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FEATURE STORY 47
The types of cells a ected by the disease also made it
a good candidate for treatment with gene therapy, Fischer
said. First, when the gene in which the mutation occurs
is functioning properly, it encodes a protein that is vital if
the precursors of T lymphocytes are to survive and prolif-
erate. Second, unlike other types of immune system cells,
T lymphocytes can sur vive for decades---sometimes even
for an entire lifetime.
These two facts meant that even if the researchers could
genetically alter only a few precursor cells, these cells might
develop---or, as the scientists say, "di erentiate"---into a
large number of mature T cells that had a lasting bene t
for the patient. "So we had the hope," Fischer said, "that
a very poor technology could---in that context, with that
Then came the drudgery. "We made vectors, retroviral
vectors, the best technology of the time, blah blah blah,"
remembered Fischer. But the tests went well. By 1998,
Fischer and his colleagues were ready to seek approval to
start human trials.
The rst trial began on March 13, 1999. "And between
99 and 2002, we had treated 10 patients," Fischer said. The
researchers took bone marrow containing the lymphocyte-
precursor cells from the patients. In cell culture, they intro-
duced the vector, a disabled retrovirus with the cor recting
gene. After several days, they injected the cells back into
the patients. "And in nine out of ten, we were pleased to
see that it worked," he said.
As Fischer and his team had expected, the number of
treated precursor cells able to generate T cells was very
low. However, he said, it was su cient to produce a nor-
mal number of T cells. "After a few months, these children
could leave the hospital and start to live normally with
their parents. And except for those who had the compli-
cation I m going to describe in a moment, they are living
normally still today."
After the rst three years, three of the ten children
treated developed a severe complication, an uncontrolled
proliferation of T lymphocytes. "I would call it a leukemia-
like disease," said Fischer. Childhood leukemia can usually
be cured with massive doses of chemotherapy, and that s
how Fischer and his colleagues treated the three patients.
One died. "The other two kids today are doing well, as
well as the other seven," Fischer said.
How much did all this cost? "A lot!" Fischer laughed
abruptly. "A lot; but the treatment of a child with such a
disease, without gene therapy, costs a lot, too." Yes, he said,
per patient, the cost of the research is huge. But "the cost of
the therapy itself is not that big. Let s assume it s commer-
cialized. I would assume the cost of the therapy itself, with
the cost of the vector---the cell treatment ex vivo---shouldn t
cost more than maybe somewhere between $30,000 and
$50,000, something like that. Per patient." About the same
as a heart transplant? "Exactly!" he said. "As it moves
toward being a kind of, quote, routine therapy, this is not
much higher than many other therapies."
And those complications? "We ll see when we have
enough follow-up to be sure," he said, adding that if the
chances of such a complication were reduced by a factor of
10, he d consider the risk-bene t ratio "perfectly accept-
able." Fischer said he does not yet know whether his meth-
ods can be generalized to other types of genetic defects; he
is not making any sweeping claims. His group is moving
rst to two other immune-de ciency diseases, involving
other genes. "So we want to go step by step from the ones
that are easiest to the most complex."
From the rst glimmer of possibility to the present day,
Theodore Friedmann has written and spoken as gene
therapy s most ardent advocate. He has seen medicine enter
a new era, which o ers "new and de nitive approaches to
therapy that were previously only the stu of dreams and
scienti c fantasy." His has also been a voice of caution, of
reason. He has had to warn his colleagues that they must
openly address their discipline s di culties, its limitations,
its failures. Yet he continues to mar vel at the unprecedented
possibilities raised by gene transfer. For the rst time, he
says, and one can sense his quiet exultation, medicine can
do more than treat the signs and symptoms. It can reach
the underlying causes. It can cure. "It s going to be di -
cult," he says. "Yet medicine has always had to work with
imperfect knowledge and technology."
Horace Freeland Judson is the author of five books, including The
Eighth Day of Creation, a history of molecular biology that was
published in 1979 and is still in print.
In November , the French halted their trials. The number
of patients was up to , but now one of those who'd gained a
fully normal immune system had come down with a disease
similar to leukemia, out-of-control proliferation of the very
white blood cells that had been restored.
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