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, and
pneumonia again-that ordinary antibiotics seamed powerless
to curb. Diagnosed with a "failure to thrive," Brianna weighed
less at one year than she did at 6 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 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 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 of 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 eye 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 the 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 1950's 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
1980's, 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
airway. 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, Washington, 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.
TIMELINE
Before the 1980’s: Doctors understood and treated only the
symptoms, including the accumulation of mucus in the lungs
and pancreas, chronic infections, and poor digestion.
Typical treatments: Clapping on the back, chest, and sides to
loosen phlegm; special diets; supplemental enzymes;
antibiotics.
Early 1980’s: Scientists discovered that cells lining the lungs
are high in salt, drawing water from the surrounding mucus.
This explains the buildup of thick mucus.
Experimental treatments: ATP/UTP and amiloride, which help
restore the balance of salt in these cells.
1989: Gene is discovered.
Future treatment: A genetically engineered cold virus
containing a replacement for the defective gene could be
sprayed into the lungs.
NOW: Capitalizing on the gene discovery, researchers have
identified the protein in the cell wall that causes the salt
imbalance and are working to produce quantities of it.
Future treatments: An aerosol spray that provides patients
with the protein they lack; Drugs that enable the defective
protein to work properly.