- BOSTON (AP) - "Genes," ordered the surgeon. Then he injected
a syringe of pure DNA and salt water into a man's beating yellow-red heart.
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- Dr. James Symes stared for a moment into
his patient's chest. The incision began just below the left nipple, ran
through the lumpy layers of fat and muscle, then between the ribs, finally
exposing the heart.
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- The surgeon moved the needle an inch.
Again he slid it into the pulsing surface. And again. And again.
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- Ten minutes later, it was over. All that
remained was for the patient to come out of anesthesia, heal up, return
home to Monticello, Ark., and wait to see if his heart felt better. On
this gray December morning, a 55-year-old logging contractor named Joe
Griffith became Patient No. 20 in a groundbreaking medical experiment.
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- The goal: Give his heart some helpful
new genetic material. If it worked as planned, these test-tube genes would
prompt the growth of tiny blood vessels in just the right spots, shuttling
blood around places where the coronary arteries were painfully clogged.
Griffith would quite literally grow his own bypass.
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- Griffith's surgeon at St. Elizabeth's
Medical Center had injected his heart with several billion identical copies
of the gene. Each carries the manufacturing instructions for a protein
known as vascular endothelial growth factor. Ordinarily humans make this
stuff only while in the womb, when it triggers the construction of their
circulatory system.
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- On this day, no one could say with certainty
what these genes would do for Griffith. Might they, as he hoped, ease his
chest pain? Restore his stamina? Just driving into the woods to check on
logging crews left Griffith exhausted. Even a little relief would be welcome.
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- The experience of the previous 19 patients
at St. Elizabeth's encouraged him.
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- There was, for instance, the very first
one in the experiment, a 67-year-old man treated in February 1998. He needed
eight nitroglycerin tablets a day for angina that came on with the slightest
activity. All of his natural coronary arteries were plugged. So were three
of the four new ones stitched in during earlier bypass surgery.
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- Three weeks after the gene injection,
his angina began to ease. Two months after the operation, the pain was
gone. He gave up nitroglycerin and took up swimming.
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- Then there was the second patient, a
69-year-old man who'd get angina after walking 10 yards. Three weeks after
the operation, nothing had changed. Then his pain gradually let up. By
two months, he was going to the gym and riding an exercise bike for a half
hour at a stretch.
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- Animal tests suggest that the genes become
lodged inside heart muscle cells, which then secrete growth hormone for
a week or two. This prompts the growth of what doctors call collaterals,
tiny blood vessels thicker than a hair but thinner than the skinniest strand
of pasta.
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- "It has surprised a lot of people
in the gene therapy field to see that it's possible to achieve these effects
with something as simple and nontoxic as naked DNA,'' says Dr. Jeffrey
Isner, who oversees the experiment at St. Elizabeth's.
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- That's not all that surprises them. Perhaps
most astonishing is the fact that the infant field of gene therapy has
taken this turn at all, that it shows its first clear promise against heart
disease, the biggest killer of mankind.
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- For the last decade, it seems, gene therapy
has been perpetually on the horizon, tantalizingly close but never drawing
nearer.
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- Those who championed the approach long
predicted it would be used first to cure rare inherited diseases, such
as cystic fibrosis. They occur because the body lacks a single critical
protein, the result of garbled genes that fail to lay out proper manufacturing
instructions.
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- The idea of gene therapy is to make good
copies of the bad genes and insert them into the body. There they will
oversee construction of the missing protein, curing the disease. Or so
scientists hoped.
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- They were heartened at first to find
they actually could put the new genes into cells and get them to work.
But the benefits didn't last. The genes petered out after a few weeks,
ending production of the protein that the body needs in steady supply for
a lifetime to reverse inherited illnesses.
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- Pioneers of the field, like Dr. Ronald
G. Crystal of New York Hospital-Cornell Medical Center, finally acknowledged
that the know-how was not good enough " at least, not yet " to
install replacement genes that would carry on forever.
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- "So we began to think: What are
the applications where you only need to change the genetic information
for a week or two?'' Crystal says. "That led to the concept of building
new blood vessels.''
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- Proteins like vascular endothelial growth
factor, or VEG-F, are triggers. They set off a chain reaction of protein
release that eventually ends in blood vessel growth. Once the process is
under way, there's no need for more VEG-F.
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- Isner, Crystal and others first showed
the power of this protein in animals, then in people with clogged leg arteries
and finally in the human heart.
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- Most of the patients have been as bad
off as Griffith, a genial, low-key man with awful chest pain and no alternatives.
He had his first coronary bypass operation at age 37. Over the years, his
arteries were reamed with routers and squeezed with angioplasty balloons.
Still, two of his coronary arteries were totally blocked. So, too, were
two veins that had been stitched in during bypass surgery.
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- Last April, a third bypass vessel closed
off. The chest pain got so bad that Griffith could barely walk 100 yards
without a rest. Ordinary medicine and surgery offered nothing more for
him.
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- The afternoon before his gene operation,
Griffith sat in pajamas on his hospital bed and told how the worsening
angina had left him barely able to run his logging business:
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- "I leave home early for the office,
get the crews going, go home to rest, get in my pickup, go to the job,
stay a couple of hours, go home and take a nap, go to the office for a
little while than then go home, exhausted.''
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- Griffith hoped for the best. "I'd
be pleased with any help at all,'' he said that day. He knew the statistics
seemed to be in his favor.
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- The first 18 patients in the program
all reported that their angina had improved. Of the 11 followed for more
than three months, six were free of pain entirely. Their average nitroglycerin
use had fallen from 60 pills a week to 2 1/2.
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- Tests, too, suggested they were doing
better. X-ray movies called angiograms showed improved blood flow. And
radioactive thallium scans revealed a one-third increase in the amount
of heart muscle getting adequate oxygen.
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- "If it works, and that's a big if,
this could play a major role in treating heart disease,'' says Crystal,
who's team has performed gene therapy on 21 heart patients. "What
we are trying to do is make the old heart young.''
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- One obvious benefit could be for the
250,000 Americans whose lives, like Griffith's, are disrupted by chest
pain, even though they have already had angioplasty or bypass surgery and
take all the standard medicines.
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- An obvious drawback is the mini-thoracotomy,
the operation Griffith had. Isner and Crystal believe the genes must be
injected directly in the heart muscle to work. Thus the need to cut open
the chest.
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- One way around this would be to thread
a catheter into the heart with a needle on the end of it. The approach
seems to work in animals, but it is not yet ready for people.
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- However, releasing fluids into the heart
through catheters is already routine. Some doctors say injecting the genes
with needles is unnecessary. Just putting some genes into the heart's circulation
should be enough. A group led by Dr. H. Kirk Hammond of the Veterans Administration
Hospital in San Diego recently started such experiments.
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- "One of the things we find very
exciting is the possibility that patients may never need to see the inside
of an operating room and still have their coronary artery disease attended
to in a very thorough way,'' says Hammond.
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- In fact, his study will involve about
100 patients with ordinary treatable angina, not the worst-case patients
of Isner and Crystal.
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- While cardiologists and surgeons are
intrigued by these experiments, many seem cautious, even dubious, about
the prospects.
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- Some believe that genes are not needed
at all. Squirting pure VEG-F into the heart might do just as well, even
though the protein lasts only 10 minutes or so. Studies of this approach
are also under way.
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- Some wonder if gene therapy has moved
too fast from lab animals to humans without enough evidence that the newly
created blood vessels will hold up over the long haul.
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- "My personal view is that this has
rushed pretty quickly to the clinic, probably before we have understood
it to the degree that would satisfy me,'' says Dr. R. Sanders Williams,
chief of cardiology at the University of Texas Southwestern Medical Center.
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- Others caution that too much is being
made of small, preliminary studies in a handful of patients.
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- "It's tremendously promising, but
it's not ready for prime time,'' says Dr. Robert Roberts of Baylor University.
"There are lots of wonderful anecdotal stories in one patient. That's
not science.''
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- One of the most often repeated concerns
is that the patients' improvement, amazing as it seems, is merely what
scientists call a placebo effect: Patients have holes cut in their chests.
They dearly want to feel better. And they do. The benefit is all in their
heads.
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- "It's hard to believe how someone
could imagine themselves into a better thallium scan,'' counters Isner.
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- Someone else is pretty sure this is no
placebo effect: Griffith. One Monday five weeks after the operation, he
woke up feeling better. Now two months have gone by, and he's back to work
full time, managing crews from 5 a.m. to dark. He still has some chest
pain, but nothing like before.
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- "I used to do most of my work from
the seat of my pickup, but it reached the point where I couldn't do that,''
he says in his quiet way. "I was unable to do just about anything.
Now I can get around without wearing myself out. I think I'm coming around.''
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