by Simon Levay
Today, the problem of hydrostatic uplift is well understood, and extensive steps are taken during a dam’s design and construction to prevent seepage of water under a dam, to drain whatever water does penetrate, and to monitor uplift pressures. Still, other modes of failure are possible. If water enters a dam’s reservoir faster than the sluicegates or spillway can discharge it, for example, the reservoir will overflow the dam and likely destroy it. This occurred in China’s Henan Province in August 1985. Storms that had been spun off by a typhoon dropped 40 inches of rain on the area within the span of three days. A total of 62 different dams on two rivers overflowed and collapsed in a chain-reaction that cost the lives of an estimated 85,000 people.
After the failure of the St. Francis Dam and the subsequent inquiries, William Mulholland resigned his position as chief engineer and general manager of the Department of Water and Power. Already in his 70s, and beset by a neurological condition that may have been Parkinson’s disease, Mulholland lived the remaining seven years of his life out of the public eye. He is often described as a ‘broken man’ in his final years. Considering the torrent of verbal abuse that he experienced after the disaster, it would not be surprising if his spirit had been broken, yet it was not, according to a memoir penned by his granddaughter, Catherine Mulholland. Catherine describes her conversations with William Mulholland’s nephew, also named William, who worked with him and knew him intimately as a family member. ‘He was not broken by that mishap,’ the nephew told Catherine, ‘because he never accepted the responsibility of something that was beyond his power.’
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.’
So
me 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.