Biology

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The Brave New World of Three­Parent I.V.F. By KIM TINGLEY JUNE 27, 2014

In August 1996, at St. Barnabas Medical Center in Livingston, N.J., a 39- year-old mechanical engineer from Pittsburgh named Maureen Ott became pregnant. Ott had been trying for almost seven years to conceive a child through in vitro fertilization. Unwilling to give up, she submitted to an experimental procedure in which doctors extracted her eggs, slid a needle through their shiny coat and injected not only her husband’s sperm but also a small amount of cytoplasm from another woman’s egg. When the embryo was implanted in Ott’s womb, she became the first woman on record to be successfully impregnated using this procedure, which some say is the root of an exciting medical advance and others say is the beginning of the end of the human species.

The fresh cytoplasm that entered Ott’s eggs (researchers thought it might help promote proper fertilization and development) contained mitochondria: bean-shaped organelles that power our cells like batteries. But mitochondria also contain their own DNA, which meant that her child could possess the genetic material of three people. In fact, the 37 genes in mitochondrial DNA pass directly from a woman’s egg into every cell of her offspring, including his or her germ cells, the sperm or eggs that eventually produce the next generation — so if Ott had a girl and the donor mitochondria injected into Ott’s egg made it into the eggs of her daughter, they could be passed along to her children. This is known as crossing the germ line, something that scientists generally agree is a risky proposition.

Ott, who is Catholic, remembers weighing whether altering the

makeup of her descendants in this way was O.K. “Being a person who’s been involved in science my whole life, the way I looked at it is: God gives us doctors to help us, and they help us with things like infertility,” she told me recently. As far as anyone knows, mitochondrial DNA (mtDNA) governs only basic cellular functions; Ott understood that her and her husband’s nuclear DNA would determine their child’s characteristics — height, eye color, intelligence and so on. “If I was doing something like, say, I only wanted a blond-haired girl, I would feel that was unethical,” she said. “But what I was trying to do was use whatever medical procedures were available to me to get pregnant, and I didn’t think that was unethical.” In May 1997, she gave birth to a healthy baby girl.

Two months later, her doctors published her case in the journal Lancet; soon, at least seven other U.S. clinics were doing the injection. Because the amount of donor mitochondria added to Ott’s egg was small, it was unclear how much third-party DNA would be present in the cells of her daughter. Ott says her doctors ran tests and did not find any, but it has been found in two other children born from the procedure. Although I.V.F. drugs and devices are regulated by the Food and Drug Administration, I.V.F. procedures (like all medical procedures) are generally not. But what media outlets came to call “three-parent babies” compelled the agency to take action. In 2001, the F.D.A. informed I.V.F. clinics that using a third person’s cytoplasm — and the mtDNA therein — would require an Investigational New Drug application.

A meeting before an F.D.A. committee followed, at which the clinics presented their research. While at least 30 women became pregnant through the injections, it was unclear what role the third-party cytoplasm played in their fertility. And there were safety concerns. Two embryos with Turner syndrome, typically a rare chromosomal abnormality, occurred after the procedure; one miscarried, the other was aborted. Further, not all of the children born from the procedure in the United States were being tracked. (They would be teenagers now, whose whereabouts and health are, for the most part, unknown.) “I think it is pretty ridiculous how little

data there is to support any of this, and that worries me,” the acting chairman of the F.D.A. committee, Daniel Salomon, a professor at the Scripps Research Institute, told the embryologists in his closing remarks. The “drug,” such as it was, has never been approved.

But now, more than a decade later, two research groups in the United States and one in Britain each believes it has nearly enough data to begin clinical trials for a new technique based on the transfer of mitochondria — only in this case, researchers want to pair the nuclear DNA of one egg with all the mitochondria of another. Their aim is not to cure infertility. Rather, they hope to prevent a variety of devastating diseases caused by mutations in mtDNA. The new technique, which they call mitochondrial-replacement therapy, is far more advanced than the cytoplasm injection — and the researchers have studied the procedure’s impact on animals and human cells up to a pivotal point: They have created what appear to be viable three-parent embryos. They have yet to implant one in a woman, though. In Britain, national law prohibits altering the germ line, but Parliament is very likely to vote later this year on whether to allow mitochondrial replacement to move forward. Likewise, this February, the F.D.A. held a meeting to examine the possibility of allowing clinical trials. If either gives the go-ahead, it will be the first time a government body expressly approves a medical procedure that combines genetic material of three people in a heritable way. The historic nature of the moment has turned the technique into a symbol, a red line separating humanity from a dystopian or progressive future, depending on how you look at it. In the months leading up to the meeting, the F.D.A. received several hundred emails from members of the public objecting to the idea of three-parent embryos on grounds that included: “It’s bizarre”; “You are walking in Hitler’s footsteps if you allow this”; and “We will have a world of mad scientists.”

As the scientists who were pressing for mitochondrial replacement kept pointing out, these fears were somewhat unfounded. It cannot allow people to design babies to their specifications — in fact, it comes with most

of the same risks and uncertainties that attend old-fashioned reproduction. It’s hard not to wonder if the argument is really about the technique or the sacrosanctity of DNA. Is our fear of crossing the germ line causing us to block a technology that could improve people’s lives, and if so, is the fear itself a thing we should also be afraid of?

Roughly two billion years ago, when single-cell organisms were the Earth’s only inhabitants, a bacterium found its way into another cell. It may have helped the cell use oxygen — newly abundant in the atmosphere and toxic to most primordial life — to convert food into energy. In any case, the two cells evolved together, becoming the cells that make up all complex life-forms, and the bacterium retained its own DNA. This is the DNA in mitochondria, which use oxygen to turn food into energy for us: When we stop breathing, our mitochondria stop working, so our cells stop working, and that’s how we die.

Mitochondrial DNA wasn’t discovered until the 1960s, and it wasn’t until 1988 that two high-profile papers, published by groups at the Institute of Neurology in London and Emory University School of Medicine, revealed that mutations in mtDNA can cause disease. Subsequent research has identified hundreds of mitochondrial diseases — largely related to impaired energy production in cells — that are incurable and can affect any system in the body, resulting in deafness, blindness, muscle weakness, cognitive impairments, heart, lung and kidney failure, diabetes and death. About 1 in 4,000 children and adults is diagnosed with mitochondrial disease, but because symptoms are so varied, doctors think many more cases are misdiagnosed; one recent study suggests that 1 in 200 people is born with a mutation that could make him or her sick.

But mtDNA doesn’t follow the classical rules of inheritance, whereby the combination of our parents’ genes determines whether we will have a genetic disease. A woman’s egg holds hundreds of thousands of mtDNA that are distributed randomly into the cells of a developing embryo. Each cell contains multiple copies of mtDNA, and the percentage of them that have mutations, and where they are in the body, determines what

symptoms will appear. And for some mutations, disorders can arise at any time in a person’s life. The notion of a heritable disease expressing itself in such a variable, probabilistic fashion “violated what people thought was true about genetics,” says Douglas Wallace, the leader of the Emory team and now the director of the Center for Mitochondrial and Epigenomic Medicine at Children’s Hospital of Philadelphia. In practice, it means that a woman who carries an mtDNA mutation that causes her only mild hearing loss might give birth to a child who has blindness and seizures, one who remains healthy throughout life or one who has symptoms in between these extremes. Some geneticists, when describing what it’s like to look at mutated mtDNA in a woman’s egg and then tell her what her odds of having a child with severe health problems will be, use the same metaphor: Russian roulette.

Why mtDNA travels directly from mother to offspring without recombining, as nuclear DNA does, is an evolutionary mystery, but as a consequence of its maternal passage, researchers trace the mtDNA of every person in the world back to a hypothetical Mitochondrial Eve, a common ancestor who lived in Africa 200,000 years ago. Over time, as Eve’s female progeny moved into Europe and beyond, her mtDNA mutated in ways that did not cause disease and, in fact, seemed to confer metabolic advantages in certain environments: People who lived near the poles, for instance, ended up with a different mtDNA type, via natural selection, than those who lived at the Equator; the same thing happened at high and low altitudes. MtDNA types are also associated with a person’s likelihood of developing certain diseases, including cancer, or characteristics like obesity, athleticism and longevity — though it’s not apparent why. Part of the reason may have to do with the fact that mitochondria send and receive signals to and from the nucleus that influence how the genes there are expressed. Some researchers claim that interfering with mitochondria could interrupt that communication, adding mitochondrial problems to the human gene pool instead of subtracting them; others, including Wallace, say that if the donor and recipient eggs have the same mtDNA

type, swapping mitochondria is comparable to a transfusion between matching blood types.

The reasons to try it go beyond the relatively few would-be mothers who might be eligible for clinical trials. Michio Hirano, a mitochondrial specialist at Columbia University and NewYork-Presbyterian Hospital, told me that many of his patients, not just women of childbearing age, get very excited about the technique. “It offers them a hope that maybe they can’t be fixed but future generations can avoid this disease,” he says, “and I think that means a lot to them.”

There is no way to know with certainty what the effects of any new medical procedure will be until you try it. But unlike a normal drug trial, in which doses of a substance can be scaled up slowly and stopped if serious negative side effects appear, mitochondrial replacement will permanently put a third person’s mtDNA in every cell of the resulting child. And all the unforeseeable risks of that experiment will be assumed by this future individual. In theory, harm could result at any time in the lives of those born from the technique or, if they are women, in their children’s lives. This makes the act of weighing risks against potential benefits, and judging when people should get to do that for themselves, especially fraught.

“There’s so much at stake here in terms of the mistakes we could be making that you would need to have an overwhelming reason to enter into this arena,” Sheldon Krimsky, an adjunct professor of public health and community medicine at Tufts University, says. He says that women with mitochondrial disease could use donor eggs or adopt; that wanting a child who shares your nuclear DNA is not motive enough to risk crossing the germ line. On the other hand, Marni Falk, a mitochondrial specialist at Children’s Hospital of Philadelphia, says: “There’s an enormous drive to reproduce — that’s just within us. I think it’s unfair to put that on people with mitochondrial disease, that they shouldn’t have that drive or desire.”

National news coverage of the F.D.A. meeting tended to frame the risk-benefit analysis in an even broader way: “You’re starting off with a

technique meant to prevent devastating illness,” Jon LaPook, chief medical correspondent of the “CBS Evening News With Scott Pelley,” said, “but there are some people who worry that down the road, it could be used to try to make so-called designer babies, kids who are more intelligent, who have other qualities that the parents find desirable.” A 2009 report by Richard Harris, a science correspondent for NPR, pushed this idea further: “It could open the door to genetically engineering a lineage of people with supposedly superior qualities. This is called eugenics, and many people find that repugnant.” Biologically speaking, however, mitochondrial replacement cannot guarantee any traits, superior or otherwise, except, if it works as planned, the absence of mitochondrial disease. In a way, the procedure would cross the germ line on a technicality: It would replace genetic material, but it wouldn’t “modify” or “engineer” genes in the same way that bacterial DNA is added to a corn gene, for instance, to create a pest-resistant crop. So what, exactly, are we so afraid of?

We know the double helix as our identity; we take personally the thought of tampering with it. One of the first times researchers tried to discuss altering DNA — specifically, whether or not to splice together the DNA from different organisms, such as bacteria, to create new life-forms — at a conference in Asilomar, Calif., in 1975, the result was a public- relations disaster. “The scientists emphasized the awesome and mysterious technology and in doing so made it un-understandable and alien to the population at large,” Willard Gaylin, co- founder of the Hastings Center, a nonpartisan bioethics research group, wrote in The New England Journal of Medicine in 1977. “Asilomar became a scientific version of ‘Jaws,’ and the public was titillated but also frightened.” Gaylin called that fear the Frankenstein factor and warned that it would unconsciously “move public opinion, even though that fear will be rationalized by overt use of more realistic arguments.” (In the end, the researchers did splice DNA; this has lead to many benefits, but not, as feared, a cancer-causing superbug.)

Consenting to the crossing of the germ line would be another watershed, and the F.D.A.’s open-door meeting in February held the

promise of revealing if the public was ready for the moment. The stated purpose of the event was not to render any decisions but to “inform potential future regulatory deliberations and actions.” Victory for the two U.S. scientists who have been pioneering the new technique and were presenting their work at the hearing would mean persuading the American public, not just the F.D.A., that clinical trials are both scientifically and ethically warranted. In Britain two years ago, the government asked for seminars to be held in which randomly selected citizens learned the nuances of how mitochondrial replacement works and then discussed the philosophical issues involved. Most of the participants ended up “broadly in favor” of it if proved safe. In the United States, it seemed as if the most vocal members of the public felt disturbed by the technique without necessarily being able to articulate why: Of the nearly 250 emails the F.D.A. received before its February meeting, most objecting to “three- parent babies,” more than half of them were form letters.

One problem the U.S. scientists had been having selling mitochondrial replacement was explaining what it was and what it would and wouldn’t be good for. Though no evidence indicates the technique can treat infertility, it might. That the early cytoplasm injections worked for some women (for unknown reasons) and involved the transfer of mitochondria has reinforced this idea. Also, as we get older, the mitochondria in all our cells become less efficient at generating power, and Shoukhrat Mitalipov, one of the F.D.A. presenters, from Oregon Health and Science University, has theorized that replacing the mitochondria in the eggs of infertile older women with donor mitochondria might rejuvenate them. “I believe that rationale is unfounded,” Mary Herbert, another presenter, from Newcastle University, told me. “I worry that it will give older women who want to conceive false hope.” What’s more, some who support mitochondrial replacement for women with mitochondrial disease are made nervous by the idea of using it to treat infertility, which is far more common, out of a sense that sheer demand could unleash it before its dangers are fully known.

Stories like that of Maureen Ott, whose daughter, Emma, now 17, gets straight A’s, is senior-class treasurer and plays varsity sports, can’t help shaping the debate. Sharon Saarinen had the injection in Michigan in 2000, when she was 36. “I don’t remember them mentioning any risks,” she says. “If there were risks, it didn’t matter. I wanted a child too much at that point.” Her daughter, Alana, like Emma, is exceptionally bright and healthy; she has never been tested to see if she has the DNA of three people — she might or might not. “From Day 1, I’ve always felt this was a miracle procedure for me,” Saarinen says. “As my daughter grew and she’s fine and so intelligent, it just backed my belief that it was the right thing to do.” These cases aren’t statistically significant; they prove nothing about the safety or effectiveness of cytoplasm injection or having a third person’s mtDNA. Medically speaking, they are barely relevant to the new technique at all. But for better or worse, they are part of the collective narrative about crossing the germ line and thus have an outsize effect on our view of it. Americans were uneasy with I.V.F. and its “test-tubes” until they saw that it created unblemished babies; 40 years and millions of births later, we now accept it as routine. It’s easy to imagine the same chain of events taking place with mitochondrial replacement and turning out just as happily — or, several decades in, discovering an unexpected problem.

Three days before the F.D.A. hearing, I called a scientist who would be making a presentation there, Dieter Egli, of the New York Stem Cell Foundation, and asked him what he thought the stakes were. Egli is Swiss, and he speaks an accented English both blunt and elegant. He said his goal was to use cells to cure disease, because we are made of cells: tiny, complex, independent ecosystems. Eggs are single cells — the largest ones in the human body — and to him, replacing their mitochondria, then putting them back into women safely and successfully, is like beginner cell therapy. Rather than open the door to eugenics, we might in fact be opening the door to curing degenerative diseases like diabetes, Alzheimer’s and Parkinson’s, even the atrophy of aging. The coming century in medicine will be the century of the cell.

“Eggs are very beautiful cells,” Egli said. I met him at La Guardia Airport, a little over 12 hours before the

hearing, for a 9 p.m. flight to Washington. He was carrying a battered brown suitcase that he liberated from his parents’ basement on his last visit to Küsnacht, Switzerland, the small town where he grew up. In the suitcase was a tie patterned in American flags, which he planned to wear for what he described as “my first function related to the U.S. government.” Later, he would show me his apartment, where an American flag and a photo of a soaring bald eagle hung on the walls. “I like America very much,” he said. “It is a country where you can do something pioneering and outstanding, and you find a lot of support. That has been the history in this country. I find here, people like to go forward and be at the forefront of research, of innovation. They like that.”

Egli has tousled blond hair, bright blue eyes and, when he smiles, two dimples in his chin that make him look considerably younger than his 39 years. He moved to the United States in 2005 to pursue postdoctoral studies at Harvard University’s department of stem-cell and regenerative biology. There, he focused on using stem cells, which can develop into any type of cell in the body, to create insulin-producing pancreatic cells for people who have Type 1 diabetes. The idea was to make stem cells by removing the nuclear DNA from an egg and implanting in its place the nuclear DNA from an adult, or somatic, cell, typically a skin cell, taken from a diabetic. The egg would then be prompted to develop and produce stem cells with the diabetic’s DNA. This technique, still incredibly hard to get right, is called somatic-cell nuclear transfer (S.C.N.T.), or cloning, an association that has made opponents of mitochondrial replacement especially suspicious of Egli’s work.

Egli is one of perhaps half a dozen U.S. scientists with experience performing S.C.N.T. on human eggs. Because even unfertilized eggs can be considered embryos, and because procedures that destroy human embryos, as S.C.N.T. does, are not eligible for federal funding, many researchers have switched to a newer way to create stem cells: chemically

reverting adult cells to their stem-cell origins. (It’s still unknown if this newer method works as well as S.C.N.T.) In 2008, Egli moved from Harvard to the New York Stem Cell Foundation, a nonprofit group and one of only a handful of privately funded stem-cell laboratories in the country, to continue his work. Two years later, Michio Hirano, a mitochondrial specialist at Columbia, approached Egli to see if he might be able to help his patients.

Two groups seeking to prevent mitochondrial disease had recently made major advances with methods similar to S.C.N.T. In 2009, Mitalipov and colleagues at Oregon Health and Science University published a paper in Nature announcing that they had taken the nuclei out of rhesus-monkey eggs, put in the nuclei from other eggs, fertilized and then implanted them, resulting in the birth of four healthy monkey babies. In 2010, in the same journal, Herbert and colleagues at Newcastle University similarly reported that they had removed the nuclei from human eggs and transferred in nuclei from eggs that an I.V.F. clinic had fertilized but judged not suitable for implantation; these pairings developed into normal-looking 5-day-old cell clusters called blastocysts. “So, I said, ‘I think we can do something about this,’ ” Egli told me. The fact that the egg did not have to reprogram an adult cell made the technique and the outcome very different from cloning. “By the end of 2011, we started to do these experiments,” he said. “To my surprise, they were immediately successful.” The combination egg produced stem cells far more readily than S.C.N.T. ever had.

At the F.D.A., the work of Egli, Mitalipov and Herbert would come up against other studies that had produced unsettling results. Researchers have done mitochondrial replacement on mice and flies from different subspecies to look for worst-case outcomes and have observed reduced exercise ability and cognitive function in the rodent offspring and accelerated aging and infertility in the flies — effects that did not show up until adulthood. Mitalipov’s monkeys, now young adults, are healthy and are being bred.

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