Severe Setback: James M. Wilson ran the institute where a fatal gene therapy experiment occurred in 1999. He now offers advice to stem cell researchers so that they can avoid similar mistakes.
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Philadelphia—Ten years ago this month the promise of using normal genes to cure hereditary defects crashed and burned, as Jesse Gelsinger, an 18-year-old from Tucson, Ariz., succumbed to multiorgan failure during a gene therapy trial at the University of Pennsylvania. Today the boardroom of the Translational Research Lab at the university is filled with artifacts reminiscent of the trial. Books such as Building Public Trust and Biosafety in the Laboratory sit on the shelves, and “IL-6” and “TNF-α” are scribbled on the whiteboard—abbreviations representing some of the very immune factors that fatally spiraled out of control in Gelsinger’s body.
These allusions to the past aren’t surprising considering how drastically the clinical trial changed gene therapy and, in particular, the career of James M. Wilson, the medical geneticist who headed Penn’s Institute for Human Gene Therapy, where the test took place. The U.S. Food and Drug Administration banned it from conducting human trials, and Wilson left his post at the now defunct institute (but he continued doing research at Penn). He disappeared from the public spotlight until 2005, when the agency announced he could begin clinical trials with a designated monitor but could not lead trials for five years and asked him to write an article about the lessons he has learned. He published it in Molecular Genetics and Metabolism this past April. Since then, he has begun giving university lectures about the importance of exercising caution as a clinical scientist, especially when it comes to stem cells, which today have the cachet once held by gene therapy.
Wilson talks about what happened in 1999 with a quiet deliberateness suggestive of a painful topic. “With what I know now, I wouldn’t have proceeded with the study,” he says in the boardroom, his back facing the whiteboard. In the 1990s scientists such as himself, he explains, were too caught up in the promise of gene therapy to realize that they did not know enough about it to warrant human testing. “We were drawn into the simplicity of the concept. You just put the gene in,” Wilson says.
The trial he conducted tested the safety of a therapy for ornithine transcarbamylase (OTC) deficiency, a rare disorder in which the liver lacks a functional copy of the OTC gene. The defect prevents the body from eliminating ammonia, a toxic breakdown product of protein metabolism. The Penn scientists had engineered a weakened adenovirus, or cold virus, to deliver a normal copy of the OTC gene into the liver.
Seventeen patients had undergone treatment before Gelsinger, who was in the final cohort—the one receiving the highest dose of the therapy. Many scientists, as well as the FDA, have raised questions as to why Gelsinger was being treated, given that several patients in earlier cohorts suffered severe liver reactions. Wilson says that they moved forward because it was “the kind of toxicity we would have expected,” based on their work in animals, and they thought it would be manageable. According to Mark Batshaw, director of the Children’s Research Institute at the Children’s National Medical Center in Washington, D.C., Wilson and the rest of the scientific community had to learn the hard way “that what you’ve learned from animals will not necessarily predict what’s going to happen in humans.” Batshaw was also involved in the 1999 trial.
The FDA questioned the decision to treat Gelsinger for other reasons, too. Just before starting treatment, Gelsinger—who suffered from a mild form of the disease—had high levels of ammonia in his blood, indicating that his liver was not functioning well. But because his levels were within acceptable parameters when he had enrolled in the trial three months earlier, the scientists moved forward anyway. Wilson, who was responsible for the protocol and its compliance, admits now that “the protocol was not written in a way in which there was enough clarity to know when the ammonia had to be what [level], and that was a significant shortcoming.”
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13 Comments
Add CommentWhether it is the tone of the author, or that there is an actual lack of sincerity in Glesingers comments on the result of his experiment Im not sure. But Gelsingers failure to acknowledge the loss of life his rash actions and his direct responsibility is quite disturbing. the protocol was not written in a way in which there was enough clarity to know when the ammonia had to be what [level], and that was a significant shortcoming. This statement is shockingly obvious to me to be a sick attempt at avoiding the blame he claims to accept. From what I can gather from this article his lesson learned was how not to be the person who catches the blame when things go wrong, not how to be more cautious when dealing with another human beings life. I think the only person he is convincing of his regret and remorse is himself.
Reply | Report Abuse | Link to thisWhether it is the tone of the author, or that there is an actual lack of sincerity in Glesinger’s comments on the result of his experiment I’m not sure. But Gelsinger’s failure to acknowledge the loss of life his rash actions and his direct responsibility is quite disturbing. “the protocol was not written in a way in which there was enough clarity to know when the ammonia had to be what [level], and that was a significant shortcoming.” This statement is shockingly obvious to me to be a sick attempt at avoiding the blame he claims to accept. From what I can gather from this article his lesson learned was how not to be the person who catches the blame when things go wrong, not how you should be more cautious when dealing with another human beings life. I think the only person he is convincing of his regret and remorse is himself.
Reply | Report Abuse | Link to thisWell ... I dunno. I didn't think "insincere" or "sick attempt" ... not even after rereading the story twice after reading Ameyjo's comment.
Reply | Report Abuse | Link to thisIt is easy to stand in judgment.
I'm sure he had long and hard thought about his guilt during his 6-year ban from performing clinical trials, and maybe at this point his comments are targeted at the current clinical researchers reading the article who could learn from what happens when a protocol isn't properly thought out or reviewed by other specialists...but hey, I'm an optimist when it comes to human nature
Reply | Report Abuse | Link to thisI'm glad that today we have all these protocols preventing dangerous accidents, but a certain part of me wonders if it's really in the best interest of science. Would past scientists have made the discoveries they did if they were so afraid of the potential consequences? I have no desire to see further loss of life, but in many fields of science some risk is required to reap the full benefits of research. Just think of what would have happened, had this trial gone according to plan - Gelsinger would have been celebrated and at the most chided briefly for the risk, and the technology developed could have saved countless lives.
Reply | Report Abuse | Link to thisThere seems to be a double standard in experimentation that goes something like this: "We'll let you experiment as long as the outcome isn't disastrous". Sometimes experiments do go horribly wrong, in ways we can't predict. This particular case isn't a great example (as they could have predicted some of the danger), but experimentation is founded on the idea of poking and prodding science we're not totally sure about. We shouldn't shy away from gene therapy simply because there's risk involved.
SciAm writes:
Reply | Report Abuse | Link to thisWilson argues, clinical scientists should always ask themselves this question: If the worst-case scenario played itself outnot the potential or likely, but the worstwould that be acceptable? If he had asked himself that question in 1999, Wilson says, he would not have proceeded.
This is the kind of question so often ignored in *any* kind of risk management discussion, not just in a scientific context. This is why the banking industry fell apart, health care is in crisis, companies are laying off/not hiring people. People tend to write off the worst case scenario as statistically unlikely and therefore not worth consideration, instead of seriously asking, "What will we do if the worst happens?"
Regardless of Dr. Wilson's feelings (which read as sincere to me, although obviously I can't look out of his eyes), the message he is promoting is a valuable one, worth incorporating in any discussion of risk.
Ameyjo, Gelsinger was the name of the person who died during the trial; Wilson is the name of the doctor who ran the trial. Aside from that, I disagree with you. Wilson appeared sincere enough to me.
Reply | Report Abuse | Link to thisThank you danshil, I thought I was crazy for a minute with Dr. Wilson's name confused. Not only did he sound sincere to me - though I wished I could read the whole text on his " lessons learned "- but I am convinced his actions will teach all of us.
Reply | Report Abuse | Link to thisOops - just realized I made that mistake too. Thanks danshil.
Reply | Report Abuse | Link to thisSeems to me Dr. Wilson is being candid about this protocol. . In order for Science to become good Medicine clinical trials must eventually be done in humans. Clinical trials,(especially Phase I trials in which a new drug or device is first used in humans) are always risky. If the patient fully understands the potential risks and benefits involved and makes a decision to participateI think it's an ethical and often noble process. Many patients with terminal illness find alot of satisfaction in finding a cure even if only the next guy may receive a benefit. Bottom line...Protocols are tough to write and review but most of the time the process works well.
Reply | Report Abuse | Link to thisthere is no benefit without some risk! even if you live in a ball of cotton, you risk small airway dis-ease! not to mention problems of nutrition, excretion and increased fire risks! worst case scenarios/disaster? you can exaggerate to the point of absurdity! INFINITE SAFETY TAKES INFINITE RESOURCES! unfortunately true, be real!
Reply | Report Abuse | Link to thisSee the commentary by Jesse Gelsinger's father, Paul Gelsinger, in The Philadelphia Inquirer, http://www.philly.com/inquirer/opinion/20090917_Seeking_justice_for_my_son.html
Reply | Report Abuse | Link to thisI was deeply touched by Dr.Wilson experience. I believe in his sincere words and I regret his misfortune, that is to be shared with all mankind. It is very hard to deal with trials involving human lives, but forward it will be a further stone covering the science way.
Reply | Report Abuse | Link to thisMRLacerda.