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The Fall and Rise of Gene Therapy
Wired, August 2013

Rarely does a whole life’s work crumble in a single week, but james wilson’s did. The first glimmer of impending ruin came on a Tuesday morning—September 14, 1999—as he sat in his office at the University of Pennsylvania. In his role as founder and director of Penn’s Institute for Human Gene Therapy, Wilson was one of the most prominent researchers in the nascent field, which sought to put genes into patients to repair their faulty DNA.

Wilson and his colleagues were adding the final patients to a two-year clinical trial, the ultimate goal of which was to treat a rare but devastating disorder. Called OTCD, or ornithine transcarbamylase deficiency, the genetic disorder renders its victims unable to process nitrogen in their blood. Nitrogen is created when protein is broken down, so the blood of OTCD sufferers becomes poisoned when they eat protein-rich foods: One bite of a hot dog can bring on a coma. As a result, just half of children born with OTCD—estimated at roughly one in 80,000 babies in the US, or 50 per year—live to the age of 5. Wilson and his colleagues hoped to treat this disease by giving sufferers a working copy of the defective gene they carry. To accomplish this, they engineered a virus carrying the functional gene; after successful trials of the virus in mice, they launched a clinical trial to test its safety in humans suffering from OTCD.

That Tuesday morning, Wilson received a call about one of the new patients in the trial: Jesse Gelsinger, an 18-year-old from Arizona. After Gelsinger received his dose of the virus on Monday, his temperature quickly climbed to 104.5 degrees—an unsurprising fact, given that the 17 previous patients had each experienced flulike symptoms after their treatment. But the following morning, there was worse news: His blood tests showed abnormally high levels of coagulation factors. It looked as if the young man’s body was seized with inflammation. “That was the first sign,” Wilson recalls, in a tone of composed regret, “that things were headed in a different direction.”

Over the next 48 hours, the teenager’s condition deteriorated. His skin and eyes turned a jaundiced yellow, a sign that his liver had been damaged. He was moved to the intensive care unit. Inflammation bloated his body. Due to a financial conflict of interest—Genovo, a biotech company that provided funding to Penn’s gene therapy research, had also acquired exclusive rights to license Wilson’s patents—the researcher was not allowed to have any contact with the participants. And so he was left receiving increasingly dire updates via telephone, listening as his scientific triumph collapsed into tragedy.

Four days after Gelsinger’s injection, just before the OTCD team’s regular meeting, Wilson’s colleague Steven Raper, who was the trial’s principal investigator, pulled Wilson aside and confirmed the worst. Gelsinger—a young man who had volunteered for the study to help save kids far worse off than he—was on life support with no hope of recovery. Together the two men briefed their team. The stunned doctors, nurses, and scientists all knew what this likely meant: not just the death of a young man but an abrupt end to their entire trial, which they had hoped might eventually help save the lives of thousands of children.

After the meeting, Raper returned to Gelsinger’s hospital room, where the patient’s family was gathered. They could hardly recognize him due to his horrific jaundice and swelling. They gave their assent for the intensive-care specialist to shut off the machines that were the only thing keeping the teenager alive.

“We were all shocked and lost,” recalls Guangping Gao, a microbiologist who at the time was associate director of Penn’s gene therapy center. But Wilson told the team they had work to do. “As professionals, we had to get beyond the emotions of that moment,” he says. “We had to focus on doing everything we could—every sample, every hypothesis—to figure this out.”

In the months that followed, Wilson’s team began to investigate Gelsinger’s death. But they themselves were now under investigation. Penn started poring through the trial records, looking for mistakes and oversights. The FDA launched its own inquiry; the National Institutes of Health summoned Wilson to a hearing; a Senate subcommittee met to discuss the risks and benefits of gene therapy. In the wake of extensive media coverage on the death and investigation, the public image of gene therapy took on a sinister cast. Gelsinger’s family became enraged as they learned details of the trial that hadn’t been disclosed to them: the fact that Wilson held equity in Genovo and that some of the animals in his trials had suffered toxic, even fatal, side effects from their injections. (The researchers didn’t think the animal deaths were relevant to the safety of the human trials, because the animals had received far higher doses of the viruses.) “This appalling state of affairs is unacceptable,” wrote Donna Shalala, then secretary of the Department of Health and Human Services, in The New England Journal of Medicine.

Soon Wilson was mired in lawsuits. The Gelsinger family sued him and the trial’s two lead researchers, along with the university and others; the case was settled in 2000 on undisclosed terms. The Justice Department sued too, in a case that would not settle until 2005.

As a consequence of this one fateful week, Wilson’s career—and with it the entire field of gene therapy—went into free fall. As part of the punishment handed out by the government, Wilson was banned from working on FDA-regulated human clinical trials for five years. He stepped down from his position at the helm of the Institute for Human Gene Therapy, remaining as a professor at Penn. Soon afterward the institute itself was gone. Compounding the pall from Gelsinger’s death, the dotcom crash wiped out the biotech money that had promised to fuel gene therapy startups. In September 1999, gene therapy looked to be on the cusp of a breakthrough in medicine. By the end of 2000, it seemed like a cautionary tale of scientific overreach.

Most people would have given up. Scientists and investors were abandoning gene therapy. Wilson was forbidden from running trials on patients. But he couldn’t let go. So he chose a new path, and a new way of being a scientist. And in the process, he has helped to bring gene therapy back from the dead.

Wilson’s path as a young scientist tracked the ascent of gene therapy as an idea. In the late 1970s, while simultaneously pursuing a medical degree and PhD at the University of Michigan, he began to study a rare disorder called Lesch-Nyhan syndrome, which causes a host of terrible symptoms ranging from arthritis to self-mutilation. After years of study, Wilson eventually traced it to a particular defect in an enzyme. But he was left with no idea of how to translate his discovery into a cure.

In 1980, though, he opened up the journal Science and suddenly understood how doctors might someday cure Lesch-Nyhan, along with thousands of other genetic disorders that had once seemed incurable. Two Stanford biologists, Richard Mulligan and Paul Berg, had figured out a way to transplant genes into cells, effectively rewriting their DNA. The phrase gene therapy had been floating around medical circles for decades, but Wilson realized that its time had come. As soon as he finished his degrees, he and his wife moved to Boston so he could learn about gene transplantation from Mulligan, now at MIT. After nearly three years under Mulligan’s tutelage, he headed back to Michigan to set up his own lab.

The first disease that Wilson targeted was called familial hypercholesterolemia, in which the patient lacks the gene that produces receptors for grabbing “bad cholesterol,” or LDL, from the blood, which the liver normally filters out. Vessels become so badly clogged that many sufferers have heart attacks in their forties and fifties, and sometimes even before age 30.

Wilson figured out how to make a “vector” to attack the condition—a virus with a working version of the gene loaded on it. He first tested it on a type of rabbit genetically prone to high levels of LDL, and the gene therapy lowered those levels considerably. For a human trial in 1992, he and his colleagues chose a 28-year-old woman from Canada. Surgeons removed part of her liver, and then Wilson and his colleagues infected its cells with the virus, which delivered a working version of the defective gene. Finally, Wilson and his colleagues injected those cells back into the woman’s liver, where they took hold and grew. The woman’s LDL levels dropped by 23 percent.

The result, published in 1994, was a milestone in the young field. “GENE EXPERIMENT TO REVERSE INHERITED DISEASE IS WORKING,” The New York Times reported, noting that Wilson’s paper was “the first to report any therapeutic benefits of human gene therapy.” Thanks to this study and others, the FDA gave the green light to more clinical trials every year, jumping from zero in 1989 to 91 in 1999. Universities set up gene therapy programs to stake a claim in the new field.

One of those was the Institute for Human Gene Therapy at the University of Pennsylvania. At age 38, Wilson became the institute’s head, overseeing a staff that soon grew to more than 200. They launched new clinical trials, including a sequel to Wilson’s study on familial hypercholesterolemia and on another genetic disorder in the liver: OTCD. Wilson now wanted to take the surgery out of gene therapy, so he and his colleagues searched the scientific literature for a virus that could seek out liver cells in the body.

They settled on a virus known as an adenovirus. Adenoviruses are best known for causing the common cold, but other scientists had found that they were very good at delivering genes into cells. Everything seemed to be moving forward nicely—until Jesse Gelsinger checked into Children’s Hospital of Philadelphia.

Copyright 2013 Carl Zimmer
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