She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity (69 page)

Interviewed thirteen years later by the
Independent
, Zhang said he regretted that decision. “I think some of my team members were
so eager to be famous,” he said. “They wanted to let the whole world know.”

The world greeted the news not with celebration they hoped for but with dismay. Critics said that Zhang and his colleagues were veering recklessly toward the manufacture of human clones. The Chinese government responded by banning the procedure, effectively ending all research on ooplasm. The experience was such a catastrophe that Zhang and his colleagues didn't even publish details of the case until 2016. “
There was too much heat,” Zhang said.

This line of research might have ground to a complete halt if not for a few scientists in England and the United States who quietly continued running experiments on mice. They did not want to invent a way to help infertile parents have children, however. They wanted to stop mitochondrial diseases.

The discovery of mutations that caused mitochondrial diseases made it possible to diagnose mysterious illnesses and make sense of their strange heredity. But it didn't immediately point to any straightforward cure. In 1997, a British biologist named
Leslie Orgel proposed a different line of attack. Rather than curing the disease, doctors could block its inheritance. In the journal
Chemistry & Biology
, Orgel published a diagram showing how to move the nucleus of a fertilized egg into another egg that had its nucleus removed. No longer burdened with defective mitochondria, the egg could give rise to a healthy child. Orgel gave his speculative procedure a name: mitochondrial replacement.

By the mid-2000s, scientists had learned enough about mitochondria and manipulating cells to try to turn Orgel's idea into real medicine. In the United States,
Shoukhrat Mitalipov launched a series of experiments at Oregon Health & Science University. He found that mitochondrial replacement therapy could cure sick mice. Then he successfully carried out the same procedure on monkeys. The monkeys grew to adulthood without any sign of harm. Meanwhile, at Newcastle University in England, Doug Turnbull led an effort on a different method that also yielded promising results. Both teams then experimented on human embryonic cells, and found that mitochondrial replacement therapy might work in our species, too. With these results in hand, Mitalipov and Turnbull went to their respective governments to ask for permission to push mitochondrial replacement therapy toward clinical trials.

Their requests opened up a fresh debate about the wisdom of human genetic engineering. Much of the debate revolved around strictly medical questions: Would mitochondrial replacement therapy be safe and effective?

Thanks to the ooplasm transfers of the 1990s, it was possible to get a few clues. By the early 2010s, the children born through the procedures had
become
genetically modified teenagers. Cohen and his colleagues tracked down fourteen of the children and found that they were going to school, trying out for cheerleading squads, getting braces, taking piano lessons, and doing all the things that teenagers typically do. Some of them had medical conditions, ranging from obesity to allergies. But these were nothing beyond what you'd expect from a group of ordinary teenagers. Still, promising as the survey might be, it was too small to put concerns about safety to rest. And there was no telling whether the teenagers might develop medical problems later in life.

Some critics also raised doubts about how effective mitochondrial replacement therapy could ever be. When researchers hoisted a nucleus out of a woman's egg,
it didn't slip out cleanly. Sometimes mitochondria remained stuck to its sides. After the researchers plunged the nucleus into a donated egg, the embryo that resulted would sometimes end up with a mixture of old and new mitochondria. Even if 99 percent of the mitochondria in the embryo came from the donor egg, the 1 percent from the mother might still put a child at risk. Making matters worse, that dangerous 1 percent might increase as the cells in the embryo divided.

Even if doctors could scrub all the old mitochondria from a nucleus, there might still be risks from mitochondrial replacement therapy. Many of the proteins that generate fuel inside mitochondria are encoded in genes in the nucleus. Once the cell makes those proteins, it has to ferry them into the mitochondria, where they have to cooperate with the mitochondria's own proteins. Some researchers wondered if mitochondrial replacement therapy would create a mismatch between the proteins, causing the mitochondria to malfunction.

To test for this mismatch, scientists carried out mitochondrial replacement therapy on mice. They gave some of their animals mitochondria from a genetically identical donor, while others got genetically distinct ones. In some trials, genetic mismatches led to troubling problems. Some mice became obese. Others had trouble learning. Some differences in the mice—such as the amount of fat in their heart and liver—appeared only late in life. Since mice have such short lives, the researchers had to wait only a matter of months to see the symptoms emerge. In humans, it might take decades
to discover such side effects. Some researchers urged that only genetically similar donors provide their mitochondria.

But a lot of the debates over mitochondrial replacement therapy were driven not by concerns over safety but by deeper passions. After all, people were talking about making three-parent babies. To tamper with heredity was deeply frightening to many people. In a 2014 congressional hearing, Jeff Fortenberry, a representative from Nebraska, condemned mitochondrial replacement therapy as “the development and
promotion of genetically modified human beings with the potential for unknown, unintended, and permanent consequences for future generations of Americans.” If it sounded like Fortenberry was describing a living nightmare, he didn't mind. “These scenarios scare people,” he said, “and I would be very worried if it didn't scare people.”

Fortenberry cast genetic engineering as a kind of hereditary plague. Once a tampered gene was introduced into one child's DNA, it would sweep through a country like a vicious strain of influenza. But that's not how heredity works. It's been estimated that
only 12,423 women in the United States are at risk of passing down mitochondrial diseases to their children. If every last one of those women underwent mitochondrial replacement therapy before having children, the result would be barely detectable. The mitochondrial DNA from the donors would become slightly more common among people in the United States. As the next generation had children of their own, that donated DNA would not become any more common. The gene pool of the United States (and the rest of the world, for that matter) would barely ripple.

To opponents like Fortenberry, mitochondrial replacement therapy not only threatened the future but desecrated the past. Every child born through the procedure had inherited their genes in a manner unlike anyone born before 1997. And any person who was a source of genes became, by definition, a parent. The “three-parent” label, first stamped on ooplasm transfer, was now attached to mitochondrial replacement therapy. “The creation of three-parent embryos is not an innocuous medical treatment,” Fortenberry warned. “It is a macabre form of eugenic human cloning.”

There's nothing macabre about the teenagers who inherited mitochondria through ooplasm transfer, and there's nothing about the egg donors
that merits the word
parent
, no matter how often congressmen and headline writers use it. We don't hand out such an important title so carelessly. When women get eggs from donors—complete with nuclear DNA from another woman—they still get to be called their children's mothers.

While opponents of mitochondrial replacement therapy have resorted to fearmongering at times, its supporters have sometimes lapsed into faulty logic of their own. One common strategy is to play down the importance of mitochondrial DNA. In 1997, Maureen Ott convinced herself that she wasn't crossing a moral line because she wasn't picking out meaningful traits, like the color of her daughter's hair. Seventeen years later, the
United Kingdom's Department of Health made much the same argument in a favorable report on mitochondrial replacement therapy they published in 2014.

“Mitochondrial donation techniques do not alter personal characteristics and traits of the person,” the report declared. “Genetically, the child will, indeed, have DNA from three individuals, but all available scientific evidence indicates that the genes contributing to personal characteristics and traits come solely from the nuclear DNA, which will only come from the proposed child's mother and father.”

When I read the report, I scoured it for a definition of
personal characteristics and traits
. I found nothing. As best I could tell, the authors dismissed mitochondria as doing nothing more than producing fuel. Meanwhile, I could only conclude, the genes inside the nucleus handled the really important stuff, like coloring our hair.

Ranking genes this way is absurd. The entire point of mitochondrial replacement therapy is to change something profound about a person: to take away a mitochondrial disease. People who inherit mitochondrial mutations may end up with traits that profoundly influence their lives and their identity, from a short stature to weakened muscles to blindness. Indeed, the huge range of symptoms that mitochondrial diseases can cause reveals just how many parts of our lives are influenced by the way we produce fuel for our cells.

And there's no organ where fuel production matters more than in the brain, where neurons have to burn a lot of it to fire signals. Some mitochondrial mutations affect the way certain parts of the brain function. Others
slow down the migration of neurons through the brain during its development, so that they fail to reach their destinations. If altering the brain can't affect “personal characteristics and traits,” I can't imagine what could.

Mitochondria have also turned out to be important for other functions besides generating fuel. Some proteins that mitochondria produce make their way into the nucleus, where they relay signals to thousands of genes there. Genetic variations in mitochondria can thus
do much more than cause rare hereditary diseases. They can influence how long we live, how fast we run, how well we handle breathing at high altitudes. Genetic variants in mitochondrial DNA can
influence our ability to remember things. Some mutations have been
implicated in psychiatric disorders such as schizophrenia.

The UK report helped persuade Parliament to take up the matter of mitochondrial replacement therapy. The health minister, Jane Ellison, reassured MPs that the procedure
merely replaced a cell's battery packs. In 2015, Parliament voted to approve mitochondrial replacement therapy, and in March 2017, a fertility clinic in Newcastle won the first license to perform the procedure.

The deliberations in the United States veered off onto a different path. In a survey of people with mitochondrial mutations, they overwhelmingly said
mitochondrial replacement therapy research was worthwhile. The National Academy of Sciences examined the evidence and came out in 2016 with a cautious endorsement. It might be wise to start using the procedure only on sons, they said, since they wouldn't be able to pass on their altered mitochondria to their own children. Scientists would also need to keep careful tabs on the children born to women who underwent the mitochondrial replacement therapy, to make sure they didn't suffer unexpected harm years later.

But all these discussions ended up being moot. Somebody in Congress—no one has ever figured out who exactly—slipped a ten-line provision into
an enormous 2016 spending bill that blocked the FDA from evaluating mitochondrial replacement therapy. Without any debate in Congress, the ban went into effect.

In that same year, however, John Zhang—who had gone to China back in 2003 to continue his research—announced that he and his colleagues
had taken another trip outside of the United States to perform
the first human mitochondrial replacement therapy.

Now working at the New Hope Fertility Center in New York City, Zhang had been contacted by a couple in Jordan for help. Their two children had developed Leigh syndrome, a rare mitochondrial disease that weakens the muscles, damages the brain, and usually leads to death in childhood. The couple's first child died at age six, their second at just eight months.

Before having children, the mother had no idea that she carried Leigh syndrome. In her own cells, only about a quarter of her mitochondria carried the mutation, while the rest functioned normally. In both her children, her mutant mitochondria became more common and crossed the deadly threshold.

The couple came to Zhang in the hopes of having another child, one without Leigh syndrome. He knew he couldn't use mitochondrial replacement therapy in the United States. But he also knew that Mexico had no regulations in place that would block him. He traveled there with the couple, carrying out the procedure at a branch of his clinic. Zhang's team transferred five nuclei from the woman's eggs to donor eggs, which they then fertilized. When they implanted one of the embryos in the woman's uterus, it developed normally, and in April 2016 she gave birth to a boy.

When
Zhang and his colleagues examined the boy, his health seemed good. But the doctors found that his mother's faulty mitochondria had not been entirely replaced. Two percent of the mitochondria in cells they sampled from his urine came from his mother. In cells from his foreskin, that fraction jumped to 9 percent. No one could say for sure what the levels were in his heart or his brain. And it was doubtful that anyone would ever find out. Barring some unforeseen medical emergency, his parents refused any further testing. The boy slipped away from science's gaze, another genetically engineered child brought into this world.

T
O
J
ENNIFER
D
OUDNA
, mitochondrial replacement therapy looked like a faint foreshadowing of what CRISPR might deliver. Doctors like Zhang were only replacing faulty genes in embyros with healthy ones. CRISPR might allow them to rewrite any of the twenty thousand or so protein-coding genes sitting on an embryo's chromosomes. And that change could be inherited by their descendants.

The last thing Doudna wanted was for CRISPR to replay the botched history of mitochondrial replacement therapy. That treatment had crept into practice without any public discussion of its ethics, and when the conversation finally got off to a late start, it was distorted by lurid visions of Frankenstein and charged language about three-parent babies. In 2014, Doudna decided that she would try to avoid such a debacle by starting a public conversation.

It was not a role Doudna relished. She felt comfortable talking about the inner workings of bacteria, not about the potential dangers of retooling human embryos. Her new role “felt foreign,” she later said. “Almost transgressive.”

Doudna started small. In January 2015, she hosted a meeting at a cozy inn in the Napa Valley, about an hour from Berkeley. Among the eighteen people who assembled in wine country to talk about CRISPR were David Baltimore and Paul Berg, two eminent biologists who had led similar
meetings in the 1970s to discuss recombinant DNA. Now as then, Weismann's barrier split the conversation in two. The Napa group divided their time talking about tinkering with somatic cells and germ cells.

CRISPR might prove superior to viruses as gene therapy, the researchers speculated, because doctors could use it to fix somatic cells with more precision. As for the germ line, some people at the Napa meeting weren't bothered by the prospect of using CRISPR to alter it. Others considered Weismann's barrier a line never to be crossed.

Despite their differences, everyone at the meeting knew that they couldn't just let their differences lay idle. There wasn't time. There were rumors that scientists in China had already used CRISPR on a human embryo. A paper from the scientists was supposedly circulating among journals for publication. Any day now, the news might break. Most of the participants at the Napa meeting agreed to coauthor a commentary, which they'd submit to a journal. On March 19, Doudna and seventeen fellow scientists published a piece in
Science
called “
A Prudent Path Forward for Genomic Engineering and Germline Gene Modification.”

The scientists didn't call for an outright ban on human germ line engineering, but they did strongly discourage it for now. They also proposed that a public meeting take place, bringing experts together from around the world to drill deeper into the risks and benefits of the new technology. Even such a big gathering as that would not be enough to settle matters, Doudna and her coauthors warned. “At present, the potential safety and efficacy issues arising from the use of this technology must be thoroughly investigated and understood before any attempts at human engineering are sanctioned, if ever, for clinical testing,” they declared.

The
Science
piece drew so much attention that the National Academy of Sciences agreed to host an international meeting just a few months later, and the Royal Society and the Chinese Academy of Sciences signed on to participate. Things were unfolding as Doudna had hoped, at least for a few weeks.

In April, she discovered that the rumors she'd been hearing were true.
Junjiu Huang, a biologist at Sun Yat-sen University, and his colleagues
reported that they had crossed the line. They had used CRISPR to alter human embryos.

Depending on how you looked at it, Huang's experiment was a historic achievement or a botched nonstory. As the Chinese scientists explained in the journal
Protein & Cell
, they set out to alter the HBB gene, the gene in which mutations can cause beta-thalassemia. They designed the experiment to sidestep ethical concerns about tinkering with viable embryos. When fertility clinics fertilize eggs, they sometimes make mistakes, allowing two sperm to fuse to a single egg. These embryos end up with three sets of chromosomes—hence their name, triploid—and they fail to develop for more than a few cell divisions. Huang and his colleagues got hold of dozens of triploid embryos to study, confident in the knowledge that these embryos could never be used to start a pregnancy even if someone wanted to.

Huang and his colleagues built CRISPR molecules that could cut part of HBB genes, allowing them to be replaced with a new stretch of DNA. They injected the mix into the triploid embryos and waited for them to divide into eight cells. Huang and his colleagues analyzed fifty-four of the embryos to see how well the CRISPR molecules had worked. They had only managed to cut the HBB genes in twenty-eight. And of those embryos, a smaller fraction had replaced the old DNA with the new material. In other embryos, the cells had accidentally copied similar genes elsewhere in their DNA.

A number of the embryos, Huang and his colleagues found, ended up as mosaics. Some cells in the mosaic embryos had an altered version of the HBB gene, and some didn't. It turned out that the CRISPR molecules needed a lot of time to find their targets in the human DNA. By the time they found the HBB gene, the single-cell zygote had divided into several new cells, some of which ended up without any of the CRISPR molecules inside.

When news of Huang's paper broke, I asked Doudna what she thought of it. She told me that it “simply underscores the point that the technology is not ready for clinical application in the human germline.”

Doudna was choosing her words carefully. From the Napa meeting onward, she wanted to avoid turning public opinion against CRISPR in general. Her fellow scientists would have to restrain their curiosity and not
carry out experiments that might seem grotesque or reckless. On the other hand, Doudna didn't want to rule out germ line engineering altogether. Perhaps someday in the future, it would be worth considering.

Her careful parsing couldn't stop the story from spiraling out of control. It caused such a worldwide commotion that Francis Collins, the director of the National Institutes of Health, released a blunt statement a few days later invoking the policies put in place in the 1980s. “
The concept of altering the human germline in embryos for clinical purposes has been debated over many years from many different perspectives, and has been viewed almost universally as a line that should not be crossed,” he declared. The NIH was pouring over $
250 million a year into gene therapy research in the hopes of curing diseases by changing genes in somatic cells. But they would not pay anyone to leap to the germ line, full stop.

When scientists like Collins talked about a line that should not be crossed, they made it sound blindingly clear. Yet scientific research was only making it harder to find. Collins spoke of altering embryos “for clinical purposes,” for example. One could argue that an experiment like Huang's had no clinical purpose whatsoever, because the triploid embryos he used could never develop into children. Was his experiment beyond the line anyway, because someone might use the knowledge he gained to alter an embryo's HBB gene and eliminate beta-thalassemia from a line of descendants?

In September 2015, the line got even harder to discern.
A scientist named Kathy Niakan at the Francis Crick Institute in London applied to the British government for permission to use CRISPR on human embryos. Niakan planned to use CRISPR to shut down genes believed to be crucial for the early development of embryos. By seeing how the embryos then developed could give Niakan clues about the jobs the genes carry out. She would study the embryos only up till they were about a week old and then destroy them. But, unlike Huang's experiment, Niakan would be carrying out CRISPR on viable embryos. Did their viability make her research an affront to all that is decent, even if she destroyed them when they were still a microscopic clump of altered cells?

The news about Niakan and Huang brought an intense urgency to the
International Summit on Human Gene Editing when it opened on December 1, 2015. At the National Academy of Sciences in Washington, David Baltimore welcomed the five hundred attendees with a provocative kickoff, echoing Hotchkiss's words fifty-one years beforehand.

“
Today, we sense that we are close to being able to alter human heredity. Now we must face the questions that arise,” Baltimore said. “The overriding question is when, if ever, will we want to use gene editing to change human inheritance?”

The conference never managed to live up to Baltimore's provocation. “
It was an extremely low-key meeting,” the reporter Sharon Begley observed, “with more and more empty seats as it went on.”

For some scientists, the low-key tone seemed like an intentional strategy. They hewed to jargon-rich prepared remarks, not wanting to stumble over any ethical trip wires. At the end of the meeting, Baltimore, Doudna, and the rest of the organizing committee came on stage to deliver a consensus statement. It didn't go much beyond what the Napa group had agreed to eleven months earlier. The committee endorsed CRISPR for somatic cells—gene therapy, in other words—as well as CRISPR-based research on early human embryos. They came out against germ line modification in embryos used to establish a pregnancy. But they didn't close the door. “
The clinical use of germline editing should be revisited on a regular basis,” they declared.

For some of the scientists at the meeting, the real question about germ line editing was whether it was even worth trying. “If we really care about helping parents avoid cases of genetic disease,” said Eric Lander, the director of the Broad Institute in Cambridge, Massachusetts, “germline editing is not the first, second, third, or fourth thing that we should be thinking about.”

Lander argued that parents would be better helped in almost every case by preimplantation genetic diagnosis. If they risked giving their child a hereditary disease, they could get the help of doctors to sort through embryos—or perhaps even eggs and sperm—to make sure their children
were not born with the disease. Only after parents tried these measures without success would it make sense to edit the germ line.

A few of the speakers came out strongly against even this restrained approach to CRISPR. Marcy Darnovsky, the executive director of the Center for Genetics and Society, painted a dark future very different from Lander's. She envisioned an unregulated marketplace where germ line editing would run rampant. “It's a radical rupture with past human practices,” she warned.

The risks—of CRISPR missing its target and rewriting a different gene, for example—were simply too great. And not only was it dangerous to change a child's DNA, Darnovsky argued, but it was simply wrong. An embryo could not give consent for the procedure. And altering the child's genes was, when you came down to it, an affront to the child's individuality. Even if CRISPR worked splendidly, its very success might create unprecedented social woes. Darnovsky could picture a world in which the rich engineered their children's genes to escape the burden of disease, while poorer children could not. And once parents started trying to get rid of certain traits in their children, where would they stop?

Deafness is not lethal, for example, but when Harry Laughlin of the Eugenics Record Office published his Model Eugenical Sterilization Law in 1922 he put it on the list. Would fertility doctors offer to knock out deafness mutations? Would other conditions, such as dwarfism, be judged intolerable burdens, too? Disabled communities might feel besieged before long. And once parents got used to altering more and more aspects of their children's biology, Darnovsky predicted, they might well start changing genes to enhance their children.

“The temptation to enhance future generations is profoundly dangerous,” Darnovsky warned. “I ask you to think about how business competition might kick in with fertility clinics offering the latest upgrades for your offspring. Think about how the market works.”

Most of the scientists at the meeting shied away from even mentioning enhancement. One exception was a towering, long-bearded geneticist from Harvard named George Church. Enhancement was coming, Church said, and it would begin not with embryos but with old people.

Here's one way that might happen. Nine percent of older people suffer from brittle bones due to osteoporosis. Cells in their skeleton start to break down the surrounding bone, releasing the minerals into the bloodstream. Some drugs can slow down the decline by sticking to cells, making it harder for them to make contact with bone. But there may be a better way to treat the disease.

One reason that cells break down bone is that in old age they make less of a protein called TERT. In 2012, researchers at the Spanish National Cancer Research Centre coaxed old mice to make extra TERT by giving them an extra copy of the gene. Their osteoporosis reversed, and their bones strengthened. It's conceivable that doctors could use CRISPR gene therapy to treat people as well. CRISPR molecules would home in on the TERT gene in bone cells and edit it. The gene would behave as it did when the patients were younger, strengthening their bones.

But gene therapy for TERT could do a lot of other kinds of good, too. The Spanish researchers who tried it out on mice found that it also reversed aging in their muscles, their brains, and their blood. It extended the life span of old mice by 13 percent. When the scientists treated younger mice with TERT gene therapy, the animals lived 24 percent longer.

If CRISPR-based gene therapy got approved for osteoporosis in humans, people might soon clamor to get the treatment for a longer, healthier life. And if it proved to be more effective the earlier it was administered, then some parents might want their children to have that benefit from the very start. Why end life with good TERT genes when you can start with them?