When Science Goes Wrong (22 page)

Jesse Gelsinger took an unpaid leave from his job and, on Thursday, September 9, he flew alone to Philadelphia, taking with him a bag of clothing and his collection of pro wrestling videos. The plan was that Paul, who could not take a great deal of time off from his work, would join Jesse a week later for the liver biopsy, which Paul perceived to be the most risky part of the trial. ‘Words cannot express how proud I was of this kid,’ Paul wrote later. ‘Just 18, he was going off to help the world. As I walked him to his [airport departure] gate I gave him a big hug and as I looked him in the eye, I told him he was my hero.’

Jesse checked into the hospital on the Thursday evening. The next few days would be devoted to tests, and the adenovirus infusion was scheduled for Monday. But almost immediately a problem arose: on Friday morning, before Jesse underwent a
15
N ammonia excretion test, his blood ammonia level was 114 µM/L – well above the permissible maximum of 70 µM/L. Batshaw and Raper gave Jesse intravenous drugs to lower his ammonia, but by Sunday, the day before the scheduled treatment, it had only fallen to 91 µM/L. This presented a final opportunity – and an obligation, according to the protocol – for the research team to drop Jesse from the trial, but they did not do so.

On Monday morning, Steven Raper inserted the infusion cannula into Jesse’s groin and threaded it up into the hepatic artery. Having checked the correct placement of the cannula tip with the help of radiography, Raper began the infusion of the adenoviral vector. A total of 38 trillion virus particles entered Jesse’s bloodstream over the course of a few minutes. When the infusion was over, Jesse had to lie quietly for a few hours and during this time Raper called Paul to let him know that everything had gone according to plan. That evening, Jesse developed a fever of 104.5°F, but this didn’t prevent him from talking with his family by phone – for the last time, as it turned out.

The next morning, Raper noticed that the whites of Jesse’s eyes were yellow: a sign of jaundice, which suggested damage to his liver or to his red blood cells – or both. Jesse was also slightly disoriented. Raper called Paul to let him know, and he also talked with Mark Batshaw, who was in Washington. Later, Batshaw called Paul to tell him that Jesse’s blood ammonia level had risen to 250 µM/L, and that he was seriously ill. Paul dropped everything and took a night flight to Philadelphia. When he arrived at the hospital on Wednesday morning, he found Jesse on a ventilator and in a coma. His blood ammonia level had risen at one point to 393 µM/L – about ten times higher than normal – but the doctors had been able to lower it to less than 70 µM/L by putting him on dialysis. Still, he remained desperately ill: in particular, his blood was being poorly oxygenated in spite of the ventilator. In addition, he was developing disseminated intravascular coagulation, a potentially deadly condition in which the blood clots inside the blood vessels. Jesse didn’t respond to any of Paul’s efforts to rouse him.

Paul called his wife and told her to come and join him. Some of Paul’s many siblings also converged on the hospital. For a while it looked as if Jesse was improving, but by late Wednesday evening it was apparent that his lungs were failing. Even while being mechanically ventilated with pure oxygen, his arterial blood contained insufficient oxygen to maintain his vital organs.

In a last-ditch effort to save Jesse’s life, Raper decided to try hooking him up to an artificial lung – a device resembling the heart-lung machines that are used during open-heart surgery. It took Raper and the machine specialist until 5am on Thursday to get the machine hooked up and running – there was major bleeding, and they had to use more than ten units of blood to make up the deficit and prime the machine. Paul spent the night waiting in quiet desperation outside the intensive care unit, with an occasional brief visit from a harried doctor and some comfort from the hospital chaplain.

Meanwhile, the elements were conspiring to echo Jesse’s crisis: Hurricane Floyd was grinding its way up the East Coast toward Pennsylvania. Paul’s wife, Mickie, made it to Philadelphia just before the airport was closed, but Mark Batshaw became trapped on a train that was stuck outside the city. He ended up giving advice by cell phone from the train.

For a while, it seemed as if the artificial lung was helping. Sometime after noon, Paul, Mickie, and several of Paul’s siblings were allowed in to visit Jesse. He was deeply comatose, and his face and body were enormously bloated. Paul was not even sure that it was his son he was looking at, until he spotted a familiar tattoo and scar.

Toward evening, Paul and Mickie returned to their hotel, but Paul was destined for yet another sleepless night. At one point he walked back to the hospital through the rain, only to find Jesse in even worse shape: he was losing blood in his urine.

When Paul and Mickie came back in to the hospital on Friday morning, Raper and Batshaw told them that Jesse’s brain had suffered irreversible damage and that his other organs were failing, too. They suggested that it was time to shut off his life support. For the final ceremony, seven of Paul’s siblings and their spouses joined Paul and Mickie and about ten of the hospital staff around Jesse’s bed. After a prayer from the chaplain and brief words from Paul, Raper clamped off the tube that carried blood to the artificial lung and switched off the machine. A minute later he put his stethoscope to Jesse’s chest. ‘Good-bye, Jesse,’ he said. ‘We’ll figure this out.’

In the immediate aftermath of Jesse’s death, Paul was not inclined to blame the researchers. ‘It was a traumatic experience for me,’ Paul told me, ‘but it was also a spiritual experience. Jesse’s example, what he was doing, demonstrated the best of humanity to me – the best that we can be. At the time, I was adopting that attitude: forgiveness, honesty, everything – the best that we can be.’ Yes, participating in the clinical trial had killed Jesse, but it seemed to Paul that it was an unforeseeable accident. Paul told Batshaw as much, and said that he would not be bringing a lawsuit.

In the same spirit, Paul invited Steven Raper to attend the scattering of Jesse’s ashes. That ceremony took place at one of Jesse’s favourite spots, the 9,400ft summit of Mt Wrightson, 30 miles south of Tucson. Jesse’s mother, Pattie, who had been ill at the time of Jesse’s death, accompanied the remainder of the family on the arduous hike. On the descent after the ceremony, she fell behind the rest of the party; she was overtaken by darkness and had to be rescued.

Paul’s forgiving attitude changed after he was invited to address a meeting of the Recombinant DNA Advisory Committee that would discuss Jesse’s death and what it meant for the regulation of gene therapy experiments. The meeting was to be held in Washington DC in early December of 1999. In the days before his trip, Paul began to learn facts about the case, such as Jesse’s high ammonia level before the infusion, which made him think that the FDA had been lax in their oversight of the trial. He said as much to an FDA staff member, and even threatened to expose what he saw as the FDA’s dereliction of duty.

Then James Wilson asked Paul Gelsinger to come to Penn a day before the RAC meeting in order to give a ‘morale boost’ to his institute’s deeply shaken staff. When Paul arrived, Wilson took him into his office. ‘He’d been all enthusiastic about my visit until that point,’ Paul told me, ‘but now he was crying, and he said that he’d just received notice, a press release [from the FDA], and they were pointing at him and his colleagues as being responsible for Jesse’s death.’ As Paul sees it, the FDA had taken fright at Paul’s accusations and had quickly moved to shift blame onto Wilson, Batshaw and Raper. It’s equally possible, however, that the FDA had simply reached this conclusion on the basis of its own weeks-long analysis of the case. (Kathryn Zoon, the responsible FDA official at the time, declined my request for an interview.)

The RAC meeting was thrown into turmoil by the FDA’s announcement: throngs of reporters and lawyers almost outnumbered the scientists and regulators. Paul Gelsinger delivered a long presentation describing his entire experience with the OTC trial. He was still not publicly blaming the Penn group for his son’s death. He told a reporter for the
New York
Times
that ‘These guys didn’t do anything wrong.’ But his mindset was rapidly changing. For one thing, Paul told me that he found out at the meeting that there was no evidence for any improvement in ammonia excretion among the volunteers who received infusions of the adenovirus vector before Jesse. This conflicted with what he says Batshaw told him before Jesse’s participation, which was that the volunteer immediately before Jesse had experienced a 50 per cent improvement in ammonia excretion. Paul began to feel that Batshaw had deceived him about this in order to make him feel that the trial was going well, when it wasn’t.

Over the following months, he probed deeper and deeper into the events preceding his son’s death, and he became convinced that there had been serious wrongdoing on the part of the Penn researchers. Besides the problems already mentioned – the failure to halt the trial when previous volunteers experienced serious adverse events and the decision to go ahead with Jesse’s infusion when his ammonia was above the allowable limits – Paul learned that James Wilson had what he considered to be a financial conflict of interest.

The details of Wilson’s financial involvements were unravelled by
Washington Post
reporters Deborah Nelson and Rick Weiss in November of 1999. Wilson owned 30 per cent of the stock of a biotech company named Genovo, which he had founded to exploit gene therapies commercially. This company was paying 20 per cent of the operating expenses of the Institute for Human Gene Therapy in return for the right to exploit the institute’s discoveries. The University of Pennsylvania also had financial ties to Genovo and a web of linked biotech corporations. How could Wilson give priority to the safety of the volunteers, Paul reasoned, when his company stood to profit from quick results?

In fact, just a few months before Jesse’s death Wilson had delivered a presidential address to the American Society of Gene Therapy in which he recommended a streamlining of the regulatory process. The initial or phase-1 trials, he said, should be explicitly designed to gain information on the
efficacy
of gene-transfer therapies, not just on their safety as had been the traditional purpose of phase-1 trials. ‘Early feedback on clinical or surrogate measures of efficacy can have broad implications in accelerating the path to commercialisation,’ he said, ‘focusing our investment in research, and minimising financial risks regarding decisions to move forward in later stage development.’ This sounded like the opinion of an investor, not of a scientist or doctor.

The University of Pennsylvania commissioned an independent panel to review the Institute of Human Gene Therapy in the wake of Jesse’s death. The panel, one of whose members was Inder Verma, recommended that clinical investigators who were testing biological therapies not be allowed to have investments in companies that were commercialising such therapies. This seemed like a rebuke to Wilson for his financial interest in Genovo, but when I asked Verma about it in 2006, he denied that. Genovo, he said, wasn’t developing the same kind of vector that Wilson’s team tested on Jesse, so there was no financial conflict of interest. ‘The newspapers liked to say that there was – it was so inflammatory – but it was a different virus.’ Robert Erickson, on the other hand, did see a clear conflict of interest in Wilson’s relationship with Genovo. He argued that, because the two vectors fell under the same umbrella of gene therapy, and because Genovo had broad rights to the Institute’s discoveries, Genovo and therefore Wilson stood to gain financially if the OTC trial got good results.

Yet another view of the matter was offered by Arthur Caplan, the Penn ethicist. ‘I think the problem was ambition, not money,’ he told me. ‘The problem was the drive to succeed, or to be the first to show something efficacious with gene therapy. Batshaw and Wilson, when they stood up in front of their peers, they were very interested in saying, “We at Penn are the very first ones to make this much-hyped idea pay off.” To the extent that they hurried or didn’t worry about signals from the animals that there were problems, that was the reason. And we haven’t figured out how to manage
that
conflict of interest.’

One year to the day after Jesse’s death, Paul and Jesse’s uncle (the administrator of Jesse’s estate) filed a lawsuit against the University of Pennsylvania, the Children’s National Medical Center (Batshaw’s institution), the Genovo Corporation, and five individuals: Wilson, Batshaw, and Raper, along with the Dean of the Medical School and Arthur Caplan. The lawsuit alleged wrongful death, fraud and other misdeeds.

Caplan was soon dropped from the suit on account of his peripheral involvement. The remaining defendants settled with the Gelsingers within six weeks of the filing. The amount of the settlement was never disclosed, but it was clearly very substantial: Paul no longer works as a handyman, and he mentioned to me that Pattie’s share of the settlement has allowed her to get good medical care for the first time in her life. Paul did not get an apology or even an admission of wrongdoing, however: the University’s position was that, while there had been lapses in the oversight and execution of Wilson’s trial, these were not what led to Jesse’s death.