When Science Goes Wrong: Twelve Tales From the Dark Side of Discovery - Simon LeVay (2008)

GENE THERAPY: The Genes Of Death

BEFORE THERE WERE stem cells, there was gene therapy. The field took off in 1990, when geneticist William French Anderson of the University of Southern California reported that he had cured a four-year-old girl of ‘bubble-boy disease’ – severe combined immunodeficiency, or SCID – by transferring the missing gene into her body. Soon, the idea of giving people new genes became the white-hot frontier of medical research. Touted as a possible cure for cancer, heart disease, diabetes, and hundreds of other conditions, this form of treatment was on everyone’s lips, and nowhere more so than at the University of Pennsylvania’s Institute for Human Gene Therapy, which was founded in 1993.

The Institute’s director, physician and molecular geneticist James Wilson, led a team that had developed a potential treatment for an inherited disorder called ornithine transcarbamylase (OTC) deficiency. In baby boys who are born with this condition, their livers cannot metabolise the ammonia that they naturally produce when they digest protein, so ammonia levels in the babies’ blood rise as soon as they have their first meal. Because ammonia is highly toxic to the brain, they quickly go into a coma and die. Wilson and his colleagues had engineered an adenovirus – a kind of common cold virus – to carry a normal version of the gene that is defective in the affected babies. The idea was to infect the babies with this modified virus (or ‘vector’), with the hope that some of the children’s liver cells would take up the artificial gene and use it, at least temporarily, to replace the function of the defective one.

As with any new treatment, this one involved some risk to the subjects who participated in the initial clinical trials. Thus the question arose as to whether it would be ethically appropriate to test the new treatment on OTC-deficient babies. Wilson discussed this issue with Arthur Caplan, a bioethics specialist who was then on the staff of Wilson’s institute. (He now heads the university’s Center for Bioethics.)

In a fateful turn, Caplan advised Wilson not to test the treatment on babies, but on adults who had a less severe form of the disease. According to a 1999 article in the New York Times, Caplan gave that advice because he thought that the parents of extremely sick infants could not give informed consent: ‘They are coerced by the disease of the child,’ he told the newspaper. When I talked with Caplan in 2006, however, he denied that this had ever been his reason; instead, he said it was a simple matter of the federal regulations that were then in force. In an initial, or ‘phase-1’, clinical trial, the focus is entirely on testing for safety, and there is therefore no prospect of benefit to the subject, he said. In those circumstances, regulations don’t allow for the use of babies as subjects if there is any possibility of using adults.

Caplan was not entirely right about this. Although safety is indeed supposed to be the focus of a phase-1 trial, the Penn researchers did envisage that OTC-deficient babies might benefit from participation. One of Wilson’s collaborators later told Science that the hope had been that the adenovirus infusion would bring the babies out of coma and keep them in reasonable health for a period of weeks or months, during which time other therapies might be brought to bear that would stabilise the children for the longer term. If that was so, the balance did not swing so decisively toward using adults in the trial.

Caplan offered another justification for his opinion, however. He said that it would have been impractical to do a clinical trial with OTC-deficient babies because of the emergency situation that arises when they are born. ‘What you’d have to do is fly in, enrol someone in a phase-1 trial within an hour – because you don’t have a lot of time here, and you’re going to show up out of the blue when they’re expecting a healthy kid – and say, “We just flew in, here’s the liver surgeon, your baby’s going to die, would you like to be in an experiment where there’s going to be no benefit?”’

If OTC deficiency kills baby boys at the very dawn of their lives, who were the OTC-deficient adults who would be available for recruitment into the study? For the most part, they were women. The OTC gene is located on the X chromosome, of which males possess one copy and females two. Females who have a mutation in the OTC gene on one of their X chromosomes usually have a normal copy of the gene on the other chromosome, and this normal gene offers them partial or complete protection. (This situation is similar to that of other X-linked disorders such as haemophilia.) Female children may have no symptoms at all, or they may have mild symptoms that can be controlled by diet and medication. There are also rare instances of males whose tissues are a genetic mix or ‘mosaic’ of normal cells and cells that are OTC-deficient; again, such males tend to have mild symptoms that allow them to survive with proper medical care.

Enter Jesse Gelsinger. Jesse was born in June of 1981, the son of Paul Gelsinger and his then wife, Pattie, of Tucson, Arizona. (Pattie and Paul divorced a few years later.) The second of four children, Jesse was an apparently normal child until late in his third year, when his behaviour and speech became erratic. ‘It seemed like demonic possession,’ Paul Gelsinger told me in a 2006 interview. ‘The voice coming out of him, the attitude, I thought it was some kind of psychiatric problem.’

Eventually, Jesse slipped into a coma, and this led to his hospitalisation and his eventual diagnosis as having OTC deficiency. No one else among his relatives had had the disorder; the mutation apparently occurred spontaneously in one of Jesse’s cells when he was a very early embryo. The descendents of that cell, but not those of the remaining embryonic cells, were OTC-deficient, making him a mosaic. Jesse’s condition was so unusual that researchers at the University of Pennsylvania wrote an article about him that was published in the New England Journal of Medicine in 1988. Thus, Jesse’s case was well known to the community of specialists who studied and treated OTC deficiency, long before he became a subject in Wilson’s clinical trial.

Jesse recovered from that episode, and thereafter he was maintained in reasonably good health with a combination of a low-protein diet and a drug, sodium benzoate, that lowered the concentration of ammonia in his blood. Still, the dietary restriction slowed his growth – he reached a final height of only 5ft 5in – and his metabolic problems affected his mental abilities to a variable extent. ‘When he was well, he was fine,’ his father told me. ‘Very intelligent – he could be an honour roll student. But at other times it was very difficult for him to focus.’

In the autumn of 1998, when Jesse was 17 years old and in his final year in high school, he and his father received some interesting news. Jesse’s geneticist, Randy Heidenreich of the University of Arizona, told them that he had received a letter from Mark Batshaw, a paediatrician and expert in OTC deficiency at the University of Pennsylvania. Batshaw had teamed up with James Wilson and a liver surgeon, Steven Raper, to run the first clinical trial of Wilson’s adenovirus vector, and Batshaw was now actively recruiting volunteers. The Gelsingers reacted very positively, but the minimum age for participation was 18, so Jesse could not sign up for the trial until the following summer.

The intervening months were turbulent ones for Jesse and his family. Jesse had no plans for what to do after high school, aside from a wholly impractical dream of turning his favourite hobby – watching professional wrestling – into a career option. He had fantasies of starting his own pro wrestling federation. Tensions developed between Jesse and his father, as Paul tried to focus his son’s attention on the need to think about his future in a serious way, particularly because his medical condition involved considerable expenses – expenses that Paul’s health insurance would cover for only a few more years.

Jesse’s normal teenage rebelliousness had a detrimental influence on his always-precarious health. ‘He consciously did not want to take his medication because of the peer effect,’ said Paul. ‘At school he would have to go to the nurse’s office to take it. He was definitely different because of the disorder, and he hated that.’ Jesse began skipping some of the 40-odd pills that he had to take every day. Sometimes he would go without his medications altogether if he felt that he was well enough to do so.

Then, in November, Jesse camped out all night outside a box office with the hope of getting tickets for a pro wrestling event. A healthy teen’s body would have taken such an overnighter in its stride, but for Jesse it was the kind of stressful event that exacerbated his illness. He began experiencing serious symptoms of his disorder, such as nausea and cognitive impairment, but he hid them from his father and from his stepmother, Mickie, in order to avoid having restrictions placed on his activities.

Three days before Christmas, Paul arrived home to find Jesse vomiting in the living room. He was admitted to the hospital, where tests revealed that his blood ammonia levels were six times higher than normal. His metabolism was falling into a vicious cycle whereby, having consumed all the fat in his body, it was now digesting his proteins, thus liberating even more ammonia. Six days later, after a rocky course, he became delirious. Thinking that he was near death, Jesse’s doctors asked Paul whether he wanted a ‘do not resuscitate’ order placed on his son. Paul vehemently refused. The doctors then decided to move Jesse into intensive care, but before they could do so Jesse stopped breathing. Luckily, Paul was present at his bedside: he summoned a doctor who called a code blue. Jesse was intubated and put on a respirator.

A new and more powerful medicine – sodium phenylbutyrate – was fed to Jesse via a stomach tube, and it eventually lowered his ammonia level to the point where he regained consciousness and began a complete recovery. He returned to school with ammonia levels near normal for the first time in his life and with a newfound resolve to follow his doctors’ orders. A few months later, he graduated from high school.

On June 18, 1999 – Jesse’s 18th birthday – the entire family flew east. After a few days’ visit with relatives in New Jersey, they drove down to Philadelphia so that Jesse could sign up for the OTC trial. The person who explained the trial and walked Jesse and Paul through the ‘informed consent form’ was Steven Raper, the liver surgeon.

Raper said that the adenoviral vector would be infused directly into Jesse’s hepatic artery – the artery that supplies the liver. The idea behind this was that most or all of the viral particles would be taken up by the liver, where the new gene was needed, and the rest of the body would be spared any ill-effects of infection by the virus. To reach the hepatic artery, Raper would have to insert a flexible cannula into the femoral artery in Jesse’s groin and thread it backward up the aorta, in a similar fashion to what is done for coronary angiography. The infusion of the vector would take a few minutes, he said, and Jesse would have to lie still for several hours afterward. Over the following days, blood tests would be done to check whether there was any effect on Jesse’s ability to metabolise ammonia. Then, a week after the infusion, Raper would remove a small sample of Jesse’s liver by means of a needle stuck through the front of his abdomen. This biopsy sample would be studied to test whether the vector had been taken up by the liver cells, whether the new gene was working and whether the vector had caused any damage to the liver. Raper emphasised that, although the infusion might cause some brief improvement in Jesse’s ability to excrete ammonia, it would not offer him any long-term benefit. The benefit might come eventually to others, especially to OTC-deficient babies: the vector might help tide them over their first neonatal crisis and save them from immediate death or brain damage. In the long run, the hope was to develop other vectors that would implant the OTC gene more permanently in the children’s genomes.

The informed consent form mentioned a laundry list of possible ill-effects that Jesse might suffer. It was quite possible that he would experience mild flu-like symptoms over the day or so after the infusion. Blood clots might break loose. The vector might cause hepatitis. The needle biopsy might cause a haemorrhage. There might be unforeseen harmful consequences. Jesse signed the consent form, and he had blood drawn to measure his ammonia level. Then he underwent a several-hour test in which he had to drink a sample of ammonia labelled with a non-radioactive isotope of nitrogen (15N). The fate of the nitrogen in this test would reveal how efficient Jesse’s metabolism was at getting rid of ammonia.

Once out of the hospital, the family did a bit of sightseeing: they went over to the Spectrum Arena to see the famous statue of Sylvester Stallone as Rocky Balboa. A photo of Jesse standing in front of Rocky, his arms raised high in triumph, later accompanied many news stories about him, and it still can readily be found on the internet. It aptly illustrated the new and positive focus that participation in the OTC trial had injected into his life – a life that otherwise was drifting rather aimlessly. After another day of sightseeing, this time in New York, the family returned to Tucson, where Jesse waited to hear more from the Penn team.

‘Informed consent’ is really a figure of speech. No layperson can truly evaluate the potential risks and benefits of participating in a clinical trial, least of all the trial of a genetically engineered virus. To some extent, signing a consent form is a confession of faith – faith that the researchers have done their homework and that the experimental protocol has been adequately reviewed by experts. In the case of Wilson’s OTC trial, it looked like the review process had been extraordinarily thorough. Wilson’s protocol for the study had been reviewed by the University of Pennsylvania’s Institutional Review Board (IRB), the US National Institutes of Health and the FDA. It had also undergone a special review by the FDA’s Recombinant DNA Advisory Committee, or RAC – a group that vetted protocols involving genetically engineered viruses and other biological therapies.

Yet all had not gone smoothly during the approval process. For one thing, there had been setbacks during the animal testing that preceded the clinical trial. Three monkeys who had received very high doses of the vector developed severe liver failure combined with a blood-clotting disorder, and they had to be killed.

In reaction to these deaths, Wilson prepared a second version of the vector that he claimed was safer. But was it? In 2006, I put this question to Inder Verma, a leading virologist and gene-therapy expert at San Diego’s Salk Institute. ‘It’s possible,’ Verma said, ‘but he had no proof of that. And in fact it’s ironic, because we proved later on that every batch of adenovirus had that problem; it didn’t matter whether it was the first, second or third version. The viral proteins are going into cells and [causing them to be] recognised as foreign by cytotoxic T lymphocytes, which destroy them.’

Some of the initial reviewers had serious reservations about the study. Among them was Robert Erickson, a paediatric geneticist at the University of Arizona who was a member of the RAC. In a 2006 interview, Erickson told me that he had been concerned by the adverse events in the animal studies and also by Wilson’s plan to infuse the vector into the hepatic artery, which Erickson viewed as a risky procedure. He changed his mind when Wilson described changes to the vector and also agreed to infuse it into a peripheral vein. (That change got reversed by a subsequent FDA panel.)

In the final plan for the trial, the vector would be administered to 18 adult volunteers. The volunteers were to be in good health, with their OTC deficiency under reasonable control, which meant their plasma ammonia concentrations could be no higher than 70 micromoles per litre (µM/L) – about twice the maximum level seen in healthy people. The volunteers would be divided into six cohorts, with three volunteers in each cohort. The volunteers in the first cohort would receive a tiny amount of the vector, and – assuming there were no ill-effects – the dose would be increased stepwise until the sixth cohort received the maximum dose. If there were serious adverse effects, they would have to be reported to the FDA before the trial could proceed further.

Another safety consideration had to do with the sex of the volunteers. Because women, with their two X chromosomes, are generally less severely affected by OTC deficiency than are men, it was decided that the first two volunteers in each cohort would be women. Men, if they participated at all, could only be the third and last in a cohort. In that way, the doctors would already have some experience with that dose level before they treated a man. Jesse would therefore be the last of his cohort to receive the vector.

A few weeks after the visit to Philadelphia, Jesse and Paul got a letter from Mark Batshaw, the OTC deficiency specialist on the Penn trial. Batshaw wrote that Jesse’s test results made him an acceptable subject for the trial. His blood ammonia was below the cut-off level of 70 µM/L, and his efficiency at excreting ammonia, as measured by the 15N test, was six per cent of normal. Because of this very low efficiency – the lowest of anyone in the trial – any increase in ammonia excretion caused by the viral OTC gene would be readily apparent.

Soon after, Paul Gelsinger had a phone conversation with Batshaw in which, according to Paul, Batshaw mentioned the good results they’d had to date. In experiments on OTC-deficient mice, he said, the gene transfer had worked so well that the mice had been protected from what would otherwise have been a lethal dose of ammonia. And because the human trial had now been under way for more than a year, Batshaw was able to give Paul some idea of the early results. The most recent of the volunteers, he said, had experienced a 50 per cent increase in the efficiency of her ammonia excretion after the infusion of the vector. He did not mention any adverse events in the human subjects, according to Gelsinger. In a brief 2007 email exchange, Batshaw confirmed to me the general content of the conversation but said that he remembered having told Gelsinger of adverse effects, including fever and short-term liver abnormalities. (Batshaw – like Wilson and Raper – declined my request for an interview.)

Both Paul and Jesse reacted with enthusiasm to this news, and Jesse was doubly excited about participating. Because the trial was now nearing its end, Jesse would be in the final cohort and he would therefore receive the highest dose of the vector. But he would have to cool his heels for a while because, as a male, he would be the last of the three volunteers in that group. Thus, he would be the final subject in the entire trial. His infusion was scheduled for October.

Jesse spent the intervening time working as a supermarket clerk and, in his free hours, riding a motorbike that his father and stepmother had given him as a graduation present. He seemed as upbeat and full of life as Paul had ever known him.

In mid-August, the co-ordinator of the clinical trial called to say that their next patient (the second patient in the last cohort) had a scheduling conflict, and that they would like Jesse to take her place. This would mean that the infusion would take place in September. Jesse agreed to the change of date.

Putting Jesse – a male – into the second position in a cohort was a clear-cut violation of the protocol that Wilson and his colleagues had agreed to. Wilson has never denied this, although public statements put out by the Institute of Gene Therapy have maintained that the FDA OK’d a similar switch in an earlier cohort, so Wilson felt entitled to make the switch in this cohort too, even without express permission.

According to Paul Gelsinger, the reason for the switch was not that the other patient had a problem with the September date, but that she backed out of the trial altogether. (I was not able to ask any of the investigators directly about this, however.) If the other patient did drop out, it might have seemed best to infuse Jesse right away and wrap up the trial, rather than endure the delays involved in recruiting another volunteer. ‘They just wanted to finish,’ Inder Verma speculated, ‘because this was the last dose and they wanted to stop and get it over with.’

Unknown to Jesse or his father, a number of untoward events occurred at Penn prior to Jesse’s visit. Several of the earlier volunteers experienced significant liver damage from the adenovirus infusions. The damage was assessed by measuring enzymes, such as transaminase, that were released from dying liver cells into the bloodstream. Even as early as June of 1998, one of the volunteers who had just been infused with the adenovirus vector experienced a surge in her serum transaminase levels to nearly eight times the upper limit of normal.

This finding indicated very significant damage to the woman’s liver, even at a dose of the vector far below that which Jesse was scheduled to receive. It was a ‘grade-III adverse event’ on the scale of severity established by the FDA, but Wilson reported it to the FDA as a milder ‘grade-II’ event. Another grade-III event (a high fever) was also reported as grade-II. Numerous other volunteers experienced grade-II adverse events – in fact, there were grade-II or grade-III events in every cohort from the second one onward. According to Paul Gelsinger, all four of the volunteers who immediately preceded Jesse experienced grade-III liver toxicity, but I could not find independent documentation of this. Nevertheless, an official letter of reprimand later sent to Batshaw by the FDA listed five grade-III adverse events, two involving liver toxicity and three involving high fever.

The protocol called for halting the trial for regulatory review if there was a single grade-III event or at least two grade-II events, but the Penn researchers did not halt the trial. They reported the adverse events many months after they occurred, if they reported them at all, and often the information was hidden in the back pages of their reports, while the summaries at the front were much more positive. In the cover letter to his IRB report of August 9, 1999, for example, Wilson wrote as follows: ‘No serious adverse effects have occurred as a result of this study. There have been no significant treatment-related toxicities or procedure-related toxicities, and all participants have remained well.’ Much later, the usually circumspect FDA described this statement with a simple and damning adjective: ‘False’.

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 15N 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.

In mid-2002, after critical assessments by the independent review panel, Wilson resigned as director of the Institute for Human Gene Therapy. Soon thereafter the institute itself was closed down.

The Gelsinger lawsuit and the closure of the institute were not the only woes that Wilson and his colleagues faced, however, because the FDA also sought retribution on the Penn team, and it did so with a single-minded focus and almost nitpicking attention to detail that far outdid its performance while regulating the clinical trial itself. Over months and years, long lists of allegations flew from Washington to Philadelphia, and even longer explanations and refutations flew back from Philadelphia to Washington. The core of the government’s case was that Wilson and his co-investigators had failed to stop the clinical trial or to properly notify the FDA when earlier participants in the trial developed severe adverse reactions to the infusion of the adenoviral vector, and that they proceeded with the infusion of Jesse Gelsinger when his high ammonia levels should have disqualified him from participation. Absent these misdeeds, Jesse would not have died.

Eventually, the FDA turned the matter over to the US Department of Justice. The DOJ brought a formal action against Wilson, his colleagues and their institutions, alleging that they had committed numerous violations of the Civil False Claims Act in their dealings with the NIH and the FDA.

Finally, in February of 2005, a settlement was reached. Under the terms of the settlement, none of the defendants admitted to the government’s allegations, but the University of Pennsylvania and the Children’s National Medical Center each agreed to pay a penalty of more than $500,000 and to enact numerous changes to strengthen the oversight of clinical trials. Wilson was banned from participating in clinical trials until 2010, and a special monitor was to be appointed to oversee his other research activities. He would have to undergo retraining if he ever planned to participate in clinical trials again. In addition, he was to write and publish an article describing the ‘lessons learned’ from the entire episode. Batshaw and Raper were placed under government supervision for a period of three years and would have to undergo retraining.

These were severe punishments for ambitious clinical researchers, but Paul Gelsinger doesn’t see it that way. ‘They got off easy, amazingly easy,’ he said to me. ‘It was medical manslaughter.’ The fact that Wilson never apologised or admitted any culpability for Jesse’s death was particularly galling to him.

With Batshaw and Raper it was a little different. Whereas Paul never met Wilson until after his son’s death, he had established some rapport with both Batshaw and Raper and had witnessed their efforts to save Jesse’s life. Although they may not have explicitly apologised or admitted culpability, Paul read their actions as expressing a desire for forgiveness. Raper, after all, climbed 5,000 vertical feet with Jesse’s family to scatter a portion of his ashes. And Batshaw, about a year after the settlement, sent Paul an email in which he said that his thoughts had turned to Jesse on the occasion of Yom Kippur, the Jewish Day of Atonement. Later the two men met briefly. Paul acknowledged to me that both Batshaw and Raper were genuinely torn up by what happened. ‘I’d like to see these guys find forgiveness for what they did,’ Paul told me. ‘But part of that is acknowledging what you’ve done.’

Did the tragedy of Jesse’s death, the ensuing publicity, the investigations, the legal manoeuvres and the ensuing tightening of regulations improve the safety of clinical trials – whether in the specific area of gene therapy or for drug research in general? To Robert Erickson, the University of Arizona geneticist who reviewed Wilson’s initial proposal, the answer is Yes. He said that, after it was revealed that Wilson had failed to report his volunteers’ adverse reactions, 700 such reports came in from other clinical investigators within a period of just a few days. ‘I think people are reporting adverse reactions much more quickly,’ he said.

Arthur Caplan takes a less positive view. ‘Paul Gelsinger tried to bring about changes so that the same thing wouldn’t happen to anyone else,’ he told me. ‘He went to a lot of meetings, he fought for subject rights, he gave of himself in a very powerful way, he became committed to trying to make change. But you know what I think the legacy of Jesse’s death was for human subjects reform? Almost nothing. Many of the problems that existed then still exist now: failure of informed consent to work well, IRBs still overwhelmed with work, no clarity on the animal data reports, difficulties in getting subject selection criteria properly understood. I would say no, it’s no better.’ And he went through a litany of clinical trials that have gone seriously wrong since Jesse’s death.

One particularly nightmarish episode occurred in 2006 – not in the United States, but in Britain. In March of that year, a drug-testing company named Parexel conducted the initial human trial of the immune-system modulating drug TGN1412, which had been developed by a German biotech company named TeGenero. The drug was a monoclonal antibody – an immune-system molecule that binds to a single molecular target in the body. The antibody was designed to stimulate the class of white blood cells known as T cells, and the hope was to utilise this effect in the treatment for rheumatoid arthritis and a certain form of leukaemia.

After uneventful trials in laboratory animals, Parexel recruited eight healthy volunteers – all men – for the initial human trial, which was to be conducted at Parexel’s unit at Northwick Park Hospital in North London. The volunteers included Navneet Modi, a 24-year-old business school graduate, Ryan Wilson, a 20-year-old trainee plumber and Mohammed Abdalla, a 28-year-old bar manager. Each of the eight subjects was to receive £2,000, a sum well above what is customary for participation in drug trials in the United Kingdom. In fact, some of the men were basically professional guinea-pigs. They derived a significant portion of their income from volunteering for drug trials. (Jesse Gelsinger, in contrast, was never offered any financial incentive to participate in the Penn trial.)

Two of the subjects received an inactive placebo, while the other six men were infused with the drug at a dosage of 0.1mg/kg. This level was considered safe because monkeys had tolerated dosages 500 times higher without any apparent ill-effects. Each infusion took about two minutes, and the eight infusions were done one immediately after the other, so that the whole procedure took about 20 minutes.

‘An hour after the drug entered my body, I was suddenly gripped by pain,’ Modi later told The Times. ‘I felt my head swelling up like an elephant’s. I thought my eyeballs were going to pop out. I screamed out, “Please, doctor, help me. Help me,” but he told me to lie down, and then came back with a single paracetamol tablet. It felt like a terrible nightmare.’

All six of the subjects who received the TGN1412 became extremely ill. They were experiencing the same kind of ‘cytokine storm’ that had killed Jesse Gelsinger.

Their heads and bodies grotesquely swollen, they were rushed into intensive care. Within 12 hours, their lungs, kidneys and other organs were starting to fail, and their blood pressure fell to dangerous levels. The subjects were treated with massive doses of steroids and other immune-suppressing drugs, and they underwent dialysis in an attempt to remove the TGN1412 from their bodies.

Four of the men began to recover within two days, but two men – Wilson and Abdalla – became critically ill with cardiovascular shock and respiratory distress syndrome, and were maintained on respirators and other life-support systems for many days. Eventually, all of the subjects recovered sufficiently to be discharged from the hospital, but they have had serious ongoing medical problems, including blackouts. Wilson had to have gangrenous toes and fingertips amputated, and all of the subjects are considered to remain at high risk of cancer and immune-system disturbances; in fact, one of them was already reported to show early signs of lymphoid cancer four months after the drug trial. ‘It’s a really bizarre feeling when you discover you might be dead in a couple of years or even in a couple of months,’ said Modi. ‘I feel like I’ve given away my life for £2,000.’

Initial investigations into the cause of the medical disaster have failed to identify any human error, such as in dosage, that might have caused the drug trial to go so seriously wrong. Nor does it seem that the drug was contaminated with bacteria or with other toxic agents. Rather, it appears that this was an unforeseen reaction to TGN1412 in its intended dosage. Nevertheless, two aspects of the way the trial was conducted seem to have played key roles in causing the harm to be so severe. First, and most obviously, the researchers did not wait to observe the reaction of the first volunteer to the drug before infusing it into the other five. ‘To me, that was insane,’ commented Robert Erickson. Second, the researchers infused the drug at a very high rate – much faster than it had been infused into the monkeys. Adverse reactions are typically worsened by high infusion rates, so a slower rate might have caused lesser harm or none at all. Nevertheless, the investigation when complete may identify other more important causal factors.

Of course, a lawsuit is now in the works. But TeGenero, a recent biotech start-up, filed for bankruptcy in July 2006, citing the drying up of investment capital after the drug-trial story broke. Each subject reportedly received £10,000 in compensation from TeGenero before it went bankrupt, but the company’s insurance policy was for only £2 million, meaning that there will not be nearly enough money to adequately recompense the six men should the company be found liable. At time of writing, I understand there have been talks between the victims’ representatives and Parexel, but the outcome of these negotiations has not been disclosed.

Gene therapy took a terrible blow from the Gelsinger tragedy. Clinical trials came to a halt and were only restarted in the most restrictive and cautious fashion. In 2006 the ‘father’ of the field, USC’s William French Anderson, was convicted of child molestation and (in the following year) sentenced to 14 years’ imprisonment. Then, in July of 2007, another death occurred. This happened during a clinical trial of a genetically engineered vector designed to treat rheumatoid arthritis and related conditions. The vector, developed by a Seattle-based company named Targeted Genetics, employed a type of virus different from (and supposedly safer than) the adenovirus that killed Jesse Gelsinger. The trial was also thought to be safer because the vector was injected locally into the affected joint, rather than into the bloodstream. Yet the patient, who has never been identified, died after receiving a second dose of the vector. An NIH inquiry concluded that the injection of the gene therapy agent was not the cause of the patient’s death. Nevertheless, the event was a blow to Targeted Genetics. Its founder and CEO resigned in 2008, and the company is now in financial difficulties

In spite of these setbacks, Inder Verma sees a bright future for the field. He points to a dozen or so SCID-affected children who are alive today because of gene-therapy procedures that they underwent in France. ‘It will become a successful therapy,’ he says.