many as 22 hours a day.
Messer was still young. She wanted another baby. But she was haunted by the suffering Ari had endured. Children inherit mitochondrial DNA from their mothers. Messer carried a typo in hers, and any children she had in the future were at risk of inheriting it. “For the longest time,” she said, “I was scared to death of getting pregnant.” She briefly considered adoption, but she really wanted a genetically related child, so she began looking for a way to fix the mutation. This sort of genetic surgery, however, had never been attempted. It would require somebody with exceptional technical skill, because it would mean correcting the DNA in hundreds of thousands of mitochondria in her egg cells, a herculean task at a microscopic scale. It would also require somebody with a certain amount of scientific gumption, not to say swagger, because that type of repair in a human being would cross a bioethical Rubicon. The change would not only modify genes in a single embryo—an idea that is plenty controversial on its own—but if that embryo grew into a woman, and if that woman had children, the kids would inherit their grandmother Danielle’s modified DNA.
Broadly speaking, this speculative form of genetic surgery in egg cells or sperm cells or early-stage embryos is known as germ-line gene modification. Tampering with the germ line is perhaps the most controversial frontier in all of medical science—in part because of safety (it might introduce an irretrievably harmful change to a child) and in part because of ethical concerns about tinkering with human inheritance. Many people fret about a future in which we will create “designer babies,” cherry-picking chromosomal DNA for intelligence or beauty. While the lowly mitochondria don’t influence those traits, altering their DNA would nonetheless introduce a heritable change that could be passed on to future generations.
Without fully appreciating the scientific and ethical mire she was stepping into, Messer turned to the internet and the scientific literature. In early 2012 she stumbled across an advertisement seeking human egg donors for experiments by a researcher named Shoukhrat Mitalipov at the Oregon National Primate Research Center in Beaverton, Oregon. Back in 2009, Mitalipov had figured out a way to replace mitochondrial DNA in the egg cells of rhesus monkeys, producing embryos and eventually offspring where the genetic change was passed along. Now he was recruiting women to attempt mitochondrial repair in human eggs.
By the time Messer saw the ad for egg donors, Mitalipov had commenced a preliminary round of experiments on healthy human donors. Then he received a message that a woman in Kentucky had tried reaching him. He returned the call later that day, and that’s when he first encountered Ari’s mother. “Shoukhrat didn’t find Danielle,” a researcher in his lab says. “Danielle found Shoukhrat.”
Mitalipov sometimes refers to himself as an “egg surgeon.” He is compact, with intense dark eyes, high cheekbones, and a brusque shock of black hair. Born of Uighur ancestry in what’s now Kazakhstan, he got his earliest exposure to biology from tending the family’s sheep and cows. That experience served him well when he obtained his PhD in 1994 at the Russian Academy of Medical Sciences in Moscow, specializing in embryonic stem cells and medical genetics. While in school, he picked up spending money playing guitar in a band, and he developed a love of the blues. When he received a fellowship to work in America in 1995, he was elated (“the birthplace of the blues!”). After an agricultural postdoc at Utah State University, he was offered a job as a staff scientist doing more advanced research at the Oregon primate facility.
Mitalipov’s scientific expertise was shaped not by medical training or patient encounters so much as by animal reproduction, and in particular by in vitro fertilization techniques for agricultural livestock. Intellectually speaking, he ran with the crew of biologists who, in the 1990s, eventually created Dolly the cloned sheep. As his cloning skills became more sophisticated, he acquired a fascination, bordering on reverence, for the secrets that lay concealed in the cytoplasm of egg cells—not just the mitochondria, but the “maternal factors” that mysteriously controlled the fate of early embryonic development.
For nearly a decade, his Oregon lab published a string of papers on embryonic development in monkeys and how to manipulate it, culminating in a breakthrough 2009 Nature paper. That paper reported the birth of the first primates—five rhesus monkeys named Mito, Tracker, Spindler, Spindy, and Crysta—created from eggs in which the mitochondrial DNA came from a separate donor egg using a method called spindle transfer. Today, on the wall just outside Mitalipov’s office at the Oregon Health & Science University, there are photographic portraits of several of those monkeys, who have appeared on the covers of scientific journals like Nature, Cell, and other bibles of the molecular arts. Some had offspring. According to a paper published two months ago, those genetically engineered monkeys have displayed normal growth, general health fitness, and no infertility issues after a decade of observation.
But Mitalipov’s goal was never to cure mitochondrial disease in monkeys; monkeys don’t appear to develop it in the first place. Rather, the primates offered him an opportunity to test the spindle transfer technique, which he hoped could be used for mitochondrial replacement therapy in humans. “Shoukhrat is very much an ‘I’m gonna do it’ guy,” says Carol Brenner, a biologist specializing in assisted reproductive technology at the University of New England. “He’s a very determined man and an excellent micro-manipulator. Technically, he’s amazing. And he works very, very hard.” Mitalipov expected IVF practitioners to pick up the baton, but none did. “I was told, ‘If you want your technology to move into the clinic, you have to do it yourself,’” he says. In 2011, with Oregon Health & Science’s support, Mitalipov established a small human embryology group to pursue his goal. He set up shop in a 13th-floor corner office with a view of Mount Hood nearly 80 miles to the east. Just three floors below is the IVF clinic where his main collaborator, Paula Amato, an infertility specialist, collects the human egg cells from women who donate them.
Many bioethicists have condemned editing eggs or embryos, religious groups have denounced it, and US government regulators refuse even to consider allowing it. That doesn’t deter Mitalipov and Amato in the least. Nor does Mitalipov draw a distinction between mitochondrial and nuclear gene modification; mitochondrial replacement therapy, he says, is “one of the forms of germ-line gene therapy”—a change that can be passed along to future generations. The Oregon group’s overarching goal is to prevent disease, and to do so by combining IVF technology with genetic correction techniques. In addition to mitochondrial disease, there are 10,000 diseases caused by inherited mutations in the nuclear DNA that affect hundreds of millions of people worldwide, Mitalipov says—Huntington’s disease, cystic fibrosis, sickle cell anemia, and some forms of breast cancer, to name just a few—and correcting those mutations very early, in egg cells or in early embryos, could reduce human suffering. At present, the only practicable approach is correction by mitochondrial replacement. That is why, in 2009, immediately after publishing the monkey experiments, he pushed to do human germ-line experiments. “Because I’m developing treatments, I have to do it,” he recalls telling his bosses in Oregon. “I cannot just keep doing everything in a monkey.”
By 2012, bioethicists and regulators seemed more willing to consider this kind of intervention, and Mitalipov began to discuss with the Food and Drug Administration a clinical trial of mitochondrial replacement using his spindle transfer technique. During early discussions about the steps necessary to move forward in humans, Mitalipov says, the FDA insisted that the Oregon group perform a second round of human egg experiments, showing that he could apply the method to the eggs of women who had already borne children with mitochondrial disease and demonstrate that the technique would eliminate all the mutated mitochondrial DNA. There was no intent to produce pregnancies; the experiments would begin and end in a dish.
Not long after the discussions began with the FDA, Mitalipov hired a researcher named Amy Koski to be a clinical coordinator for the trial, and he dispatched her to meet with families associated with the United Mitochondrial Disease Foundation. By the fall of 2014, Koski had identified four women who had borne children with mitochondrial disease and were willing to donate their eggs for Mitalipov’s research. One of those women was the one who’d called Mitalipov three years earlier, Danielle Messer.
Messer was eager to participate in Mitalipov’s study. But the process was complicated. For scientists interested in tinkering with the human germ line, there are three places to introduce edits—in a woman’s egg cells, in a man’s sperm cells, or in the earliest stages of an embryo, when all the genes are housed in stem cells, and tissues have not yet begun to specialize. In the case of mitochondrial disease, however, most of the action is confined to the egg. The experiments would require Messer to go through the arduous procedure of egg harvesting. Then researchers would create test tube embryos from those eggs; they did this to harvest embryonic stem cells, so they could track and analyze the genetic changes that had been introduced. The creation of embryos required the use of donor sperm, but Danielle’s husband had a lifelong fear of flying and balked at the idea of boarding an airplane to join her for the monthlong research visit. So in the fall of 2014, the couple got into their Nissan Pathfinder and drove, with their three dogs, the 2,300 miles from Louisville to Portland.
Unlike the main repository of nuclear DNA, the mitochondria are like hundreds of thousands of branch libraries of genetic information floating around in the cytoplasm of a human egg cell. Each branch has its own satellite compartment of DNA comprising 37 genes, compared to the 30,000 genes in the nucleus.
That’s why Mitalipov cultivated his skill as an egg surgeon. “We’re egg-centric,” he says with a smile. The spindle transfer technique he developed involves a manipulation of the egg cell at precisely the right moment.
As soon as the eggs are retrieved in Amato’s IVF clinic, from both a woman with mutated mitochondria and a healthy donor, they take an elevator ride up to the 13th floor. There, with the aid of a high-powered microscope, a custom-designed polarized lighting setup, and a deft touch honed on cow and monkey egg cells, Mitalipov creates a modified human egg cell. The spindle is a kind of internal scaffolding that latches onto and guides the movement of chromosomal DNA during a particular stage of reproductive cell division. The technique allows Mitalipov to locate and remove the spindle with its otherwise invisible chromosomes from the egg cell of a healthy donor, leaving behind the cytoplasm (with its normal mitochondria). From the egg of a carrier like Messer, he uses the same technique to isolate the spindle-and-chromosome complex, gently separating it from the rest of the cell—“like chewing gum,” he says—until it forms a self-contained pouch of chromosomal DNA. This little bud of DNA is then fused to the healthy cytoplasm of the donor cell.
When the procedure works smoothly, the remodeled egg cell will possess the chromosomal DNA of a prospective mother like Messer and the mitochondrial DNA of the donor. In other words, the technique preserves the mother’s central genetic library, while all the branch libraries, with their corrupted DNA text, are left behind. Then the modified egg is immediately fertilized using standard IVF techniques to produce an embryo; the embryo is never implanted, but is rather used to harvest embryonic stem cells, which allow continuing molecular analysis.
There is a scientific poster displayed in the hallway just outside Amy Koski’s office at Oregon Health & Science showing four human eggs that were altered by Mitalipov’s team. It’s not written anywhere on the graphic, but all four oocytes came from Messer, and they explain her terror about pregnancy. Three of them had negligible traces of the mutation, but the other had 40 percent mutated mitochondria, which meant a high risk of passing along disease. Any pregnancy would be a roll of the dice.
One of the conditions for participating in these studies was that the donated eggs could not be used for reproductive purposes. Messer knew that. But she still had hope. She recalls asking both Mitalipov and Koski whether there was any way to save one of the experimental embryos for later transplantation. “She was very, very specific that she only wanted her eggs to be fertilized with her husband’s sperm, just in case we could ever get approvals for anything,” Koski recalls. “And I said, ‘That’s never happening, Danielle.’” Mitalipov had to tell her no too. “Every single woman who donated to that project asked and begged and clarified and double-checked and asked again, ‘Are you sure we couldn’t maybe just freeze one of those?’” Koski says of the experimental embryos. “And I kept saying, ‘I’m so sorry, I’m so sorry.’ It was the same story, every single time.”
Even if the Oregon research team was forbidden from transferring or even saving those embryos, Messer nurtured the hope that she might be able to participate in a clinical trial some day. During 2014 and 2015, according to Mitalipov, the Oregon group continued to negotiate with the FDA about developing a trial to attempt mitochondrial replacement in women who carried mutations. In the meantime, Messer and her husband made a crushingly difficult life choice: The family was relocating to South Carolina, where Messer had gotten a new job. They decided Ari, who was now 11, was better off staying at the care facility in Louisville.
Mitalipov was not the only scientist pursuing mitochondrial replacement. A formidable group at Columbia University had been developing techniques for the treatment, along with a group at Newcastle University in England. Indeed, a debate had been unfolding in the United Kingdom over what the press called “three-parent babies.” Unlike the US, the UK had a formal scientific and bioethics process to discuss this attempt at germ-line modification. A government agency known as the Human Fertilisation and Embryology Authority had, since the early 1990s, regulated the IVF industry in Britain, and it considered the scientific merits of mitochondrial replacement very early on. Parliament debated the ethics of mitochondrial replacement before approving the use of the technology in 2015. With these stamps of approval, a group at the Institute of Genetic Medicine at Newcastle University applied for, and later received, a license to apply mitochondrial replacement therapy.
Matters unfolded very differently in the US. Early on, germ-line modification—like embryonic stem cell research before it—got entangled in right-to-life politics and bioethical controversy. In December 2015, without any of the extensive and transparent debate that marked the British process, Republican lawmakers in the House of Representatives inserted a rider—one sentence in a 2,000-page omnibus appropriations bill, which included funding for the FDA—that banned all forms of germ-line modification. What’s more, the rider forbade the FDA to even “acknowledge receipt of a submission” of, much less approve, any proposed clinical trial in which a human embryo was modified. The insertion of the rider was “a stealth operation,” according to Eli Adashi, the former dean of medicine and biological sciences at Brown University and a reproductive endocrinologist who has closely followed emerging IVF technologies. “This all happened in the dead of night, without any discussion in the House or Senate.” Representative Robert Aderholt, the Alabama Republican who reportedly inserted the midnight rider, later called it “a tremendous victory for those who are concerned about life.”
Danielle Messer was furious. At the time the congressional rider was slipped into the omnibus bill, Ari had turned 12 years old and remained severely disabled. For more than a decade, he had never known life without a ventilator, a feeding tube, and round-the-clock ministrations from pulmonary nurses struggling to keep his airways clear. In 2014 he had suffered multiple organ failure and barely survived the experience. And yet, in so much of the public debate, germ-line gene modification was routinely equated, in headlines as well as in bioethics commentary, with “designer babies.”
“It drives me crazy when all these opposing opinion people write stuff about the slippery slope and designer babies,” she says. “That’s not even what this particular thing is. It’s not the nuclear DNA that you’re messing with, first of all. And it’s for people who have a known genetic mutation that don’t want to have an unhealthy child and have their child suffer. It’s not because I want a blond-haired, blue-eyed football player, or a cheerleader, or Ivy League whatever.” Plenty of things that once seemed outrageous, she says, become normal. “Now you get pig parts put in you,” she said. “You can have somebody else’s organ donated to you. But I can’t have some cytoplasm?”
The Oregon researchers were stunned by the congressional ban too. Because the rider now prevented the FDA from even acknowledging their proposed clinical trial, Mitalipov’s group eventually began to look outside the US. They explored collaborating with doctors in Thailand and China but quickly learned that wasn’t possible, because those countries forbid egg donation. Messer said she was ready to fly anywhere in the world to undergo the replacement therapy. But her husband still refused to fly anywhere at all, and he—or at least his sperm cells—needed to be present during the procedure. In an odd bit of global trade arcana, the Oregon group learned that it is illegal to ship human gametes, including sperm cells, from the United States.
In late December 2015, just weeks after the congressional rider became law, the Oregon team discovered an even bigger problem, one related to the mysteries of human biology not bureaucracy. Eunju Kang, a postdoc in Mitalipov’s lab, noticed something very strange in the experiments the FDA had originally requested. It was so strange, in fact, that at first she blamed her coworkers for screwing up.
The Oregon researchers had been working feverishly through the Christmas break to finish analyzing stem cells derived from the manipulated eggs. By that point, they had refined the transfer technique so that they were able to replace as much as 99 percent of defective mitochondria with healthy mitochondria; only a tiny residue of the disease-related DNA still clung to the spindle when it was fused to the healthy donor egg. So they expected that the resulting embryonic cells would possess the normal mitochondria. But at one point, Kang, who was leading the effort, saw that wasn’t the case. “The mutation is there!” she exclaimed. “Somebody’s messed up! Everything is wrong!”
But no one had messed up. In some of the modified embryonic stem cells, the “good” mitochondrial DNA gradually began to disappear, seemingly overtaken by the mutated “bad” mitochondria. Kang meticulously checked all the cell lines. Several cell lines derived from the three-parent embryos were initially healthy, but somehow, inexplicably, the mutation had begun to reappear with each subsequent generation of cells.
At first, Mitalipov didn’t believe the results, either. Right after the holidays, he convened an early-morning lab meeting to go over the data. The researchers were still reeling from the news of the congressional rider, and now the mutation had so unexpectedly reemerged. On top of that, British politicians had recently given permission for scientists in the UK to pursue a similar mitochondrial replacement experiment in humans. The surprising Oregon results suggested that the technique might not be as safe as the monkey experiments had indicated.
Mitalipov still believed an error had been made; they hadn’t seen anything like that in the monkeys. But Kang kept monitoring the cell lines—“kind of quietly,” as Koski puts it—and finally amassed so much evidence that everyone had to accept her conclusions. As Mitalipov recently put it, “Who would have thought 99 percent wouldn’t be good enough?”
The Oregon group rushed out a paper on the phenomenon, known as reversion; Nature published it in December 2016. The paper triggered a fierce scientific debate between the Portland and Newcastle groups, which has continued to play out in the pages of Nature and other venues to this day. Since 2017, when the Newcastle group received regulatory approval to attempt its first two cases of mitochondrial replacement therapy in humans, the British scientists have declined to comment on their ongoing clinical trials. As of January 2021, the health and fertilization authority had approved the use of mitochondrial replacement therapy in 22 cases in England, all to the Newcastle group. An authority spokesperson said, “Owing to the small number of treatments, we are unable to disclose information on ongoing pregnancies or outcomes.” The spokesperson added, “We have received no reports of reversion occurring.”
The discovery of reversion has given pause to everyone thinking about mitochondrial—and, in a larger sense, germ-line—modification. It’s one more reminder that science is about exploring the unknown, and sometimes Mother Nature replies to an experimental question with a totally unexpected answer. It was enough to convince the Oregon researchers that the procedure might not eliminate disease without further safeguards. “It was a small percentage of cases,” says Amato—just two of 15 stem cell lines showed evidence of reversion. “But if it happened, it could have been catastrophic.”
The reversion also at least temporarily scuttled any hopes for mothers who carried mutations. When Messer described the entire saga to me over coffee at a café in Colorado Springs, Colorado, where she and her family now live, her eyes teared up at precisely the moment we were discussing the issue of reversion, with its implication that MRT might not be ready for women with mitochondrial mutations who want to have their own children. Messer said she was still willing to try MRT, even with the possibility of reversion. But then there was yet another unexpected development. Messer became pregnant in 2016.
While Mitalipov and his team could not correct Messer’s mutation, they still managed to help. With special permission from the hospital’s institutional review board, they performed sophisticated mitochondrial analysis on tissue from Messer’s prenatal tests as her pregnancy progressed. The analysis determines a percentage known as the mutation load, which can vary from tissue to tissue. Families know the highest percentage by heart because it spells out the odds of having either a healthy infant or a devastatingly compromised child. A mutational load over 40 percent is likely to produce serious disease. In some of Ari’s tissues, it was 97 percent. “If they were unable to do any kind of testing for me, I don’t think I would have continued with the pregnancy,” Messer says. “It’s too risky to not know. Even when you kind of know, that’s scary.” The tests, although preliminary, indicated that the child would not suffer from mitochondrial disease. Sylus, her third son, was born in 2016 with a low mutation load, around 10 percent, and has remained healthy.
The landscape of germ-line modification—scientific, social, legislative, and ethical—has become, if anything, more complicated since Sylus’ birth. The reversion seen in the mitochondrial experiments came as a surprise, but Mitalipov held fast to his belief that germ-line modification could make dramatic improvements in human health. So as they were pursuing mitochondrial repair, the Oregon group also focused on developing techniques that would allow them to reach into the cell nucleus of either egg cells or early embryos and repair a disease-causing mutation. They began this effort using Crispr, a tool that promised the ability to target very specific stretches of DNA, cut out mutations, and drop in genetic corrections.
And they appeared to achieve success. In 2017, in Nature, Mitalipov, Amato, and their colleagues reported the first peer-reviewed attempt to correct a genetic mutation in a human embryo—one that causes an inherited heart condition called hypertrophic cardiomyopathy. The experiments didn’t go beyond the lab, and no embryos were implanted in a person. The 2017 report stirred up controversy, and it has been so contested that several months ago researchers at Columbia University, led by Dieter Egli, published a paper in the journal Cell suggesting the Oregon team had made a mistake. Mitalipov stands by his findings, but he will be the first to tell you that the early version of Crispr is a pretty blunt instrument for gene editing. It’s great for creating mutations, which has been incredibly useful in basic research, but it can gouge DNA in unexpected places and is inefficient at correcting mutations. For that reason, Mitalipov has moved on to other methods for gene editing.
And Mitalipov and Amato continue to work on mitochondrial replacement therapy. On January 31, 2018, after years of preliminary experiments conducted at the FDA’s request, the Oregon research team’s formal request to conduct a human trial of mitochondrial replacement therapy arrived at FDA headquarters. They knew the book-thick proposal would be dead on arrival because of the congressional rider, but they felt that the FDA’s refusal even to acknowledge the request would legitimize efforts to find an overseas site for a clinical trial.
Then the political atmosphere for germ-line modification got even worse. In November 2018, at a meeting in Hong Kong, Chinese scientist He Jiankui revealed that two children in China had been born from embryos he had edited. He had used Crispr to knock out a gene known as CCR5, which creates the portal by which the HIV virus gains access to human cells. Amato, who was at the Hong Kong meeting, followed the Twitter storm from her hotel room as news of He’s rogue experiment broke. The following day, she was on a panel on germ-line modification along with He, whose description of his experiment dominated the discussion and prompted almost instantaneous global condemnation and calls for a moratorium on such research. “It certainly raised awareness,” Amato says dryly.
When he first heard the news back in Portland, Peter Barr-Gillespie, executive vice president and chief research officer at Oregon Health & Science University, recalls thinking, “Holy shit! That’s going to create problems!” When asked about it a year later, his reaction was more measured. “It was an irresponsible thing to do,” he says of He’s experiment. Barr-Gillespie estimates that we are at least five years from embryo editing that follows “a responsible pathway.” “There’s a lot of science that needs to be worked out,” he says, “most importantly, how do you do this safely?” A report issued in September 2020 by an esteemed international committee suggested that researchers should be allowed to continue developing the technology under strict guidelines while working on safety, efficacy, and ethical consensus.
Cutting-edge science is littered with monuments to hubris, impatience, and headlong speed by researchers intent on changing the world. And yet, sometimes those efforts lead to real advances. The unauthorized attempts at gene therapy by UCLA’s Martin Cline in the 1980s resulted in widespread censure; gene therapy has now shown increasing promise. The initial clinical trials of monoclonal antibodies in the 1990s were failures; monoclonals are now important therapies for diseases, including Covid-19. The extravagant claims about immunotherapy in the 1980s didn’t pan out, but now a class of immunotherapy drugs has revolutionized cancer treatment. And ethical queasiness with new technologies does not necessarily predict their demise. The persistent and undeterred pioneers of in vitro fertilization, Robert Edwards and Patrick Steptoe, were regarded as charlatans and publicity hounds by their many detractors but ultimately overcame stiff scientific, social, and legislative opposition.
A recent paper by the Oregon group may in fact have revived the prospects for mitochondrial replacement therapy in humans. In the early animal experiments conducted at the behest of the FDA, Mitalipov’s group continued to follow the original five monkeys created by mitochondrial replacement. Those monkeys were reproductively normal, but in one, researchers found evidence of reversion. The amount of maternal mitochondrial DNA rose from negligible to 17 percent in several internal organs, but this was still “well below the threshold for disease manifestation” had it been in humans, according to Amato. They also managed to challenge some long-standing biological dogma by showing that, in two of the monkeys, some of the mitochondrial DNA in the second-generation offspring came from the fathers rather than the mothers. Amato said the overall results were “reassuring,” adding, “I personally feel very confident about moving forward with clinical trials. I would be very happy to do that in the United States, tomorrow, if we had approval.”
As the science creeps forward, Aristotle Messer remains alive in Louisville, still on a ventilator and feeding tube, still needing round-the-clock care as he approaches his 18th birthday. Because of the coronavirus pandemic, his parents can no longer visit him. Prior to the virus, Messer tried to see him as often as she could. “I don’t think he knows anymore that I’m there or not there, who I am,” she says quietly.
Messer, who will turn 43 this month, realizes that, even if safety and efficacy would be improved, she has probably aged out of any potential clinical mitochondrial replacement therapy trial. But she has not aged out of childbearing, which may be the last—and happiest—twist in this improbable cautionary tale about tinkering with the human germ line. In the early spring of 2019, she became pregnant again, became exhilarated and terrified all over again. Danielle’s fourth son, Dakota, was born that November. She arranged to send the placenta, umbilical cord, foreskin, urine, and blood of her newborn to Portland for a postnatal analysis of his mitochondrial DNA. “They can’t find any detectable mutation,” she told me. In the mysterious and unpredictable ways in which biology and politics and ethics mingle, where we forbid tinkering with germ-line genes but consider an entire childhood lashed to a ventilator as ethically defensible, where Danielle Messer says she would have been tearfully willing to try mitochondrial replacement therapy despite the evidence that it might not work, this fiercely maternal woman—“a mother with a capital M,” Mitalipov said of Danielle at one point—did not need to edit her genes at all.
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