TIME: Almanac 1993/TIME Almanac 1993.iso/time/092490/0924350.000

Text File | 1992-08-28 | 15.5 KB | 323 lines

                                                                                MEDICINE, Page 74

Giant Step for Gene Therapy


An experiment on a young girl opens a new era in the fight
against hereditary diseases

By LEON JAROFF -- Reported by Andrea Dorfman/New York and Dick
Thompson/Washington


    She weighed around 35 lbs., came down with an occasional
cold or ear infection, and appeared to be a healthy
four-year-old. But a dark cloud hung over her future. She
suffered from ADA deficiency, the rare, incurable and deadly
genetic disease that shuts down the immune system -- a disorder
similar to the one that in 1984 finally claimed the life of
David, the famous but unfortunate "bubble boy." Only the weekly
injection of a newly developed drug seemed to stand between the
little girl and the same fate.

    Last week, on the 10th floor of the massive Clinical Center
of the National Institutes of Health (NIH) in Bethesda, Md.,
the still unidentified child assumed a historic role. In the
first federally approved use of gene therapy, a team of doctors
introduced into her bloodstream some 1 billion cells, each
containing a copy of a foreign gene. If all goes well, these
cells will begin producing ADA, the essential enzyme she
requires, and her devastated immune system will slowly begin
to recover.

    The procedure lacked the drama of an epochal event. For 28
minutes, a grayish liquid in a suspended plastic bag dripped
intravenously into the left hand of the child, who sat upright
in a bed in the Clinical Center's pediatric intensive-care
unit. That was it. But if the technique works as the doctors
hope it will, the results could be little short of miraculous.
Their patient may eventually begin to lead a normal life,
without need for the costly and only partly effective drug now
used to extend the lives of young victims of the disease.

    The landmark experiment, led by Dr. W. French Anderson, a
pioneering advocate of gene therapy, and Drs. R. Michael Blaese
and Kenneth Culver, raised the curtain on what some experts
believe will be a new era in medicine, when many previously
incurable genetic diseases will be contained or even conquered.
The long-term impact on society could be enormous. Up to 5% of
the infants born in the U.S. are afflicted with often
debilitating and sometimes fatal genetic diseases. In most
cases, no effective treatment exists for these disorders, which
are caused by one or more faulty or missing genes among the
estimated 100,000 genes in human DNA.

    Each gene consists of a segment of the DNA that is found in
the nucleus of every one of the body's 100 trillion cells (with
the exception of red blood cells, which have no nuclei). And
each gene is responsible for the manufacture of a particular
protein that contributes to either the structure or the
functioning of the body. If the gene is defective, protein
synthesis will be faulty and a deformity or genetic disease
will result.

    The object of gene therapy, simply put, is to provide the
body with healthy replacement genes that can fulfill the
intended role of defective ones. "Gene therapy is actually a
sophisticated drug-delivery system," Anderson explains.
"Anything given now by injection -- growth factor, factor VIII,
insulin -- you can just engineer the patient's own cells to
pump them out. The advantage is that it's a one-time treatment."

    It all sounds rather straightforward, but medical
researchers will have to overcome some formidable technological
barriers before gene therapy becomes commonplace. Delivering
replacement genes to particular cells, inserting them into the
correct place in the DNA of those cells and then coaxing the
genes to function properly are goals that still often elude
scientists.

    And there are risks. If a gene is accidentally spliced into
a vital segment of a cell's DNA, it could disrupt the
functioning of another critical gene. Or it might activate a
nearby oncogene, initiating the growth of a tumor. Transplanted
without all its accompanying regulatory DNA, the new gene might
order the production of too much or too little of a protein,
with unforeseen consequences.

    These risks and the fears of some critics that the technique
could be misused have raised safety and ethical issues that the
practitioners of the new art are quick to recognize. "For the
first time, we're altering an individual's genes," says W.
("Dusty") Miller, a gene-therapy  researcher at the Fred
Hutchinson Cancer Research Center in Seattle. "That's a new
frontier, and you had better make sure you're doing the right
thing. These are really exploratory times for gene therapy, and
no one knows where it will lead." Despite his enthusiasm for
gene therapy, Anderson too is aware of its implications. "The
emotional impact of having somebody manipulate the fundamental
blueprint of a human being is very frightening," he
acknowledges. "We need to have the public understand it and to
have adequate safeguards."

    Anderson is painfully familiar with safeguards. He and
Blaese first submitted their proposal for treating ADA
deficiency in April 1987. Since then, it has been reviewed a
dozen times by a variety of NIH regulatory committees and
altered again and again to meet their requirements. At long
last, early this month, the acting head of the NIH gave final
approval, and the way was cleared for the researchers to
proceed. Concedes Jay Greenblatt, of the Regulatory Affairs
branch of the National Cancer Institute: "The levels of review
of this proposal have been incredible."

    The gene at the center of all this concern "codes," or
provides the blueprint for, adenosine deaminase (ADA), an
enzyme that breaks down toxic biological products. In the rare
cases of ADA-deficiency children, the gene and, consequently,
the enzyme are missing. As a result, the toxins accumulate in
the bloodstream, killing essential T cells and B cells and
inactivating the immune system. With little or no defense
against disease except germ-free environments, like the famous
bubble, victims usually died early in childhood; ADA injected
directly into their bloodstream could not help; it deteriorated
within minutes.

    Then, earlier this year, the FDA approved treatment with
PEG-ADA, a drug consisting of the enzyme with a chemical sheath
that enables it to exist in the bloodstream for days. Weekly
injections, at an annual cost of $60,000, have kept some of the
dozen or so ADA-deficiency children in the U.S. alive. But a
longer-lasting, even permanent treatment that would generate
ADA in the bloodstream is obviously preferable.

    Anderson and Blaese are confident that gene therapy could
fit the bill. Ideally they would prefer to insert ADA genes
into bone-marrow stem cells, which would continuously
manufacture blood cells containing the gene and ensure a steady
supply of the enzyme. But researchers have yet to find a way
to isolate marrow stem cells effectively. Instead, the NIH
researchers opted for T cells, immune-system cells that can
survive in the bloodstream for months and even years.

    Extracting viable T cells from their young patient, Anderson
and Blaese exposed them to mouse leukemia retro-viruses into
which human ADA genes had been spliced. The retroviruses,
rendered harmless by genetic engineering, were the vectors, the
vehicles that would deliver the genes to their target. They
invaded the T cells and, as retroviruses are wont to do,
burrowed into the T-cell DNA, carrying the ADA gene with them.
Finally, a billion or so T cells, now equipped with ADA genes
and floating in the gray solution suspended above the little
girl's bed in Bethesda, were dripped into her veins.

    Several months may pass before doctors can confirm that the
ADA genes are being "expressed" and that the enzyme is being
produced. Even so, the child will not be cured. She will have
to return monthly for at least two years to the NIH, where
doctors will infuse her with more engineered T cells and check
for possible side effects. But Anderson and Blaese are
optimistic. "We're very comfortable with the concept," says
Blaese. In the meantime, as a precaution mandated by the FDA,
the girl will continue to receive the PEG-ADA drug treatment.

    The milestone event should be quickly followed by a second
application of human gene therapy, now apparently close to
final approval. It has been proposed by NIH's Dr. Steven
Rosenberg for treating patients with advanced cases of
melanoma, a deadly skin cancer that afflicts 28,000 Americans
annually. "We now use radiation, chemotherapy and surgery --
external forces -- on cancer patients," Rosenberg says. "But
gene therapy uses the body's own internal mechanism. We're
trying to make the body itself reject the disease."

    Rosenberg's strategy, devised with the help of Anderson, is
to extract immune cells called tumor-infiltrating lymphocytes
(TILs) from the  tumors of melanoma patients. Rosenberg bathes
the TILs in a solution of interleukin-2, a natural substance
that invigorates them, and then exposes the TILs to
re-engineered mouse leukemia retroviruses.

    Like the retrovirus used by Anderson, Rosenberg's delivery
system has been made harmless and endowed by recombinant DNA
techniques with a human gene. But this gene codes for tumor
necrosis factor, a naturally occurring compound that attacks
cancer cells. The altered viruses insert themselves and their
piggyback gene into the genetic material of the TILs, which are
then injected back into the bloodstream of the melanoma
patients. If everything goes as planned, the activated TILs
will home in on the tumors like guided missiles, attacking the
cancerous cells and at the same time releasing the antitumor
factor to help finish them off.

    Across the U.S., other scientists are preparing their own
gene therapy experiments, some using retroviruses, others
creating synthetic carriers or experimenting with chemical,
electrical and even mechanical techniques to insert genes into
cells. At St. Jude Children's Research Hospital in Memphis, Dr.
Malcolm Brenner is working with "reporter" genes, which have
no therapeutic value and are used merely as markers, in an
attempt to learn more about how bone-marrow cells behave in the
body and how they could best be used for gene therapy. He is
seeking NIH approval to insert reporter genes into the marrow
cells of children with cancer in an effort to learn why the
disease recurs after remission.

    In Ann Arbor, Dr. James Wilson, a University of Michigan
geneticist, is polishing a technique for introducing healthy
genes into internal organs and blood vessels with genetic
defects. Working with rabbits afflicted with familial
hypercholesterolemia, a metabolic disorder, Wilson is trying
to transfer good genes into defective hepatocytes, cells in the
liver that, when functioning properly, help clear LDL
cholesterol from the blood. Eschewing a retrovirus vector, he
and two University of Connecticut scientists have developed a
synthetic protein-DNA complex to deliver the healthy genes.
Essentially a gene encapsulated by a protein, the complex zeros
in on a receptor on the hepatocyte and is absorbed by the cell,
which then incorporates the gene into its own DNA.

    After all the controversy that has long surrounded genetic
engineering and gene therapy, reaction to last week's
pioneering effort has been generally favorable. Abbey Meyers,
executive director of the National Organization for Rare
Disorders, was ecstatic, noting that people with genetic
diseases have been waiting nearly 15 years for the first round
of gene therapy experiments. "If we could find a cure for a
disease with a genetic component such as diabetes," she says,
"that would probably be the most important medical advance of
the century, if not of all time."

    Arthur Caplan, director of the Center for Biomedical Ethics
at the University of Minnesota, who has kept a close eye on
genetic advances over the years, is convinced that any ethical
concerns "have been adequately met. The risks are similar to
those involved when you are trying any innovative, invasive
procedure. I don't think there's anything special about it
because it's genetic."

    Still, the gene therapy currently being practiced affects
only the patients. Opposition is bound to swell again if
scientists turn toward a goal that is still far off: the
genetic engineering of sperm and egg cells. Such Brave New
World-style manipulations would affect the genetic endowment
of future generations, raise new ethical issues and pose
unknown risks.

    For now, however, the promise of gene therapy appears to
outweigh any potential pitfalls. And the acceptance of the new
techniques is particularly sweet for longtime advocates.
"Twenty years ago, you couldn't utter the phrase gene therapy
without being told you were talking nonsense," says Dr.
Theodore Friedmann, a molecular geneticist at the University
of California, San Diego. "Now it's taken for granted that it's
coming." He sees the day when doctors will be able to treat not
only the thousands of diseases caused by a single faulty gene
but even complex disorders like Parkinson's and Alzheimer's
diseases, which are probably caused by a multitude of genes.
Hyperbole? Not at all, says Friedmann. "When it comes to
genetics, it's dangerous to be conservative."

    Perhaps most gratified by the week's events was Anderson.
Ever since his undergraduate days at Harvard, he has been
insisting that genetic disease could be cured by genetic
alterations. In 1968 his paper suggesting the probability of
gene therapy was rejected by the prestigious New England
Journal of Medicine on the grounds that it was too speculative.

seriously is so delightful."


____________________________________________________________
FUTURE TARGETS


    HEMOPHILIA

    Affecting only males, hemophilia results from a genetic
mutation that impairs the production of one or more factors
involved in blood clotting. Hemophiliacs can inject themselves
with concentrated preparations of clotting factor at the first
sign of bleeding, but taking doses of cells containing normal
clotting-factor genes could be an easier way of controlling
the disease.

    DIABETES

    Patients are incapable of producing sufficient amounts of
insulin, the hormone responsible for regulating glucose levels
in the blood. Thought to be at least partially hereditary, the
disease arises when insulin-secreting cells in the pancreas
mysteriously begin to die. Although daily injections of
insulin or, in some cases, a strict diet can control diabetes,
it may be possible to treat the disease by replacing the genes
involved in insulin production.

    PARKINSON'S DISEASE

    A progressive disorder of the central nervous system,
Parkinson's results from the gradual degeneration of cells in
the brain that produce a vital chemical called dopamine.
Because an anatomical barrier prevents many substances injected
into the bloodstream from entering the brain, intravenous doses
of dopamine- producing cells would not be successful. Instead,
researchers are trying to devise ways to graft genetically
altered cells directly onto neurons in the brain.

    AIDS

    The human immunodeficiency virus that causes AIDS attacks
the immune system by binding to specific sites, called CD-4
receptors, on the surface of cells. By constructing a decoy
containing a gene that produces soluble CD-4, scientists hope
to confuse the HIV and prevent it from latching onto
immune-system cells.