As many would-be biotech entrepreneurs have learned, one of the scariest things about bringing a new biomedical technology into the world is when an unexpected and very public problem crops up, especially during clinical trials. You can’t tell if you’ve merely hit a bump in the road or run smack into a brick wall. At the moment of impact, they feel much the same.
The road to gene therapy, which has been nothing if not rocky over the last two decades, hit another one of those sickening bumps last September, when word spread from Philadelphia that a fatality had occurred in a gene therapy trial at the University of Pennsylvania’s Institute for Human Gene Therapy. Eighteen-year-old Jesse Gelsinger, according to university officials, died four days after receiving experimental treatment for a genetic disorder known as ornithine transcarbamylase (OTC) deficiency. In reporting the episode, publications like the Wall Street Journal suggested that the death was “raising new questions” about a beleaguered technology.
As readers of my book A Commotion in the Blood already know, I’ve cast a pretty jaundiced eye on the extraordinary hype and the extraordinarily unimpressive results that have come out of this area of research so far. The field’s pioneering practitioners seemed at least as interested in making history as in making patients better when the first authorized attempt at gene transfer occurred at the National Institutes of Health in 1989; more than a decade later, after hundreds of clinical trials, there has yet to be published a single study
that unambiguously demonstrates gene therapy works. It is typical of the headlong (or is it headstrong?)ambition of the field that we now learn of other deaths in clinical trials, which went unreported to the NIH at the discretion of the investigators (many of whom relinquish the moral high ground when they have financial interests in the work).
For all that, this technology has immense intuitive appeal. The idea of turning engineered viruses into biological smugglers, using their evolutionarily honed ability to infiltrate cells and insinuate therapeutic DNA into the cell’s chromosome, strikes almost everyone as an elegant and supremely clever way to correct enzymatic deficiencies and other genetic diseases. Indeed, the swelling list of genes identified by the
Human Genome Project provides an attractive list of potential cargo for these viral vectors to deliver.
For a more general perspective, there was only one expert whose views I was interested in: Theodore Friedmann, professor of pediatrics, biomedical ethicist and director of the gene therapy program at the University of California, San Diego. Over the last two decades, Friedmann has worked on the science, charted the hype and chastised journalists and headline writers. He has also perfected the long view, in an
age when even scientists who should know better seem hellbent on instant gratification. “At worst, I think it’s another pothole in the road,” he said from San Diego.” There is no question in any reasonable person’s mind that the overall approach makes sense and is going to pay off in the future in the clinical treatment of disease. It’s beyond retrieval. It’s born, and it can’t be unborn.”
It might sound cold to liken a death to a pothole, but Friedmann refused to play the Claude Raines role here and profess shock-Shock!-that such a thing could occur. “Things happen,” he said, “That’s why it’s called research. We don’t know what’s going to happen. And, in general, it’s not a surprise that these kinds of things will happen.” Despite those legalese disclaimers warning of uncertainty and risk on company prospectuses, the day-to-day syntax of biotechnology, the inflection in the voices that promote it, the body language of its
enthusiasts, is all inevitability: We will insert these genes, we will engineer these viral vectors, we will slam them in and we will get them to work, doing what we want and where we want. But science, especially cutting-edge science, remains steadfastly unpersuaded by imperative entrepreneurial verbs. Just last June, Phillip A. Sharp, a director at Biogen, spoke glowingly about a new drug in the pipeline called Antova, which was in advanced clinical trials; in October, Biogen halted clinical trials because of unexpected side effects.
Things happen, including deaths. Horrified as the biomedical research community was over the death of this bright and courageous young patient at Penn, fatalities are going to be part of the equation of progress in this business. They will often be unexpected and they will always be shocking, but they are, unfortunately, the price of admission to 21st century medicine. One hopes the field honors Jesse Gelsinger’s death as it would any unexpected observation in an experiment:as an opportunity to learn something new, and perhaps something important, about the way nature works. And one hopes that the failure of some investigators to be forthcoming about all their data will not mortally compromise the future of gene therapy precisely when it seems poised to hit smoother pavement.
“By and large, the trajectory of gene therapy is still correct,” Friedmann said. “Within a year or so, there will probably be the first credible, believable clinical results. Perhaps that will be ballyhooed, too. But at least then we’ll know that there’s a There there.”