When Science Goes Wrong (20 page)
The complete order of events, as visualised by Rogers, was roughly as follows. Reservoir water entered the foundations of the left abutment, causing hydrostatic uplift of the abutment and promoting an incipient landslide. Failure of a segment of the dam near the base of the abutment opened an orifice that allowed high-pressure water to extend the hydrostatic uplift to the central section of the dam and to trigger a massive landslide that collapsed the entire abutment. As the landslide material was washed away, a scouring of the dam’s foundations caused the leftmost part of the central sector of the dam to collapse. The remaining portion of the centre of the dam did not fall, but it tilted and (as was determined by triangulation after the disaster) moved slightly to the east. This caused a separation from the right abutment, which therefore lost its stability and collapsed, allowing water to pour through on that side too. Rogers calculated that the maximum rate of flow past the collapsed dam and down the canyon was about 1.7 million cubic feet per second, which is nearly three times the average flow of the Mississippi River at New Orleans. The reservoir emptied in less than an hour.
The Los Angeles Department of Water and Power soon replaced the broken dam with a new, earthen dam in a nearby canyon, and with time the St. Francis Dam and its tragic demise faded from memory. Still, the disaster had wide-ranging consequences for dam-building elsewhere. For a start, several committees looked into the question of what to do with the Mulholland Dam. Eventually, it was decided that the dam could be operated at a lower reservoir level, but as a precaution against failure 300,000 cubic yards of earth fill were placed against the dam’s downstream face, completely burying its elegantly stepped facade. The construction of a much higher dam in San Gabriel Canyon, east of Los Angeles, was halted when a Berkeley geologist discovered that the western wall of the canyon, much like San Francisquito Canyon, was the site of an ancient landslide.
The disaster also caused great concern for the designers of the Hoover (or Boulder) Dam on the Colorado River, then in the planning stage. Politicians opposed to the dam, such as the governor of Arizona, used the disaster in their campaign to prevent the dam’s construction. Although the dam, when finally built, incorporated some design changes that took account of the failure of the St. Francis Dam, it nevertheless experienced some percolation of reservoir water into its foundations, and gradually increasing hydrostatic uplift pressures were measured. Finally, in the 1950s, a programme of pressure grouting of the dam’s foundations reduced seepage to an acceptable level.
A tragic repeat of the St. Francis disaster occurred in 1959. The Malpasset Dam, near Fréjus in the south of France, collapsed when the reservoir was filled for the first time, killing between 400 and 500 people. As with the St. Francis Dam, it appears that the collapse was caused by hydrostatic uplift of the dam’s left abutment, according to an analysis by Electricité de France.
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.
