TIME: Almanac 1993/TIME Almanac 1993.iso/time/022492/0224350.000

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                                                                                MEDICINE, Page 60

Laying Siege to A Deadly Gene


Thanks to a series of breakthroughs, doctors are closing in on a
cure for cystic fibrosis

By ANDREW PURVIS


    Brianna Oas has never drawn an easy breath. When she was
a baby, her tiny chest convulsed at the slightest irritation.
Instead of laughing, she would cough; instead of crying, gag.
She succumbed to an endless string of respiratory infections --
pneumonia, a cold, bronchitis, pneumonia again -- that ordinary
antibiotics seemed powerless to curb. Diagnosed with a "failure
to thrive," Brianna weighed less at one year than she did at six
months. Finally, last August, just after the child's third
birthday, her anxious parents took her to the University of
Washington pulmonary clinic in Seattle. Chest X rays revealed
that a thick, bluish mucus had started to accumulate in her
airways. "She already had some permanent scarring to the
lungs," recalls Dr. Bonnie Ramsey, Brianna's physician and an
expert in lung disease. "She was a very sick little girl."

    Brianna was suffering from cystic fibrosis, the most
common inherited disorder among whites and a disease that
afflicts 25,000 Americans, killing more than 500 every year.
Just 10 years ago, the prospects for a girl her age were as
bleak as they were inevitable. As the combination of chronic
infections, clogged airways and digestive problems took their
toll, she could not have expected to outlive her teens. But now,
says Ramsey, "Brianna has an excellent chance of living into
adulthood." In fact, although Ramsey and other clinicians are
reluctant to raise false hopes, Brianna and thousands of other
babies born with CF in the past few years may even live to see
a cure. Says Ramsey: ``In the next decade, we are going to see
a revolution in treatment for this disease. We can really, truly
think about a cure."

    In the past two years alone, researchers have reported
preliminary success with two separate therapies that for the
first time treat the underlying cellular disorder as opposed to
just the symptoms of the disease. More promising still, doctors
are closing in on a technique for replacing the defective CF
gene, which was discovered in 1989. The discovery has spawned
an unprecedented proposal to screen tens of millions of
Americans for the defect, so that couples can avoid having an
affected child. After decades of relative quiet on the CF front,
scientists have their eyes on the prize. "This is a wonderful
place to be right now," says Michael Knowles, a CF researcher
at the University of North Carolina. "Just a decade ago, these
therapies were abstractions."

    For half a century, doctors have been treating cystic
fibrosis symptom by symptom, doing their best to stem the rising
tide of mucus triggered by the disease. As this abnormally
thick fluid builds up in the lungs, pancreas, liver and other
organs, it not only serves as fertile ground for damaging
infections but also blocks the passage of vital digestive
enzymes to the intestine and stops up sperm in the testes. As
a result, patients have difficulty breathing, digesting food and
even reproducing. "This is a disease that simply wears you
down," says Ramsey.

    Using simple therapies, such as clapping young patients on
the back and chest several times a day to clear the lungs or
providing a special nutrient-rich diet, scientists have made
impressive strides against the ailment, extending the average
life-span from just five years in the 1950s to 28 today. Recent
developments in genetic engineering may refine this tactical
approach still further. One drug promises to prevent a protein
called elastase, produced in dangerous quantities by the CF
patient's own immune cells, from attacking lung tissue. Another
synthetic enzyme called DNase instantly dissolves leftover DNA
from dead immune cells, one of the bulkiest components of the
accumulating mucus. The thinner fluid can then be cleared by the
body's own self-cleansing mechanisms.

    But even such sophisticated mucus busters would do little
to stop the buildup of fluid at its source. In the early 1980s,
scientists at the University of North Carolina opened the way
for a radically new kind of therapy that would attempt just
that. The doctors noticed that cells taken from the lungs of CF
patients contain abnormally high levels of sodium and chloride
-- the constituents of salt. This did not come as a complete
surprise, since CF patients' sweat is known to be abnormally
salty, a sign that their bodies do not handle the mineral
properly. But the U.N.C. researchers realized that this
imbalance in the lungs could explain why thick mucus was
accumulating there. An excess of salt within cells was leaching
water out of the mucus. This apparently was the basic defect
behind the disease.

    In the past 24 months, the U.N.C. team hit upon two drugs
that could help repair this cellular malfunction. One, a
blood-pressure medication called amiloride, slows the uptake of
sodium. The other, containing naturally occurring substances
called ATP and UTP (for adenosine and uridine triphosphate),
stimulates the secretion of chloride. Both have proved effective
in early trials, although a marketable treatment is still
several years away. "The ultimate fantasy," said U.N.C.'s
Knowles, "would be to give these drugs in tandem to very young
children and keep them healthy until another therapy comes
along."

    Another therapy may be coming along sooner than Knowles
thinks. Since Francis Collins and Lap-Chee Tsui discovered the
CF gene on chromosome 7 in the summer of 1989, researchers from
around the world have been struggling to devise a way to bring
that finding to the bedside. The challenge: to transport
corrected versions of the DNA into the lungs of CF patients. Dr.
Ronald Crystal at the National Heart, Lung, and Blood Institute
believes the best vehicles are ordinary cold viruses, which (as
most people know too well) have a special fondness for the
linings of the airways. Ordinarily, these viruses infect host
cells by injecting their own DNA through the targets' outer
membranes. Crystal hopes to harness this propensity by first
disabling the microbes, so that they no longer cause colds, and
then inserting a corrected version of the CF gene into the viral
DNA.

    When laboratory rats had this reconstructed virus sprayed
into their tiny lungs, they not only absorbed the foreign gene
but actually sprouted, in their airways, the human protein that
scientists believe will cure CF (Since the cells that line the
lungs are shed periodically, this aerosol gene therapy will
probably have to be repeated every two or three months.) While
Crystal has yet to try the therapy in humans, he is supremely
optimistic: "We now know it works in the test tube and in
animals. I can guarantee that we can correct the defective
protein in humans."

    Another futuristic therapy involves the manipulation of
the errant protein itself. This molecule, which scientists have
already reconstructed using the blueprint provided by the CF
gene, could conceivably be goaded into working properly with the
right medication. Alternatively, doctors could implant a healthy
version of the CF gene in embryonic mice or goats, harvest the
resulting protein from the adult animals' milk, and then spray
the protein directly into patients' lungs. "Basically, we're
talking about a four-legged manufacturing plant," said Dr.
Robert Beall of the Cystic Fibrosis Foundation.

    The discovery of the CF gene has revolutionized the
diagnosis of CF. Some public health experts believe that since
doctors can identify the defective DNA (which occurs in 1 out
of 25 Americans) they should screen all prospective parents. Men
and women who find that they are both carriers might then
choose to adopt or conceive with donor sperm or eggs. Last
November the National Institutes of Health financed a handful
of pilot projects to help it decide whether a massive screening
program would be worth the considerable cost.

    Many doctors are not so sure. "Just because we technically
know how to test for the DNA, doesn't mean we are ready to do
this on a large scale," asserts Collins. The test is imperfect,
he notes; it picks up just 85% of carriers. A positive result,
moreover, means only that the couple has a 1 in 4 chance of
having a baby with the disease. Without proper counseling,
Collins says, people might feel needlessly alarmed.

    For those already suffering from CF these are exciting but
still trying times. The promise of new discoveries is tempered
by the knowledge that most patients past puberty have already
suffered too much lung damage to be saved by even the most
sophisticated therapies. Younger patients have a chance, but
there are no guarantees. In Poulsbo, Wash., Brianna Oas' parents
are philosophical. "We're fully aware that whatever they come
up with may not be in time for our daughter," concedes Jim Oas,
a naval-yard manager. Brianna has been in and out of the
hospital in recent weeks, but, he adds earnestly, "we are still
very hopeful." For the first time in the history of this
devastating disease, that hope is warranted.