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Splice Of Life

An OHSU geneticist's breakthrough could prevent horrible diseases before a baby is even born. The problem for many: The child will have the DNA of three parents.

aylight slices in through the wood-slat shades of Kimberli Freilinger’s bedroom. She knows she must get out of bed. She’s got to eat. She hears her teenage sons downstairs and needs to check on them. She needs to go to the bathroom. She can’t do any of it. Groggy, she thinks it’s 7 am. She’s wrong. It’s noon.

"This extreme fatigue is the most bizarre thing I've ever felt in my life," she says. "It feels like you've got layers of bricks on top of you that are literally holding you down."

Freilinger, 42, is suffering what she calls a "mito crash." Our bodies run by mitochondria, part of our basic cell structure that fire the energy we need to thrive.

But not for Freilinger. A decade ago, she saw several doctors after feeling listless and rundown. The eventual diagnosis: mitochondrial disease. A genetic glitch was causing her mitochondria to fail.

Her mutated mitochondria, she says, are like dying batteries in a flashlight. Her body is the flickering beam.

"On my best days, I'm optimistic that they will find a way to slow the progression in my lifetime," Freilinger says. "On the hard days, a cure can't come fast enough."

She knows, however, that for her a cure is not likely to arrive in time.

Sixty miles north, in a hot, dark lab at the Oregon National Primate Research Center on the edge of Hillsboro, Yeonmi Li peers into a flat screen inches from her face. She watches the colorless image of a translucent globe float before her, a mouse egg magnified 300 times.

Li is about to create a healthy egg out of two, one from the mother, one from a donor. It's in effect a rehearsal for a therapy that could someday be used on humans. It wouldn't help people like Freilinger, but could prevent children from being born with the same deadly condition.

It could also mark a profound change in the nature of what makes us human.

The room is a punishing 90 degrees—kept close to the body's temperature so as not to spoil the eggs. Sweat beads on Li's forehead as she deftly uses a joystick to bring a tiny glass tube into the picture.

The pipette, which resembles a thin chopstick, penetrates the donor egg. The pipette sucks out the nucleus, home to 99.9 percent of the DNA.

Li has just created what is in effect the shell of the donor's egg, yet still filled with healthy mitochondria.

She then injects the nucleus from another egg—that of the mother—into the donor egg. Once fertilized, the newly combined egg would produce the mother's genetic baby without passing on her mitochondrial defects.

Put another way, the baby is cured of a fatal disease even before it's an embryo.

For some researchers and ethicists, this remarkable procedure—developed at Oregon Health & Science University's primate center—has a serious drawback: The child will carry a tiny amount of the egg donor's DNA.

The sperm will come from one father; the egg from two mothers.

Genetically speaking, the baby will have three parents.


The scientist who has unleashed what many hail as a breakthrough therapy—and some see as an intrusion into the nature of what it is to be human—is a geneticist at OHSU, Shoukhrat Mitalipov.

His innovation has made Mitalipov, 53, world famous. He has successfully bred so-called "three-parent" rhesus macaque monkeys. He is on the doorstep of using it for the first time on humans. The U.S. Food and Drug Administration could soon release guidelines for human trials to see if the technique can be safely used to prevent mitochondrial diseases.

At OHSU, Mitalipov's fame has been overshadowed in part by Dr. Brian Druker, whose advancements in genetic-based cancer treatments have become the hospital's headline-grabbing innovation, prompting a $1 billion fundraising campaign spurred by Nike chairman Phil Knight and talk of a Nobel Prize for Druker.

Yet Mitalipov's therapy—intended for use on a small number of women who carry mitochondrial defects and want their own children—is arguably just as groundbreaking. And it poses a far greater opportunity and moral challenge to the human race.

The blending of two women's DNA in a single egg crosses what scientists call the germline, the series of cells through which parents' genes are passed to their children.

Tinkering with the human germline is so widely considered a disruption of the natural order of things that 40 countries currently ban it. (The U.S. does not.) 

Some researchers and ethicists say there has been far too little research and public debate about a technique that could change the fundamental genetic trajectory of humans.

The procedure to address mitochondrial diseases could not be used to genetically engineer babies, but the underlying breakthrough has put us at the doorway of someday being able to do exactly that.

"It's difficult to see all the potential consequences of altering one's own species' collective genome permanently," says Paul Knoepfler, a biologist at the UC Davis School of Medicine. "I'm not sure top scientists, even if they are exceptionally smart, technically savvy, and knowledgeable, are necessarily any wiser than humanity as a whole."

Mitalipov's discovery could be used in human trials before the fundamental moral and ethical questions are addressed—leaving unsettled whether this is a cautious move toward treating a rare and terrible group of diseases, or a boundless step into darkness.

When Shoukhrat Mitalipov smiles, the lines around his eyes betray an underlying fatigue.

Dressed in an ironed blue button-up and slacks, he's been explaining the science behind his discoveries. His thick mop of dark hair makes him look younger than he is.

But at the mention of critics of his discoveries, Mitalipov's voice lowers. In his work, he says, he's dealt with animal-rights activists who object to the testing done at the Oregon National Primate Research Center. But the debate he now faces is new and unexpected. He has been focused on his narrowly drawn mission, not the broader meaning for humanity.

"With genetic diseases, we have to find cures for those diseases not only to children born with them but to prevent them," Mitalipov says, his English heavily imprinted by his native Russian. "I think this is ethical, and we have to work toward it."

That critics are challenging the ethics and morality of his work has taken him by surprise.

"I've never been religious," he says. "When we switched to humans, there was lots of opposition. And I wasn't quite ready for their views."

"He's a very strong person," says Mitalipov's wife, Gulinur Nassyrova. "I never see him cry. He doesn't want to show his weakness, even to me. But the negative reaction is hard."

Mitalipov was born in 1961 on the outskirts of Almaty, then capital of Kazakhstan, nestled in the southwest of the former Soviet Union. Both his parents were teachers, but they raised livestock as did neighboring families, and after school Mitalipov tended sheep until dusk, often miles from home. They didn't have a telephone landline until after he left for college.

By the time he was a teenager, Mitalipov, an avid reader, had come across biologist Anne McLaren's 1977 book, Mammalian Chimaeras, about merging two or more eggs or early embryos to create one organism. He saw chimeras as a tool to understand development and genetics. He was hooked.

Mitalipov studied genetics at the Timiryazev Agricultural Academy in Moscow, playing blues guitar in a cover band to help pay the bills. He married while still a student, and his first wife, Nina, chose to  stay in their native Kazakhstan with their baby daughter, Linda. Mitalipov turned in what his professors said were the highest scores in the school's history and graduated with a master's degree in 1989. But the distance took its toll on his marriage. He and Nina divorced in 1991, leaving him alone in Moscow with his work.

Mitalipov focused on the emerging field of stem cell research. He was drawn to the idea that scientists could use embryonic tissues to grow any kind of replacement cells for hearts, livers, even blood. He earned his Ph.D. in developmental and stem cell biology at the Research Center of Medical Genetics in Moscow, but funding for stem cells (not to mention most research endeavors) had grown scarce after the fall of the Soviet Union in 1991.

He joined the wave of young Russian scientists applying for fellowships to study in the U.S. and Western Europe. He'd already published a few early studies on so-called "master" stem cells, and won a fellowship at Utah State University in 1995. His ex-wife and their daughter stayed in Kazakhstan.

At Utah State, he worked with stem cells from cows, and in 1998 took a job at OHSU's primate center, affording him the rare opportunity to work with monkeys, which share nearly 98 percent of their DNA with humans.

Mitalipov was soon drawn to the role of mitochondria in human cells.

Mitochondria are, in fact, ancient aliens to the human body. The prevailing theory is that they were independent organisms billions of years ago that eventually merged with other organisms to become the powerhouse of cells. Their ability to convert oxygen into energy, scientists now believe, sparked the evolution of complex life.

"That's why I came to mitochondria," Mitalipov says. "This was one of the breakthroughs of evolution; it used to be single-cell organisms struggling to make energy, but as soon as [mitochondria] joined other organisms, the cells had so much energy they became multicellular, and evolution just took off."

Mitochondria also have a dark side.

They exist in our cells (except red blood cells), and when mitochondria fail to provide energy, they cause tissue and even major organ systems to misbehave and sometimes die.

Symptoms can include muscle weakness, pain, stunted growth, dementia, and vision and hearing problems. Other diseases can result, from neurological and heart disease to diabetes. The diseases can attack at any time, from infancy to old age, although it is most often diagnosed in children. (Many mitochondrial issues in older adults resemble normal aging.) Victims can suffer seizures, developmental delays and chronic exhaustion. No matter the age, the results are often fatal.

An estimated 4,000 children are born in the U.S. every year with mitochondrial diseases. But understanding the effects is relatively new, and researchers believe that number is far too low, given how few doctors are trained to diagnose the hundreds of mitochondrial diseases, which comprise a relatively new field of study. Mitochondria are passed down through the mother. About one in 200 women is thought to carry defective mitochondrial DNA.

Mitalipov believed doctors could prevent the onset of the diseases by getting rid of the flawed mitochondria from the start. This first required identifying women who carried mitochondria that could lead to genetic problems—a discovery made only after a woman has a child with a mitochondrial disease. And then it would require getting rid of bad mitochondria, even before sperm meets the egg.

How to do it? Mitalipov worked with engineers and software developers to design an "embryonic manipulation" station that could harmlessly grasp a fragile egg while replacing its nucleus.

They were making steady progress when in 2004 his work was suddenly interrupted. His ex-wife and daughter, Linda, then 16, were murdered in a robbery gone bad, bludgeoned to death by a suspected drug addict. Their bodies weren't discovered for a week.

Mitalipov flew to Almaty to find the criminal investigation had been botched. Detectives hadn't even dusted for fingerprints. Even worse, Mitalipov was called to the morgue to identify the bodies, but the place was such a mess officials didn't know where they'd been placed. In his grief, he was forced to spend two hours looking at stacked corpses before he found his daughter's. She was so badly decomposed he had to identify her by her birthmarks and teeth.

"For a year or two it was devastating, hard to manage," Mitalipov says. "I don't think I was too productive at work."

Mitalipov eventually immersed himself back into his research. His team had struggled to find a way to spot the nucleus in an egg under a microscope. They developed a light that illuminated the genetic material without damaging the DNA, allowing them to swap the mother's nucleus into a donor's egg with healthy mitochondria. They called the technique a spindle transfer.

In 2009, Mitalipov and his co-authors reported in the scientific journal Nature they had successfully bred twin rhesus macaque monkeys (named Mito and Tracker) using spindle transfer. The announcement made worldwide news. Mitalipov predicted this therapy, used on humans, could prevent inherited disorders and save thousands of lives.

"With the proper governmental approvals," Mitalipov said in a statement at the time, "our work can rapidly be translated into clinical trials for humans, and, eventually, approved therapies."

After Mito and Tracker, Mitalipov's team produced three more monkeys and moved to human embryos. In 2012, they reported in Nature they had successfully grown 13 human embryos after replacing mitochondria in the eggs and using traditional in vitro fertilization.

Federal law prevented him from implanting the embryos into women without FDA approval of a testing protocol. But Mitalipov stands on the doorstep of altering the human genetic chain in the name of trying to fix these inherited diseases.

"What we're changing is the gene that codes the essence of the disease that is devastating for the family and child," he says. "We're correcting mostly, not trying to change it. That's how I see it, and I think it's ethical to do it for this treatment."

The medical ethics of Mitalipov's technique have been challenged on several fronts.

The idea of a "three-parent" child creates visions of a baby whose characteristics are a blend of two mothers and a father. And that leads to fears genes can be manipulated to choose the child's height, hair and eye color, and even intelligence.

Replicating a human or getting a designer baby is not possible using the specific technique Mitalipov wants the FDA to approve for trials. The transfer unites just 37 genes from the donor's mitochondria with the 25,000 from the mother's nucleus. And the type of DNA swapped doesn't code for things like intelligence or appearance.

Mitalipov acknowledges the success of the spindle transfer procedure, however, opens the door to other methods that would allow us to someday tinker with our nuclear DNA.

And that's what has many ethicists worried: Regardless of what Mitalipov intended to accomplish, he has now knocked down the doors for the very cloning that has had scientists and the public concerned for decades.

"It's correct this technique isn't human cloning, but it's the key procedure for human cloning," says Sheldon Krimsky, a Tufts University professor and expert in biomedical ethics. "The advancements he has made put us closer to human cloning."

Krimsky says the U.S. decided three decades ago that research should not breach the germline. And it's the unintended outcomes that most worry scientists and ethicists. Krimsky says "crosstalk" from two different DNA within the same human could create mutations and a host of health problems. And once the germline is breached, he says, those problems could persist for generations.

The limited testing in animals—which many argue should be tracked over generations—has yet to establish that problems wouldn't occur in humans.

"When I begin to see a consensus of people who don't have any conflicts or financial interests in it, I’d get to be comfortable,” Krimsky says. 

Some ethicists believe that once the germline is crossed, even in a limited way, there will be no going back.

Ronald Green is a Dartmouth professor who teaches religion and family medicine while directing the college's Institute for the Study of Applied and Professional Ethics. He calls Mitalipov's advancement "a decisive step into genetic human engineering."

Green believes that—whatever narrow use Mitalipov and others intend when it comes to treating mitochondrial disease—other scientists will push further across the germline.

The question for society, Green says, is not just whether the germline should be crossed but why. The potential to cure terrible diseases such as those caused by mitochondrial failure, he says, could carry enough scientific and ethical weight to justify doing so.

"If you are going to leap across the line, you need to be pretty confident there is a very good reason for leaping," Green says. "Is it safe, and is there a good reason to do it? I'd say both of those are potentially present here."

Others believe gambling with a child's genetic history is not worth the risks.

"There's no one's life here who is being saved," says Marcy Darnovsky, executive director of the nonprofit Center for Genetics and Society in Berkeley, Calif. "It's providing the possibility of a child to a woman, yes, but that's not saving a life."

Mitalipov tends not to engage in the ethical debates. He sees the practicality in what he is attempting to do. The other issues, he says, are often besides the point.

"I have, of course, my ethical grounds," Mitalipov says. "You have to do this for the sake of these patients and families. And in terms of ethics, we always ask the wrong people to tell their ethical grounds, like professional or religious ethicists. I think it's most ethical if you ask the patients or families themselves, and I think those should be the deciding voice in whether we should proceed or not."

The spindle transfer technique transplants the mother’s nuclear DNA into a donor’s egg with healthy mitochondria.
Image courtesy of OHSU

Mitalipov—as his reputation grew and the debate over his work intensified—still saw doctors and researchers treat the publication of his articles as a major event. But he stumbled in 2013 when a leading science journal, Cell, published an article on another landmark discovery: Mitalipov’s team had successfully grown stem cells through cloning.

A similar claim in 2005 by a South Korean researcher had turned out to be a fraud, so the Cell article came under close scrutiny. Within days, an online reviewer discovered four errors. They were essentially typos that didn't undermine the basic assertions of the article, but it looked sloppy. In a publication process that typically takes months, the article had been accepted three days after submission and published 12 days later as Mitalipov raced to present his findings at an international conference.

The journal Nature reported that many found it "unfathomable" that Mitalipov and Cell would try to rush such a huge finding into print. "Maybe it was rushed, but it was nothing to do with Cell," Mitalipov told Nature. "It was my mistake."

In February, the FDA panel with the power to approve human trials of the spindle transfer technique held hearings in suburban Washington, D.C. Mitalipov is still waiting for the panel—which focused on safety, not ethics—to outline what conditions must be met for human trials to get the green light.

The FDA panel appeared unconvinced the procedure had been studied closely enough to try in humans. FDA records show the panel says it doesn't yet know if there are risks of abnormal fetal growth, unexpected genetic modifications and long-term health problems.

OHSU holds the patent on Mitalipov's work, and Mitalipov is working to create a startup around his discovery.

Daniel Dorsa, OHSU's senior vice president for research, says the application of spindle transfer for mitochondrial disease is such a small market that the technique probably won't make "a ton of money."

Dorsa, however, sees a potential for broader applications for his work, and believes OHSU would not move forward without a broader discussion of the ethics of human trials.

"[The FDA] have sort of dragged their feet in telling us under what conditions they'd let us do this, so we're trying to push the envelope and trying to get a clear condition," Dorsa says. Once that happens, he says, "Quite frankly we'll probably bring the public into an open discussion about what we're doing."

Meanwhile, Mitalipov is working with counterparts in the United Kingdom, whose oversight agency declared after extensive public debate the procedure to be sufficiently safe to test on humans. Unlike in the U.S., however, scientists there will need Parliament to repeal a law forbidding genetic changes that alter the germline. A vote is expected later this year.

Kimberli Freilinger doesn't find the debate so fraught. The Monmouth psychologist suffering from "mito" believes the public would demand approval of the procedure if it could be used to treat better-known diseases, such as breast cancer. She dismisses concerns that Mitalipov will alter humans' genetic legacy.

"To me it's win-win because you're not messing with God's child," she says. "You're just taking out the bad parts. I don't want to pick out a blond-haired, blue-eyed tall kid, picking your child's traits, but to rule out a potentially lethal chronic illness brings in a whole different story.”