The swashbuckling pace with which investigators were publishing results made some observers nervous. Harold Varmus, then director of the NIH, commissioned a report on gene therapy. “Today, the announcement of a [disease] gene being discovered is tantamount to the belief that gene therapy exists for the condition. We’ve seen an extrapolation from hope to hype. In the long run, this will be destructive to basic clinical science,” said Varmus sternly. The report criticized the rush to clinical trials without sufficient understanding of disease pathology, the low frequency of gene transfer, and overselling of results leading to “the mistaken and widespread perception that gene therapy is further developed and more successful than it actually is.”21
Nevertheless, by 1999, Friedmann and his fellow gene therapists were euphoric about the future. Despite the efforts of critics who had “fomented mistrust and misunderstanding of the goals and techniques of gene therapy,” the inevitability of the science had been established “long before it was able to provide truly believable clinical benefits.”22 Friedmann continued: “The success of the concept of gene therapy has been phenomenal and represents a truly epochal new direction for medicine.”
Even before the ink was dry on Friedmann’s essay, those words rang hollow.
In 1984, a few months shy of his third birthday, Jesse Gelsinger fell into a coma while watching Saturday morning cartoons on television. After a lengthy hospital stay, he was diagnosed with a rare X-linked genetic disorder, ornithine transcarbamylase (OTC) deficiency. A missing enzyme results in an inability to process nitrogen (found in all proteins and other biomolecules) and a toxic buildup of ammonia. About fifty OTC deficiency babies are born in the United States each year; only half will live past the age of five.
Jesse’s father, Paul, and his partner put Jesse on a low-protein diet to manage the disease. Fortunately he had a mild form of the disease, but if he forgot to take his pills (up to fifty per day), he could fall into another coma. In September 1998, Paul heard about an OTC deficiency clinical trial being conducted at Penn. But that Christmas, Jesse fell into a coma and almost died. Shortly after graduating from high school, Jesse volunteered to take part in the clinical trial as soon as he was eligible. The following June, the Gelsinger family flew to Philadelphia on Jesse’s eighteenth birthday. They visited the usual tourist landmarks, with Jesse posing next to the statue of Rocky, arms aloft in a Minnesota Twins T-shirt.
The Penn doctors explained that the purpose of a phase I trial was to test safety, not to expect any clinical benefit. There would likely be side effects such as flu-like symptoms as Jesse’s immune system ramped up to attack the virus. The doctors also explained that while OTC deficiency was rare, affecting one in 80,000 people, there were at least two dozen similar metabolic liver disorders, in total affecting one in five hundred people. Jesse would be a pioneer for thousands of other patients. Three months later, Paul took Jesse to the airport for his flight from Arizona to Philadelphia. “Words cannot express how proud I was of this kid,” Paul said. “Just eighteen, he was going off to help the world.”23
The OTC trial was directed by James Wilson, the founding director of Penn’s Institute for Human Gene Therapy. Because Wilson had founded a biotech company, Genovo, he was not allowed to have direct contact with the patients. On Monday September 13, 1999, Jesse received his first infusion of a recombinant adenovirus containing a normal copy of the OTC gene. As planned, he received the highest dose among the eighteen volunteers. He soon developed a fever but that was not unexpected. Jesse spoke to his father by phone that evening. It was the last conversation they would have. The following morning, Jesse had developed jaundice and his ammonia levels were spiking. They informed Paul and Wilson. Over the next two days, Gelsinger’s kidneys and liver started to fail. He was put on an artificial lung to help his breathing. When Paul finally got to Jesse’s bedside, he didn’t recognize his son because Jesse’s face was swollen beyond recognition. He had suffered irreparable brain damage.
With seven of his siblings and spouses in attendance, Paul held a brief bedside ceremony for his son. At 2:30 P.M. on September 17, physician Steve Raper shut off the ventilator and pronounced Jesse dead. “Goodbye Jesse, we’ll figure this out,” he said. The grim news reached the press two weeks later. “Teen Dies Undergoing Experimental Gene Therapy” was the Washington Post headline.24 Ironically, Wilson had never met Paul or Jesse Gelsinger.
In early November, Paul led about two dozen mourners on a hike to one of Jesse’s favorite places—Mount Wrightson, close to the Mexican border. After Paul shared some memories of his son, Raper read a poem by Thomas Gray:
Here rests his head upon the lap of earth
A youth to fortune and to fame unknown.
Fair Science frowned not on his humble birth,
And Melancholy marked him for her own.
Moments later, Paul and other mourners scattered Jesse’s ashes into the Arizona air.25
A short time later, Wilson flew out to meet Paul Gelsinger for the first time. Sitting on Gelsinger’s back porch, Wilson shared Jesse’s autopsy results and told Paul that he was just an unpaid consultant to Genovo. Initially supportive, Gelsinger learned that the Penn team had seen fatalities in animals (albeit receiving much higher doses of virus) and adverse events in some patients before Jesse’s fateful enrollment. Gelsinger eventually filed a lawsuit against Wilson and his two senior colleagues that was settled out of court. Wilson’s gene therapy center was disbanded, and he was forbidden from running any clinical studies until 2010. In the formal scientific report published by Raper, Wilson, and colleagues, much of the blame was cast on the viral vectors that triggered Jesse’s fatal cytokine storm.26
Writing shortly after the Gelsinger tragedy, molecular biologist Peter Little reached a grim diagnosis:
I suspect the judgment will be that we were arrogant and came extremely close to using humans as experimental animals; we knew too little and expected too much, and the expectation of success was used to roll back objections.27
In his book The Gene, Siddhartha Mukherjee condemned the OTC trial as “nothing short of ugly—hurriedly designed, poorly planned, badly monitored, and abysmally delivered. It was made twice as hideous by the financial conflicts involved; the prophets were in it for profits.”28 Wilson, when interviewed for The Gene documentary, said: “I’ll think about [the tragedy] frequently until the day I die. I don’t know what else to say.”29
The Gelsinger tragedy was soon compounded by news from across the pond. In 2000, French physician Alain Fischer of the Necker Hospital in Paris held a press conference to mark the preliminary success of gene therapy in two infants with an X-linked form of SCID. Fischer was using a retrovirus vector to shuttle the healthy gene into the patients’ blood stem cells. But two years later, two boys were diagnosed with a form of leukemia that was traced back to the therapy itself, and one eventually died. Retroviruses work by integrating directly into the host genome, like hiding the joker in a pack of cards. In most cases, the integration event is harmless, but in rare instances it can trigger a cancerous event. Fischer’s viral vector was finding a comfortable landing spot in the host DNA, inadvertently switching on an adjacent oncogene with devastating results. In 2003, the FDA responded by halting the use of retroviruses in the United States.