When 18-year-old Jesse Gelsinger died on September 17, 1999, in the first known death directly resulting from a gene therapy experiment, his father spoke admiringly of the doctors who had conducted the study. His father explained that Jesse had journeyed to the University of Pennsylvania (U. Penn) to volunteer for a clinical trial aiming to cure his rare metabolic disease - even though his condition was already under control with more conventional medicine - because Jesse hoped that his service would help save children with more severe cases and would someday lead to drug-free lives for all people with ornithine transcarbamylase (OTC) deficiency. Yet, a few months after his death, Jesse's father brought a lawsuit against James Wilson, the lead researcher in the study that killed his son. The Institute for Human Gene Therapy (IHGT), which Wilson led, is now prohibited from conducting clinical trials. And, the Food and Drug Administration (FDA) may soon ban Wilson from conducting clinical trials ever again.

According to reviews by the FDA, Wilson violated his own protocol on several occasions and was not truthful with regulators; his team enrolled ineligible patients and did not monitor them properly; and they did not report all the cases where patients had suffered serious side effects during the trial. Genovo, a company that Wilson cofounded, maintained close ties with IHGT and, apparently, had a financial interest in the OTC experiment, which Wilson had originally denied. In a blow to the reputation of the entire field of gene therapy, investigations by federal agencies and news organizations brought to light cases of scientists at other institutions who were not properly reporting illnesses and deaths in the course of their studies.

But it was U. Penn and the IHGT that came in for the heaviest barrage of negative publicity. A number of committees met, and continue to meet, to consider how to react, what new regulations to institute, and how to restore public confidence in clinical trials - which, after all, simply use human beings as experimental animals. It is understandable that people at U. Penn are skittish about any more attention. Some officials were reluctant to answer questions or offer comments for this article.

In February 2000, Judith Rodin, U. Penn's president, appointed a panel of professors unaffiliated with the university to evaluate IHGT's oversight of clinical trials and to recommend actions for future clinical trials at IHGT. The committee, headed by William Danforth, a chancellor emeritus at Washington University at St. Louis and a medical doctor, issued its report to the university president in May.

The university released the Danforth Committee Report to the media and announced a series of actions, inspired by the committee, to strengthen oversight and monitoring of clinical trials at U. Penn. The university banned IHGT from engaging in trials involving humans and suggested that the institute concentrate on basic science, animal models, and other preclinical work. IHGT had served as a central resource, supported by grants from corporations, as well as the National Institutes of Health and nonprofit foundations, sponsoring clinical trials for researchers affiliated with a number of academic departments at the university.

"We took primary responsibility for organization," explains Nelson Wivel, the present deputy director of IHGT, who is also affiliated with the Department of Molecular and Cellular Engineering at U. Penn. "Now principal investigators lack the infrastructure support [for clinical trials] that they had through IHGT before. . . . They can't rely on the corporate support that IHGT could offer before." IHGT still offers university members various services, for a fee, through their basic science cores. For example, IHGT staff members will construct a vector for a gene transfer experiment and continue to do gene transfer experiments on rodents and nonhuman primates.

After receiving the Danforth Committee Report, the university also instituted new guidelines for clinical trials throughout the university. The university announced, in a press release, that it would create a new database for tracking reviewers' concerns about trials, start a 24-hour hotline for reporting adverse events during trials, establish new requirements for training and education of staff involved in trials, and hire more people in the Office of Regulatory Affairs, who will assess the monitoring each clinical trial requires.

There are no plans to permit clinical trials at IHGT in the future; the university laid out no criteria for the institute to clear before it could resume conducting clinical trials. Still, a wide range of clinical trials do continue at U. Penn, including at least two clinical trials involving gene therapy, according to gene therapy researcher Katherine High, though, she notes, the accrual of subjects in gene therapy trials has slowed.

"There were clearly irregularities, as defined by the FDA" at IHGT, notes Inder Verma, a member of the Danforth Committee, a geneticist at the Salk Institute of Biological Studies and editor-in-chief of Molecular Therapy, the journal of the American Society of Gene Therapy. "IHGT cannot do clinical trials. U. Penn said that it didn't make sense for one institution to do it all."

Danforth says, "I think the University of Pennsylvania took action in a very responsible way." He continues, "Our committee felt, and most people I know believe, there's great promise for gene therapy for the future and that research should certainly continue. . . . The Gelsinger case had some effect, but gene therapy will go on." Meanwhile, Verma estimates that, if anything, the number of gene therapy trials in the country is going up. He sees no untoward effects from the Gelsinger death on the field of gene therapy or on the reputation of scientists, but believes that scientists have become more "sensitized."

"The only thing that has changed is that there's more clinical training," Verma says. "I'm optimistic because the fundamental technique and the fundamental concept are still very strong. Execution is just a matter of technology." With fortunate timing, the bombardment of bad publicity about gene therapy was leavened by the news last year that French researchers apparently succeeded in curing severe combined immunodeficiency (SCID) in a small number of children by supplying them with new genes. A New York Times editorial headline sounded relieved: Success in Gene Therapy, At Last. After a decade of scientific disappointments, careful, painstaking research in gene therapy appears to be yielding fruit.

The field of gene therapy has emerged intact after a rocky year-and-half. Only the general innocence about clinical trials appears to have faded. The public knows better what the scientists conducting such trials have always known. "Clinical trial are inherently risky. We all know that," says Danforth. Jesse Gelsinger's death "was a tragedy. Other tragedies could happen. We can hope that it will never happen again, but that would be an overoptimistic hope."