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million a year for gene-therapy research, and big pharma-
ceutical r ms and swarms of biotechnology startups were
thought to be spending as much again, not a single suc-
cess with humans had been reported in any peer-reviewed
journal. In May 1995, Varmus convened a panel headed by
Stuart Orkin, a professor at Harvard Medical School, and
Arno Motulsky, a geneticist at the University of Washing-
ton, Seattle, to review the state of gene-therapy research
and assess how funds should be apportioned among gene-
therapy research areas.
Orkin and Motulsky reported in December, at length and
scathingly. The promise of gene therapy appeared great,
but its failures had persisted despite the RAC s approval of
more than a hundred protocols. Most clinical trials were
too small and exploratory in nature to evaluate the medical
merits of the treatment; they lacked adequate controls and
rigorously stated goals. Gene therapy, the panelists con-
cluded, had been widely and har mfully oversold.
The balloon was pricked. The RAC had been consider-
ing approximately 15 protocols at each of its regular ses-
sions; but the next meeting, scheduled for March 1996,
was canceled. No proposals requiring public review had
Three years later came Jesse Gelsinger s death.
Gelsinger and the 17 other patients in the trial at the
University of Pennsylvania were being treated for a de -
ciency of the enzyme ornithine transcarbamylase, which
the liver uses to break down ammonia, a by-product of
protein digestion, into harmless waste products. In its
most severe form, the de ciency kills babies in their rst
year. Gelsinger had been kept alive on a strict diet and
a regime of pills. When he learned of the gene-therapy
trial, he volunteered.
The trial was carried out at the university s Institute
for Human Gene Therapy, which was headed by James
Wilson. It was one of the top such centers in the country.
The corrective gene was loaded into an adenovir us. The
18 patients were divided into groups that got increasingly
large doses. Gelsinger got the biggest---a culture of 38 tril-
lion vir us particles. He received the dose on September 13,
1999. By September 15, his vital signs were falling precipi-
tously. With his father s assent, he was taken o life sup-
port, and he died on September 17.
Jesse Gelsinger s death was the rst directly attributed
to gene therapy. An alert went out to the hundred or so
experimenters using adenovirus vectors. In the press and
in scienti c jour nals, the case was reported as a disaster
for the eld.
NIH investigated and called a special public meeting for
December 8, 9, and 10. The problem became clearer. The
protocol for the trials, as approved four years earlier by the
RAC and the FDA, had called for the adenovir us vector
to be injected intravenously. The FDA had subsequently
authorized direct injection of the vector into the hepatic
artery, which was the method actually used. Nonetheless,
Gelsinger s autopsy found that the vector was widespread
in his spleen, lymph nodes, and bone marrow.
Meanwhile, the FDA was conducting its own inquiry.
Investigators were harshly condemnatory. Selection of
trial participants had been sloppy at best: Wilson and his
colleagues were unable to produce proof that any of the
volunteers had met the criteria for the trials. Informed-
consent procedures had been grossly inadequate. Federal
rules require that bene ts and risks be explained fully and
clearly; Paul Gelsinger, Jesse s father, told the New York
Times that the family had been led to think the treatment
might help Jesse, though the trial had been designed only
to test the safety of a treatment being developed for infants.
Further, the consent form had failed to mention that mon-
keys had died after a similar though stronger treatment.
In 1992 Wilson had founded a private research company,
Genovo, in which he held stock. The company had not
put money into this particular study, but it did contribute
a healthy portion of the Institute for Human Gene Thera-
py s overall budget.
On January 21, 2000, the agency ordered a temporary
stop to all gene-therapy trials at Wilson s institute. In 2005,
Wilson settled with the U.S. Department of Justice: he
was not to lead any clinical trials regulated by the FDA for
Hope for cures based on gene therapy, it appeared, had
all but died with Jesse Gelsinger. But in Febr uary 2000,
Friedmann gave the opening talk at a Monday-mor ning
session of an annual meeting of the American Associa-
tion for the Advancement of Science, in Washington, DC.
He reviewed the fundamental di culties of gene therapy,
spoke of the many hundreds of protocols approved but so
far not productive. He reminded his audience of Varmus s
impatient charge in 1995 that the eld had been wildly
oversold. Then---with a marked change in tone---he said,
"We are on the verge of therapeutic e cacy."
Two lines of work seemed to him to "have the feel of
being correct." A pair of American laboratories were begin-
ning clinical trials of gene therapy for hemophilia. Proper
blood clotting requires a cascade of responses, controlled by
a series of proteins. Hemophilia A, the most common form
of the disease, is caused by a defect in the gene for one of
those proteins, factor 8; hemophilia B is caused by a defect
in the gene for another, factor 9. The study Friedmann
thought had that "sense of correctness" came from work
with hemophilia B by Katherine High, a hematologist at the
Children s Hospital of Philadelphia. At Stanford, the gene
therapist and virologist Mark Kay was also working with
hemophilia B. Kay and High had combined their e orts.
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