The U.S. Food and Drug Administration last month rejected a letter
of explanation by Dr. James M. Wilson, director of Penns 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.
Wilsons 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
subjectsand 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 Gelsingers 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.
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 FDAs associate
commissioner for regulatory affairs, said that the agencys offer
to enter into a consent agreement remains open. No final decision
has been made on Wilsons eligibility to continue using investigational
drugs, Baker added.
| Mar/Apr Contents | Gazette
the Ethics and Science of Stem Cells
hopeful about the future of stem cellsbut I have a lot of concerns,
Dr. John Gearhart was saying at a recent symposium on stem-cell research
at Penns School of Medicine. Continued...
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 studentsand that it would quickly lead to their curating
an important exhibition on campus. Continued...
by Jim Graham
Nobel, on the Wall
is people, Dr.
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 laboratoriesbut you have to have
the right people working in those laboratories. Continued...
Price Religious Freedom?
In light of
the attacks on
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...
School Gets Sweet Diabetes Grant
of Medicine has
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.
Turning Back the Clock on Stem Cells
group of researchers at Penn and other universities has identified
a receptor that plays a key role in restricting embryonic stem cells
pluripotencythe ability to develop into virtually any one of an
adult animals 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 Penns School of Veterinary
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.
a sense, were 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 schools
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 Scholers 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, its like taking
a can from the bottom of a pile in a supermarketefficient 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.
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 gastrulatingwhen
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.
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 theyre successful, he adds, we will try to clone the cellular
| Mar/Apr Contents | Gazette
Copyright 2002 The
Pennsylvania Gazette Last modified 2/28/02
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 agencys 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
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 were very proud of that.
But it can affect our mortality rate and benefit theirs. Were
not going to change that, but we need to be clear about why
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
News & World Report named HUP one of the nations top
hospitals in its recent Best Hospitals issue, ranking it 14th
in the nation and highest in the Delaware Valley in 13 specialties.