Two years after the Cline affair, Bob Williamson, a prominent gene hunter in London at the time (and my PhD supervisor) argued in Nature that gene therapy, while not on the immediate horizon, “will be possible in the future, and it should be considered now, before the headlines break on us all.”9 But whereas Williamson preached caution, Anderson felt it would be unethical not to embark on human trials once issues of safety had been met. In 1984, he wrote:
[A]rguments that genetic engineering might someday be misused do not justify the needless perpetuation of human suffering that would result from an unnecessary delay in the clinical application of this potentially powerful therapeutic procedure.10
Despite increasingly vocal opposition from anti-biotech campaigners led by Jeremy Rifkin, the realization of gene therapy had turned from a matter of if to when. “Egos and expertise will clash like cymbals as the technology of gene splicing keeps racing along so fast that it laps ethical debates about what it all means,” wrote Jeff Lyon and Peter Gorner in Altered Fates.11
The year 1990 was an annus mirabilis for human genetics, notably the launch of a fifteen-year, $3 billion enterprise known as the Human Genome Project under the leadership of Jim Watson to build the definitive roadmap to identify the locations and identities of all genes, including those underlying the most devastating genetic diseases. In October 1990, I savored a taste of things to come as thousands of scientists traveled to Cincinnati, Ohio, for the annual conference of human geneticists. Late one evening, with the World Series featuring the hometown Cincinnati Reds blaring in every hotel bar, UC Berkeley’s Mary-Claire King hit a walk-off home run. In front of a standing-room-only crowd, she announced that she had mapped an errant gene, BRCA1, that when mutated increased a woman’s risk of breast cancer.II
Identifying human disease genes was big news, and the genetic detectives commanding those search expeditions like King and Collins and Lander became scientific celebrities. Identifying the genes mutated in CF or DMD or hereditary breast cancer marked a transformation in medical diagnostics and immediately raised hopes for a successful drug or gene therapy. The genomics gold rush spread to Wall Street, but identifying a disease gene is just the start: it takes on average a decade and $1.3 billion to bring a drug to market, and even then success is not guaranteed.12 The molecular basis of sickle-cell disease was identified in the 1950s but the disease is still incurable sixty years later. It took more than twenty-five years since the discovery of the CF gene in 1989 for Vertex Pharmaceuticals to develop a drug that successfully treated a subset of patients with a particular gene mutation.
Shortly before King’s walk off in Cincinnati, a group of clinicians at the NIH took a major step on the path to gene therapy by treating a young girl with a rare genetic disease. If a disease is caused by a typo in the genetic code, then the most logical way to treat that disease is to introduce a normal copy of the same genetic sequence. If the disease was caused by a faulty nonfunctional gene, then why not just replace the gene? A gene transplant, if you will. After two decades of false starts and deliberation, gene therapy was about to get real. But as generations of gene therapists can attest, it is anything but easy.
After three years of fierce debate, French Anderson finally won approval to start the first official gene therapy trial in the United States. Doctors and nurses gathered in the pediatric intensive care unit of the NIH Warren Grant Magnuson Clinical Center. It took all of twenty-eight minutes for the first history-making infusion to take place after the final paperwork was completed earlier that morning.
On September 14, 1990—12:52 P.M. to be precise—Kenneth Culver took a small syringe and injected some liquid into the left arm of four-year-old Ashanthi de Silva from Cleveland. Wearing a white top and turquoise trousers, Ashanthi was a model patient, distractedly sticking cartoon stickers on her doctors’ lab coats. About one billion genetically modified T cells slowly flowed into her body. “She was wonderful, a lot calmer than I was,” said lead investigator Michael Blaese.13 Ashanthi suffered from a rare form of severe combined immune deficiency syndrome (SCID), caused by a deficiency of the enzyme adenine deaminase (ADA). Only about a dozen children are born with this recessive disorder each year in the United States. Ashanthi had been sick for most of her life—about as long as the bureaucratic wrangling over the trial.
This was Anderson’s medical Mount Everest, a scientific summit he had wanted to conquer since his audacious manifesto was dismissed by the medical establishment two decades earlier. As a student, inspired by the double helix and Roger Bannister’s four-minute mile, Anderson had two goals in life: “I was going to be in the Olympics and I was going to cure defective molecules.”14 His first goal had already come true: he was a team physician for the U.S. Olympic team in Seoul in 1988.15 As Anderson, Blaese, and Culver exhaled after Ashanthi’s treatment, Anderson could reflect on twenty-five years of hopes and dreams. “At long last, the great adventure has started,” he said.16
Four months later, Anderson’s team began treating another pioneer, ten-year-old Cynthia Cutshall. In order not to treat the two girls as guinea pigs, Blaese and Anderson continued to administer the standard treatment, PEG-ADA. Did the gene therapy work? Well, yes and no. A twelve-year follow-up on Ashanthi declared that about 20 percent of her T cells were producing the ADA enzyme.17 More than twenty-five years after the trial began, Blaese said the amount of ADA produced in the treated cells was only about 15 percent of what had been expected. But the two girls are “both beautiful young ladies”18 who happily invited Blaese to their weddings. Anderson was elated. “I eat and sleep and breathe gene therapy 24 hours a day,” he told a New York Times reporter.
There was a giddy euphoria in gene therapy circles in the years following the NIH trial as more disease genes were identified, many amenable to genetic therapy. As the founding editor of Nature Genetics, I was down for the ride. More and more manuscripts arrived in our Washington, DC, office touting advances in gene therapy. Ted Friedmann, whom Horace Freeland Judson called “gene therapy’s most ardent advocate,” wrote a review I entitled “A Brief History of Gene Therapy.” Friedmann declared that the first phase of human gene therapy—the emergence and acceptance of the general concept—was over. “We are now in an explosive second phase—one of technical implementation.”19
In March 1994, I took the train up to Philadelphia to attend a press conference led by a rising star in the field. James Wilson of the University of Pennsylvania walked onto a makeshift stage in his pristine lab coat, flanked by two colleagues, to discuss his latest study that we were publishing the next day. Wilson’s team had treated a patient with an inherited form of coronary artery disease by removing part of her liver, treating it with a recombinant virus, and restoring the liver. The woman’s LDL cholesterol levels fell by 25 percent. Among the reporters in attendance was New York Times Pulitzer Prize–winner Natalie Angier. Her front-page story said Wilson’s study was “the first to report any therapeutic benefits of human gene therapy.”20 It happened to be April Fool’s Day.