She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity (68 page)

Cline tested this idea first on mice. After injecting the engineered stem cells back into the bones of the animals, he waited two months to let them multiply. Cline then drew blood circulating through the mice and inspected the cells. Half of the cells had inherited the gene he had added.

That was good enough for Cline. He immediately set out to use gene therapy to cure people. He chose for his disease beta-thalassemia. This hereditary disorder disables a gene called HBB, leaving blood cells unable to build hemoglobin. People with beta-thalassemia can die because their blood can't deliver enough oxygen around their bodies. To Cline, the need for a cure justified trying out his new gene therapy techniques on people. But when he submitted his proposal to UCLA, the university judged it reckless and turned him down. That didn't stop Cline. He went abroad, recruiting a patient in Israel and another in Italy.

In 1980, Cline performed gene therapy on both patients. He extracted cells from their bone marrow and added working HBB genes to them. Then Cline injected the altered cells back into the patients' bones, where they could proliferate. The new bone marrow cells would inherit the HBB cells and produce working blood cells.

At least, that was the plan. After the procedure, Cline's patients didn't experience any improvement in their symptoms. And when word got out of the experiment, the scientific community roundly condemned Cline. Not only had he leaped far beyond his studies on mice, but he had changed his protocol midway through the human experiment without telling anyone—not his colleagues, not the committees overseeing his research, not even his two patients.

In the wake of the scandal, the National Institutes of Health took away Cline's grants, and UCLA forced him to resign as chairman of his department. In an editorial headlined “The Crime of Scientific Zeal,” the
New
York Times
even singled him out for condemnation. “
He was rightly punished,” they declared.

With all the news about Cline's reckless experiments, test-tube babies, and human-bacteria chimeras, a general alarm about genetic engineering began to blare. In 1980, President Jimmy Carter dispatched a commission to explore the ethical landscape of human genetic engineering, and soon after, Congress asked the Office of Technology Assessment to also look into the matter. They followed Hotchkiss's lead fifteen years earlier. To dissect the ethics of genetic engineering, they split it into August Weismann's two fundamental categories: somatic and germ line.

Somatic genetic engineering—otherwise known as gene therapy—got a green light. Politicians and scientists alike agreed that it might eventually cure thousands of hereditary diseases. As long as the research went carefully, as long as the treatments were safe, no one saw any serious ethical concerns.

The green light in the 1980s prompted a number of scientists to begin work on gene therapy. They needed first of all to find a new way to deliver genes to cells. Cline's method worked only for types of cells that could be removed from a patient, altered in a petri dish, and then put back in. If someone needed gene therapy for a brain disease, no one would try pulling chunks of gray matter out of their head.

Viruses offered a promising solution. Scientists figured out how to paste human genes into viruses, which could then infect cells to deliver their payload. By the 1990s, scientists were getting promising results from viruses in experiments on mice, and they had even been encouraged by a few human trials. But it turned out the viruses were not as safe as once thought. An ill-fated trial for a metabolic disorder in 1999 brought gene therapy research to a halt for several years. One of the volunteers, a nineteen-year-old man named Jesse Gelsinger, had an intense immune response to the viruses. He developed so much inflammation that he died in a matter of days.

After Gelsinger's death, the clinical trials of gene therapy stopped. The few researchers who remained in the field took a step back, searching for safer viruses. Within a few years, new clinical trials started, and after a few
more years they began to deliver promising results.
Philippe Leboulch of the Paris Descartes University and his colleagues tackled beta-thalassemia, the disease that had bested Martin Cline thirty years earlier. The French researchers extracted bone marrow cells from a boy, infected them with a virus carrying HBB, and then injected the cells back into his bones. In 2010, they reported that his cells started to make normal hemoglobin again, and he stopped needing a monthly transfusion of blood to stay alive.

People who suffer from other diseases, such as muscular dystrophy and hemophilia, are waiting in the hope that gene therapy will help them as well. Instead of struggling with difficult diets, many people with PKU look to
gene therapy as a true cure.

In the debates over genetic engineering in the 1980s, almost everyone agreed that somatic cells were a promising target, but germ cells had to stay out of bounds. “
Deciding whether to engineer a profound change in an expected or newborn child is difficult enough,” President Carter's commission concluded in its 1982 report. “If the change is inheritable, the burden of responsibility could be truly awesome.”

When the Office of Technology Assessment looked into the matter, they agreed. There were too many uncertainties—both medical and ethical—to even investigate a technology that might someday alter heredity. “The question of whether and when to begin germ line gene therapy must therefore be decided in public debate,” they concluded. In 1986, the US Recombinant DNA Advisory Committee, which determined what sort of research in genetic engineering could be funded, cut off the money. They flatly declared that they “will not at present
entertain proposals for germ line alteration.”

And that, for the next three decades, was pretty much that. From time to time, a few scientists would rattle the regulatory cage, arguing that germ line engineering would be a boon to humanity, not a threat. In 1997, the American Association for the Advancement of Science revisited the matter with
a forum about germ line intervention. The assembled scientists and philosophers granted that tinkering with the germ line might bring good changes. But they weren't willing to give a full-throated endorsement for
the idea. They warned that genetic engineering “might some day offer us the power to shape our children and generations beyond in ways not now possible, giving us extraordinary control over biological and behavioral features that contribute to our humanness.”

And yet, even as the forum tried to peer into the future from 1997, that day had already come. A few doctors had gone ahead and tampered with human heredity in a way no one had ever imagined, without asking anyone's permission.

In 1996, a woman named
Maureen Ott went to Saint Barnabas Medical Center in Livingston, New Jersey, in the hopes of having a baby. Seven years of in vitro fertilization had failed. Her eggs seemed healthy, but whenever her doctors implanted embryos in her uterus, they stopped dividing. Now, at age thirty-nine, Ott was watching her biological clock wind down. She came to Livingston because she had heard that doctors there had found a way to rejuvenate eggs.

The Saint Barnabas team, led by a French-born doctor named Jacques Cohen, had run some
encouraging trials on mice. In the experiments, they drew off a little of an egg's jellylike filling—its ooplasm—and injected it into a second, defective egg. This microscopic injection raised the odds that the defective egg would develop into a healthy mouse embryo. The researchers speculated that the procedure worked because molecules from the donor egg undid some unknown damage.

If the procedure worked on mice, it might also work on humans. Cohen and his colleagues recruited healthy young women to donate eggs for a study. The doctors would draw off ooplasm from the donated eggs and inject it into the eggs of women struggling to have children—women like Ott.

Ott's doctors warned her that the procedure was far from a sure thing. Ooplasm contains many different kinds of molecules. Some of those might rejuvenate an embryo, but others might cause harm. It was even possible that the doctors might inject some mitochondria from the donor eggs into the eggs of the patients. If that happened, any children born through the
procedure would inherit the mitochondrial DNA from the donor. Its genetic inheritance would come from three people instead of two.

To Ott, the prospect of her child inheriting someone else's genes wasn't a reason to stop. Mitochondria were merely responsible for making fuel and for other basic tasks in the cell. They didn't create the traits that defined a person. “If I was doing
something like, say, I only wanted a blond-haired girl, I would feel that was unethical,” Ott later explained to a reporter.

Cohen's team injected ooplasm into fourteen of Ott's eggs. They fertilized the treated eggs with her husband's sperm, and nine of the embryos began to divide. Nine months later, in May 1997, Ott gave birth to a healthy baby girl, Emma. A cursory look at Emma's cells revealed no sign of the donor's mitochondria.

Two months after Emma's birth, Cohen's team published an account of
Ott's unprecedented experience in the
Lancet.
Newspapers reported in awe about the revival of Ott's flagging eggs. Other couples struggling to get pregnant besieged Cohen's team. Fertility specialists in the United States and abroad used the
Lancet
paper as a cookbook recipe for performing ooplasm transfers of their own.

But it didn't take long for the enthusiasm to curdle into suspicion. In June 1998, a
Sunday Times
journalist named
Lois Rogers reported how doctors in California were offering ooplasm transfer to their own patients. Rogers didn't portray the effort as a way to help would-be parents. In her articles, it turned into a dangerous experiment in heredity.

Rogers said that embryologists and politicians were fretting “that the treatment is being given without a full debate over the biological and ethical implications of a child inheriting genes from two mothers.” What the doctors were actually doing, Rogers wrote, was creating “the three parent child.”

That turn of phrase locked onto the public consciousness and proved impossible to shake off. A Canadian columnist named
Naomi Lakritz railed against the quest for “three-parent children,” attacking doctors for concerning themselves only about the science involved. “Never mind science,”
Lakritz declared. “What about the ethical implications of cooking up a human omelet which results in the hapless child carrying the genetic material of two mothers?”

In 2001, the fear of three-parent babies flared even higher when Cohen and his colleagues published a new paper on their work. They closely examined the DNA of some of the babies that had developed from their rejuvenated eggs. Cohen's team found two children with a mix of mitochondria from their mother and the ooplasm donor.

“This report is
the first case of human germline genetic modification resulting in normal healthy children,” the researchers announced.

By then, dozens of children had been born through ooplasm transfers. Some of them were probably genetically modified as well. Despite two decades of government-sanctioned hand-wringing over genetic engineering, fertility specialists had waltzed right over Weismann's barrier. The rules that had been put in place had applied only to research funded with government grants. Cohen and his colleagues, working at a clinic, had done their work in private.

That freedom didn't last much longer. A month after Cohen and his colleagues published their report, they received a letter from the FDA. So did all the other American fertility clinics that were performing ooplasm transfers. The FDA pointed out that it had jurisdiction over the procedure. From now on, it would give ooplasm transfer an official status as an Investigational New Drug. That designation meant that anyone who wanted to try to carry it out would first have to fill out a mountain of paperwork and follow a lengthy set of procedures to make sure it was safe. Big pharmaceutical companies could handle those demands, but not small fertility clinics. Cohen and the other ooplasm transfer practitioners in the United States gave up.

But two American doctors, Jamie Grifo and John Zhang of New York University School of Medicine, refused to stop. When the FDA sent out their letter in 2001, Grifo and Zhang had been working on an advanced version of ooplasm transfer. Instead of using a bit of ooplasm from a donor egg,
they wanted to try using all of it. They would put a woman's nucleus into a donor's nucleus-free egg.

Now unable to carry out their work in the United States, Grifo and Zhang went to China. There they collaborated with doctors at Sun Yat-sen University, looking for struggling parents who would volunteer for a study.

The doctors carefully removed the entire nucleus from each donated egg. They replaced the original nucleus with a nucleus from one of the patient's unfertilized eggs. After they fertilized the egg with the partner's sperm, the new zygote began to divide in a normal fashion.

Chinese doctors at a local hospital implanted embryos from this procedure into a thirty-year-old woman. Three of the embryos went on to develop regular heartbeats. Grifo, Zhang, and their colleagues urged the woman and her partner to come to the United States to get better medical care, but the couple decided to stay at the local hospital. About a month later, their doctors decided to remove one of the embryos to improve the odds of survival for the other two, despite protests from the Sun Yat-sen team. The remaining twins developed for another four months. Then one fetus's amniotic sac burst and it died soon after an early delivery. The woman developed an infection—possibly due to the delivery of the first baby—and the second baby died as well.

Although the experiment ended in heartbreak for the would-be parents, Grifo and Zhang saw it as a step forward for the procedure. With a fresh supply of ooplasm, the woman's embryos had developed normally, and they might have even survived if she had gotten better prenatal care. In 2003, the scientists decided to present their results at a conference and share the news with reporters from the
Wall Street Journal
.