The Gene: An Intimate History - Siddhartha Mukherjee Page 0,201

causes a common cold but is not associated with any severe disease. It seemed like a safe, reasonable choice—the blandest of viruses used as the vehicle for one of the boldest human genetic experiments of the decade.

In the summer of 1993, Batshaw and Wilson began to inject the modified adenovirus into mice and monkeys. The mouse experiments worked as predicted: the virus reached the liver cells, disgorged the gene, and transformed the cells into microscopic factories for the functional OTC enzyme. But the monkey experiments were more complicated. At higher doses of the virus, an occasional monkey raised a brisk immune response to the virus, resulting in inflammation and liver failure. One monkey hemorrhaged to death. Wilson and Batshaw modified the virus, shaving off many of the viral genes that might elicit immunity, to make it a safer gene-delivery vehicle. They also reduced the potential human dose by seventeenfold to doubly ensure the safety of the virus. In 1997, they applied to the Recombinant DNA Advisory Committee, the gatekeeper for all gene-therapy experiments, for approval for a human trial. The RAC was resistant at first, but it too had changed: in the decade between the ADA trial and Wilson’s, the once-fierce guardian of recombinant DNA had turned into an enthusiastic cheerleader of human gene therapy. The fizz of enthusiasm had even leached beyond the committee. Asked by the RAC to comment on Wilson’s trial, bioethicists argued that treating children with full-blown OTC deficiency might result in “coercion”: What parent wouldn’t want to try a breakthrough therapy that might work on a dying child? Instead, ethicists recommended a trial on normal volunteers and patients with mild variants of OTC, such as Jesse Gelsinger.

In Arizona, Gelsinger, meanwhile, was chafing against the elaborate restrictions on his diet and medications (“All teenagers rebel,” Gelsinger’s father, Paul, told me, but teenage rebellion might feel particularly acute when it involves “a hamburger and a glass of milk”). In the summer of 1998, when he was seventeen, Gelsinger learned of the OTC trial at the University of Pennsylvania. Gelsinger was gripped by the thought of gene therapy. He wanted a respite from the grinding routine of his life. “But what got him even more excited,” his father recalled, “was the idea that he was doing it for the babies. How do you say no to that?”

Gelsinger could hardly wait to sign on. In June 1999, he contacted the Pennsylvania team through his local doctors to enroll in the trial. That month, Paul and Jesse Gelsinger flew to Philadelphia to meet Wilson and Batshaw. Jesse and Paul were both impressed. The trial struck Paul Gelsinger as a “beautiful, beautiful thing.” They visited the hospital and then wandered through the city in a haze of excitement and anticipation. Jesse stopped in front of the Rocky Balboa bronze outside the Spectrum Arena. Paul snapped a picture of his son, his arms raised in a boxer’s victory stance.

On September 9, Jesse returned to Philadelphia with a duffel bag filled with clothes, books, and wrestling videos to start the trial at University Hospital. Jesse would stay with his uncle and cousins in the city and admit himself to the hospital on the appointed morning. The procedure was described as so quick and painless that Paul planned to pick up his son one week after the therapy had been completed to bring him back home on a commercial flight.

On the morning of September 13, the day chosen for the viral injection, Gelsinger’s ammonia level was found to be hovering around seventy micromoles per liter—twice the normal level and at the upper edge of the cutoff value for the trial. The nurses brought news of the abnormal lab to Wilson and Batshaw. The protocol, meanwhile, was in full swing. The operating rooms were on standby. The viral liquid had been thawed and sat glistening in its plastic pouch. Wilson and Batshaw debated Gelsinger’s eligibility, but decided that it was clinically safe to continue; the previous seventeen patients had, after all, tolerated the injection. At about 9:30 a.m., Gelsinger was wheeled down to the interventional radiology suite. He was sedated, and two large catheters were snaked through his legs to reach an artery close to the liver. Around 11:00 a.m., a surgeon drew about thirty milliliters from a bag clouded with the concentrated adenovirus and injected the puff of virus into Gelsinger’s artery. Hundreds of millions of invisible infectious particles carrying the OTC gene streamed into the liver. By noon, the procedure was done.

The afternoon