She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity (67 page)

The Fairfax Cryobank, located in Virginia, lets customers search by a donor's astrological sign, favorite subject in school (arts, history, languages, mathematics, natural science), religion, favorite pet (bird, cat, dog, fish, reptile, small animal), personal goals (community service, fame, financial security, further education, God/religion), and hobbies (musical, team sports, individual sports, culinary, craftsman). Looking at that list, I picture parents putting their child in a wood shop and waiting for freshly carved coffee tables to pile up.

In order to become a sperm donor, men have to get through a screening for sexually transmitted diseases, as required by the FDA.
But there aren't any regulations about checking DNA, and so genetic screening varies from clinic to clinic. Many of them look at a prospective donor's family history for signs of a hereditary disease. Many also carry out a few genetic tests to see if donors are carriers of diseases such as cystic fibrosis.
Sometimes a dangerous variant can slip through the screening. In 2009, for example, a Minnesota cardiologist discovered that
a young patient with a hereditary
heart condition had been the result of sperm donation. He tracked down the donor and discovered that he carried a dangerous variant. Out of twenty-two children he fathered with donated sperm, nine inherited his faulty gene. One of them died of a heart attack at age two.

The falling price of DNA sequencing may be able to eliminate most of these disasters. Rather than look for a handful of common disease variants, it is now possible to
scan every protein-coding gene in a potential sperm donor. Men with a dominant disease-causing mutation could be barred altogether from donating sperm. To avoid recessive diseases, doctors could sort through sperm and eggs to make sure they couldn't combine two dangerous mutations.

Muller was right to expect eggs to be harder to use for Germinal Choice. In the 1930s, scientists were able to fertilize rabbit eggs in a dish with rabbit sperm and coax the embryos to start dividing. But it wasn't until the 1960s, however, that two scientists—a University of Cambridge physiologist named Robert Edwards and a gynecologist named Patrick Steptoe—figured out how to get viable eggs from women. Their next challenge was to find a chemical cocktail—the “
magic fluid,” as Edwards called it—that could keep the eggs alive in a dish long enough to be fertilized. In 1970, Edwards and Steptoe announced that
they had succeeded at last. After they fertilized human eggs, they managed to keep them alive for two days, during which they divided into as many as sixteen cells.

Edwards spoke about this milestone at a meeting in Washington, DC, in 1971. One of his fellow panelists was a professor of religion named Paul Ramsey. After Edwards finished speaking, Ramsey declared the procedure an abomination that must be banned. He believed it would bring the world closer to “
the introduction of unlimited genetic changes into human germinal material.” Heredity, in other words, was a sanctuary that humans dare not enter.

Edwards and Steptoe weren't scared away by Ramsey's warnings. Instead, they invited couples having trouble getting pregnant to come to them for help. In 1978, they had their first success: a healthy girl named Louise Joy Brown. Louise's birth led people to see in vitro fertilization not as the
first step to human genetic engineering but as a treatment for infertility. In the 1980s, in vitro fertilization clinics opened up across the world, capitalizing on the pent-up demand of struggling couples. The procedure remained hit-or-miss, though, with many embryos failing to implant. To improve their odds, fertility doctors would produce batches of embryos and then pick out the healthiest among them.

In time, it became possible to inspect an embryo's DNA, too. Scientists would analyze a single cell removed from an embryo in its first few days of life and analyze its genes. (If a cell is removed at that stage, the remaining ones can still proliferate into a healthy fetus.) Fertility doctors could use this method to reduce the odds that parents would pass down a genetic disorder to their children.

In one early experiment, a team of British doctors treated women who carried disease-causing mutations on one of their X chromosomes. The women themselves were healthy, thanks to their second X chromosome, which lacked the mutation, but any sons they might have would run a 50 percent chance of developing the disorder.

There was a straightforward way to avoid this suffering: make sure the women had only daughters. In 1990, the British doctors
screened the embryos of two women who carried X-linked mutations. One had a variant causing mental retardation, the other a potentially devastating nerve disorder. The women both underwent in vitro fertilization, and then the doctors plucked a cell from each embryo to examine. They used molecular probes that could detect a distinctive segment of DNA repeated many times over on the Y chromosome, and only the Y chromosome. The doctors set aside any embryo that tested positive and used the rest for implantation. Nine months later, each mother gave birth to twin girls. Because the babies carried a normal X chromosome from their fathers, all of them turned out healthy.

By the early 2000s, it became possible to test embryos for mutations on other chromosomes, too. Karen Mulchinock, a woman living in the English city of Derby, had grown up knowing that Huntington's disease ran in her family. Her grandmother had died of it, and she had watched her father
decline through his fifties, dying at age sixty-six. Mulchinock got a test at age twenty-two and found she carried a faulty copy of the HTT gene as well. She and her husband decided to use in vitro fertilization to prevent the next generation of her family from inheriting it. In 2006, she had her eggs harvested, and her doctors tested the embryos for the Huntington's mutation. Over the course of five rounds of IVF, she gave birth to two children, neither of whom had to worry about the disease. “
The curse is finally broken,” she said.

Couples who worried about other inherited disorders began coming to fertility doctors to ask for the same tests, tailored instead for their own mutations. When an English couple had their first child, they were surprised that she had PKU. Like Pearl and Lossing Buck, neither of the parents knew before that they carried a faulty copy of the PAH gene. The parents decided to have more children, using preimplantation genetic diagnosis to prevent their other children from inheriting it.

After fertility doctors produced a set of embryos from the parents, they tested the PAH in each one. They
successfully detected the mutations in some of the embryos, and implanted the mutation-free ones in the mother. In 2013, they reported that she gave birth to a healthy boy. He was free not only of PKU but of the worry of passing down a faulty PAH gene to his own children.

Preimplantation genetic diagnosis has grown more popular as the years have passed, not just in Europe and the United States but also in developing economies such as China. But the procedure is still rare. Despite the gripping stories of parents like Karen Mulchinock, only a tiny fraction of people affected by Huntington's disease (roughly 200,000 people worldwide) use the procedure. The cost puts it out of reach of many. Even in Europe, where the procedures are covered by government-provided health insurance, few people with Huntington's disease follow Mulchinock's example. Between 2002 and 2012, only an estimated
one in one thousand cases of Huntington's disease was prevented.

Many children with Huntington's disease don't get tested themselves, since there's no treatment they could get if they turned out positive. Because
Huntington's disease doesn't affect people until after fifty, they usually start their families long before they find out if they inherited the allele. If they have a 50 percent chance of having Huntington's disease, the odds for their children are one in four. They may be so busy caring for their sick parent that they don't want to bother with the time, money, and frustration that in vitro fertilization demands.

In other words, we are not living in Muller's eugenic utopia. Nor are we living in a nightmare of the sort Aldous Huxley imagined in his 1932 novel
Brave New World.
Of the small fraction of people who are using in vitro fertilization, an even smaller fraction is using it to control the inheritance of their children. We have the technology right now to effectively eradicate Huntington's disease from the planet, along with many other genetic disorders. But the messy realities of human existence—of economics, emotions, politics, and the rest—override the technological possibilities.

In April 1963, a microbiologist named Rollin Hotchkiss traveled from New York City to the town of Delaware, Ohio. He had been invited to take part in a meeting that must have felt at the time like a feverish dream. As Hotchkiss later put it, he and nine other biologists spent a day together at Ohio Wesleyan University “to consider whether man can and will
change his own inheritance.”

One of Hotchkiss's fellow speakers was Hermann Muller. Muller described to the audience his plan for sperm banks and Germinal Choice. To Hotchkiss and the other scientists, there probably wasn't much surprising in what Muller had to say, given that he had been talking about his reform eugenics for more than thirty years. But when it was Hotchkiss's turn to talk, he described something that was fundamentally different from Muller's Germinal Choice—or from any of the eugenic breeding schemes bruited over the previous century.

Hotchkiss raised the possibility of directly altering human DNA. He used a new term to describe what he and some of the other scientists at the meeting envisioned:
genetic engineering
.

It might seem odd for a microbiologist to talk about changing humanity's inheritance. But in 1963, Hotchkiss had come as close as anyone on Earth to carrying out genetic engineering. In the 1950s, he had begun working with Oswald Avery, following up on the original experiments on the “transforming principle” that turned harmless bacteria into killers. Hotchkiss and his colleagues performed more sophisticated versions of Avery's original experiments, proving beyond a shadow of a doubt that the transforming principle was DNA. By moving this DNA into bacteria, Hotchkiss was effectively engineering their genes. In later years, Hotchkiss discovered how to transform bacteria in other ways—moving genes into microbes to make them resistant to penicillin, for example.

At the Delaware meeting, Hotchkiss predicted that the same procedure would be used on humans. “I believe it surely will be done, or attempted,” he said.

After all, Hotchkiss pointed out, our species was always searching for improvements. We started by finding better food and shelter, and now our search had evolved into modern medicine. When Hotchkiss spoke in 1963, doctors were celebrating their recent victory over PKU, thanks to their ability to identify babies with the hereditary condition and treat them with a brain-protecting diet. “We cannot resist interfering with
the heritable traits of the phenylketonuric infant by feeding him tyrosine at the right time to form a normal nervous system,” Hotchkiss said. If scientists learned how to rewrite the faulty genes that caused PKU, Hotchkiss predicted, it would be hard to resist the temptation to do it in people. “We are going to yield when the opportunity presents itself,” he said.

Hotchkiss left the Delaware meeting convinced that the world had to get ready for that opportunity. Humanity had to think ahead to all the benefits and risks that the opportunity might bring. Hotchkiss gave lectures and wrote scientific prophecies. Genetic engineering would not follow the traditional eugenic game plans, he said, driven by government decree. It would instead be driven by consumers. People would be persuaded by seductive ads for the latest “gene replacements” to alter their own DNA.

At first, Hotchkiss predicted, doctors would use genetic engineering to cure hereditary diseases like PKU in both adults and children, changing their genes as Hotchkiss changed genes inside bacteria. “One would presumably want to act at the earliest possible time in the development of the organism,” Hotchkiss said. “
Even
in utero
.”

Hotchkiss could see the appeal of genetically engineering embryos. Doctors might be able to fix a genetic defect across much of the body if they could manipulate just a tiny clump of cells. But these doctors might accidentally alter germ cells, too. If those unborn patients grew up and had children, they might very well inherit the gene replacement. And they would pass the gene replacement down to their own children.

“Now one is meddling with the gene pool of the entire race,” Hotchkiss warned.

If a gene replacement turned out to be harmful, it would be bad enough to make one patient suffer. But if that gene was replaced in the germ line, future generations could inherit the suffering as well. To Hotchkiss, the decision to alter the genes of people yet to be conceived was an assault on liberty. No man should ever be given total discretion to determine his brother's fate. The same held true for his great-grandchild.

Hotchkiss turned out to be a pretty good prophet. To look into the future of genetic engineering from 1964, he could rely only on what little hard evidence existed at the time—much of it coming from his own crude experiments on bacteria. Within a decade, some of the pieces of his vision would already fall into place. Rudolf Jaenisch was breeding mice with DNA he had pasted into their genomes. Robert Edwards and Patrick Steptoe were growing human embryos in petri dishes. And by the mid-1970s, some scientists were even trying to cure hereditary diseases in people, with Hotchkiss's gene replacements. They called it gene therapy.

One of the pioneers of gene therapy was a hematologist at UCLA named
Martin Cline. He developed a method for getting genes into mouse cells, jolting the cells with a pulse of electricity to open temporary pores in their
membranes. As a hematologist, he turned his mind immediately to blood disorders. Blood cells came from lineages of stem cells nestled in bone marrow. If Cline could slip a working version of a broken gene into a patient's stem cells, their daughter cells would inherit it. He could thus create a lineage of healthy blood.