SANCTIONS

Wilson’s Explanation Rejected

The U.S. Food and Drug Administration last month rejected a letter of explanation by Dr. James M. Wilson, director of Penn’s Institute for Human Gene Therapy (IHGT), concerning allegations that he violated safety procedures in a clinical gene-therapy trial that resulted in the death of 18-year-old Jesse Gelsinger in 1999. Saying that his written explanations “fail to adequately address the violations,” the FDA offered him a regulatory hearing to determine whether he will be “entitled to receive investigational new drugs.” As the Gazette went to press last month, it was not known whether he would participate in such a hearing.

Wilson’s letter to the FDA, written last March, was a response to charges that he had “repeatedly and deliberately violated federal regulations” as an investigator in clinical trials using human subjects—and to being informed that proceedings were being instituted to prevent him from conducting further genetic testing on human subjects [“Gazetteer,” March/April 2001].

Gelsinger suffered from a hereditary liver disorder known as ornithine transcarbamylase deficiency (OTCD), which prevents the liver from properly processing ammonia. Scientists at the IHGT had developed a technique for delivering corrective genes into the liver through an injection of a modified cold virus, but several days after receiving the drug in September 1999, Gelsinger died of acute-respiratory-distress syndrome and multiple-organ failure.

After the FDA found “numerous serious deficiencies” in the oversight and monitoring of the OTCD trial, Wilson and the researchers at the IHGT acknowledged certain lapses in protocol, but argued that those lapses did not contribute to Gelsinger’s death. In September 2000, the Gelsinger family filed a lawsuit against the University, Wilson, and several other scientists connected with the incidents; six weeks later, the case was settled out of court.

“This most recent letter is a continuation of the administrative procedures that were begun by the FDA two years ago,” said Wilson, the John Herr Musser Professor and Chair of Molecular and Cellular Engineering, in a statement. “I will continue a dialogue with the FDA in an effort to reach a resolution satisfactory to all parties.”

In his letter to Wilson, Dennis E. Baker, the FDA’s associate
commissioner for regulatory affairs, said that the agency’s offer to enter into a consent agreement “remains open.” No final decision has been made on Wilson’s eligibility to continue using “investigational drugs,” Baker added.


Previous issue's Gazetteer | Mar/Apr Contents | Gazette home


 

SYMPOSIUM Pondering the Ethics and Science of Stem Cells “I’m hopeful about the future of stem cells—but I have a lot of concerns,” Dr. John Gearhart was saying at a recent symposium on stem-cell research at Penn’s School of Medicine. Continued...

STUDENT ACTIVITIES The Art of Youthful Exhibitionism Last September, the Arthur Ross Gallery and the art-history department launched a new museum-studies seminar. That in itself was not remarkable; nor was the fact that it focused on the creation and development of an exhibition. What was unusual was the fact that it was designed for undergraduate art-history students—and that it would quickly lead to their curating an important exhibition on campus. Continued...
Photo by Jim Graham

HONORS Nobel, Nobel, on the Wall … “Science is people,” Dr. Alan MacDiarmid, the Blanchard Professor of Chemistry, was saying in his resonant, New Zealand-accented baritone. “You can have the most beautiful buildings and you can have the most beautiful laboratories—but you have to have the right people working in those laboratories.” Continued...

SYMPOSIUM What Price Religious Freedom? “In light of the attacks on September 11th, we have had to reconsider the relative importance of many things,” Cardinal Anthony Bevilacqua, archbishop of Philadelphia, was saying to an audience in Irvine Auditorium this past November. “But the role of religion is not one of them.” Continued...

GRANTS Medical School Gets Sweet Diabetes Grant The School of Medicine has been awarded a grant worth more than $15.5 million for diabetes research from the Juvenile Diabetes Research Foundation International (JDRF). The money will go to two centers at the medical school: the JDRF-W.W. Smith Charitable Trust Center for Islet Transplantation and the JDRF Center for Gene Therapy. Continued...

RESEARCH

 


Turning Back the Clock on Stem Cells

A group of researchers at Penn and other universities has identified a receptor that plays a key role in restricting embryonic stem cells’ pluripotency—the ability to develop into virtually any one of an adult animal’s many kinds of cells. By repressing that mechanism, it may be possible to find new ways of creating embryonic stem cells without using embryos, says Dr. Hans Scholer, the Marion Dilley and David George Jones Chair in Reproduction Medicine and associate professor of reproductive physiology at Penn’s School of Veterinary Medicine.

Although Scholer and his colleagues were using mouse embryos for their experiments, the implications of their discovery are considerable, given the ethical, political, and practical issues involved in using human embryos. (Last August, President George W. Bush announced that federally funded research would be limited to those stem-cell lines already harvested from frozen embryos, prompting many researchers to seek alternative sources.)

The receptor, known as GCNF (for Germ Cell Nuclear Factor), is the first factor known to repress the Oct4 gene, which is expressed in pluripotent embryonic cells.

“In a sense, we’re hoping that understanding what GCNF actually does as it shuts down genes will let us turn back the clock on cellular development,” said Scholer, who also serves as director of the school’s Center for Animal Transgenesis and Germ Cell Research. “This knowledge may permit us to convert ordinary adult cells back to embryonic stem cells for research purposes.” An article detailing the results of Scholer’s work appeared in the September issue of the journal Developmental Cell. His Penn colleagues were Dr. Guy Fuhrmann and Dr. Ian Sylvester.

Though there “very likely” are other factors besides GCNF that can repress Oct4, Scholer says, “if you take away one, it’s like taking a can from the bottom of a pile in a supermarket—efficient repression collapses.” And so far, the Oct4 gene is the only one known to play an essential role in maintaining pluripotency. When its expression is repressed, pluripotency is lost.

“The question was: how does the embryo switch Oct4 off?” notes Scholer, who has been probing the secrets of that gene for several years. He and his colleagues focused on the time when the embryo is “gastrulating”—when the body is starting to be formed from embryonic stem cells: between the sixth and seventh days after conception in mice. That is when an embryonal stem cell, according to its “positional information” (the location within the embryo), starts to differentiate instead of renewing itself. And by comparing the Oct4 genes from human, bovine, and mouse, Scholer adds, they learned “which areas of the gene are required for down-regulating the Oct4 gene.”

“The repressors probably come, set a [chemical] mark, and then leave,” says Scholer, who came to Penn in 1999 from the University of Heidelberg, where he headed a research group in the European Molecular Biology Laboratory. Asked what his next step is, he replies: “We think we know which mark is set by GCNF, and will now try to remove it chemically.” And if they’re successful, he adds, “we will try to clone the cellular molecules.”

Previous issue's Gazetteer | Mar/Apr Contents | Gazette home

Copyright 2002 The Pennsylvania Gazette Last modified 2/28/02

HEALTH CARE

Report of Higher Death Rates Disputed by HUP

In five of 22 medical-care categories, the Hospital of the University of Pennsylvania (HUP) had death rates that were significantly higher than expected in 2000, according to a report compiled by the Pennsylvania Health Care Cost Containment Council. The independent state agency’s Hospital Performance Report for Southeastern Pennsylvania found that HUP had unexpectedly high mortality rates in vascular operations, kidney and urinary-tract infections, kidney failure, hip operations (other than hip replacements), and septicemia (blood infections).

According to Dr. P. J. Brennan, chief of health-care quality and patient safety for the University of Pennsylvania Health System (which includes HUP), the report fails to take into account a number of important factors, and thus “paints with a broad brush.” One factor, he says, is that HUP is the “most complex hospital in the region,” and thus accepts patients with “highly complex” problems and more severe underlying conditions than other hospitals.

“We are the hospital that physicians and patients rely on when no one else is able or willing to handle the problem,” he said. “We take patients in transfer from hospitals that have open-heart programs that are rated very favorably, yet they will send their most complicated patients to us. And we’re very proud of that. But it can affect our mortality rate and benefit theirs. We’re not going to change that, but we need to be clear about why that’s happening.

“We have had expert clinicians do a review of every one of the death charts, and we have not found quality problems in any one of them,” he added. “We believe that every one of the deaths was expected.”

U.S. News & World Report named HUP one of the nation’s top hospitals in its recent “Best Hospitals” issue, ranking it 14th in the nation and highest in the Delaware Valley in 13 specialties.