Growing up in Tucson, 18-year-old Jesse Gelsinger was always one of the smallest kids in his class. He'd been born with ornithine transcarbamoylase (OTC) deficiency, a rare metabolic disorder that disables the liver and causes a toxic buildup of ammonia, which can lead to brain damage and death. Half of those stricken die by age 5, but Jesse controlled his condition through diet and medication, and he never let it interfere with such pursuits as gunning his motorcycle across the desert. Says biking buddy Garrick Exarhos, 19: "He wanted to prove he was as much a man as anyone."
In typically gung ho fashion, Jesse jumped at the chance to volunteer last June for the highly regarded seven-year-old gene-therapy program at the University of Pennsylvania in Philadelphia. Still in the experimental stage, gene therapy has been hailed as the new frontier of medicine. By injecting patients with corrective genes to replace missing or defective ones, doctors hope someday to vanquish a host of inherited ills, even some forms of cancer. Last September, Jesse entered an OTC study that, though unable to offer him long-term benefit, might one day aid others. "He was going to help save lives," says his father, Paul, 47, a handyman. "The doctors told him it was a very unselfish act."
It turned out to be the ultimate sacrifice. Penn doctors said that within 24 hours after Jesse received his first infusion, he was suffering from a life-threatening clotting disorder in which red blood cells were breaking down faster than the liver could metabolize them. Having already slipped into a coma and experienced multiple organ failure, he was declared brain dead on Sept. 17, and his father allowed them to disconnect life support. "They said even if he recovered," recalls a tearful Gelsinger, "he wouldn't be Jesse anymore."
Jesse's death staggered the medical community, for he was the first patient known to die as a direct result of gene therapy. Compounding the sense of loss, the Food and Drug Administration last month suspended gene-therapy trials at Penn after an investigation into Jesse's death revealed serious rules violations. The U.S. Senate has also begun hearings into the program and gene therapy in general. Penn's research "will be on clinical hold," says the FDA's Lenore Gelb, "until the trials can be run in accordance with regulations."
The FDA, which with the National Institutes of Health oversees genetic studies, said Penn's Institute for Human Gene Therapy gave Jesse and other patients a consent form that differed from that approved by the agency—and omitted mention that lab monkeys had died during similar experiments. What's more, they said, Jesse's liver wasn't working well enough to withstand the trial. "I encouraged my son to do this," Paul Gelsinger told a Senate subcommittee on Feb. 2. "But I wasn't given all the information."
Apparently, scientists in gene-therapy trials have routinely been lax in reporting unexpectedly serious side effects. The NIH is supposed to be informed of those cases immediately, but agency officials say that only 39 of the 691 "adverse incidents" occurring in trials like Jesse's in the last seven years were promptly reported. Sen. Bill Frist of Tennessee said the revelations "sobered us all" and voiced concern that conflicts of interest can arise when scientists are competing for drug patents, which could be worth millions. It's unclear what action, if any, the Senate will take, but the furor over Jesse's death has made researchers skittish. As a precaution, the Cystic Fibrosis Foundation temporarily suspended two similar gene-therapy studies in December, and earlier this month Boston's Beth Israel Deaconess Medical Center halted hemophilia trials. As for the Penn research team, neither James Wilson, its head, nor his colleagues have commented. But university spokesman Ken Wildes says Jesse's death "hit a lot of us very, very hard. It's horrific."
Those sentiments are of little solace to the Gelsingers. Jesse was born in New Jersey but raised in Tucson, where his father and mother, Pattie, 48, divorced. His disease manifested itself when as a 2-year-old he lapsed into a coma. Thereafter required to down dozens of pills a day, he covered any anxiety about his illness with attitude. "Some people thought he was cocky, but he was a great kid," says Tereasa Martin, 30, a coworker at Fry's Food and Drug. "He was funny and sarcastic and always had a joke." He faced gene therapy with typical élan. Before the fatal experiment, Jesse climbed the steps of Philadelphia's art museum to mimic Sly Stallone's triumphal pose from Rocky. "That," says his father, "was pure Jesse."
Three months later, Gelsinger was at his son's side as the boy slipped away. Even after scattering Jesse's ashes over Tucson's Mt. Wrightson, Gelsinger at first supported the researchers who had inadvertently ended Jesse's life. "They had the same intent my son had—it doesn't get any purer," he told the NIH as recently as December. Now he's not so sure, "Jesse was doing the right thing," Gelsinger says. "Now it looks like he was the only one."
Jerry Kammer in Tucson and Matt Birkbeck in New York City
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