- Before penicillin became the medical
world's darling, crusading doctors crisscrossed the globe armed with bacteriophagesbacteria-killing
viruses that, when administered to diseased patients via injection or potion,
could be powerful healers. First discovered at France's Pasteur Institute
in 1917, phages were considered medicine's most promising panacea for an
array of nasty diseases until antibiotics debuted in the 1940s. Drugs such
as penicillin seemed infallible, while phages, their biologies poorly understood,
were hit or miss. The once celebrated viruses slipped into oblivion.
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- Now, a half century after being cast
aside, phages are getting a second look, as a weapon against "superbugs"
that have developed resistance to antibiotics. Bacteria such as staphylococcus,
enterococcus, and streptococcus, once considered licked, are re-emerging
as prolific killers; many of the nearly 90,000 Americans who died of hospital-acquired
infections last year were affected by antibiotic-resistant strains.
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- In April 1996, Nobel laureate Joshua
Lederberg, an authority on infectious diseases, helped revive interest
in phages with an upbeat commentary in the Proceedings of the National
Academy of Sciences, which declared that in light of the shortcomings of
antibiotics, there "should be a renascence of study of bacteriophages."
This past July, the biennial Evergreen International Phage Meeting at Evergreen
State College in Olympia, Wash., for the first time attracted several large
biotechnology companies, including industry giant 3M. "In the scientific
community, when people hear 'phage therapy,' they think, 'Oh, that doesn't
work,' " says Elizabeth Kutter, the Evergreen State biophysicist who
organized the meeting. "It's an ingrained prejudice. But there's a
large body of evidence that suggests that this is really a viable approach."
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- Phages, which are about 1/40th the size
of most bacteria, are perhaps the simplest, most abundant organisms on
Earth, thriving wherever bacteria growin raw sewage, in our bodies, in
the oceans, and nearly everywhere else. Their extraterrestrial appearancesgene-filled
heads, narrow tails, and spiderlike legsserve them well in their role as
nature's rudest houseguests. Using their legs to grip the surface of a
bacterium, phages bore in with their tails and inject genetic material
into the cell. These genes force the host to produce copies of the phage;
eventually, so many "daughters" are producedmore than 100 in
30 minutesthat they burst the cell wall, destroying the bacterium. The
newborn phages then travel forth to adjacent bacteria, repeating their
invasion until there are no hosts left to slaughter.
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- Bubonic plague. It is a process that
Canadian microbiologist Félix d'Hérelle hoped could be harnessed
to combat the world's most vicious ailments. While researching dysentery
in Paris in 1917, d'Hérelle stumbled upon phages, which he observed
decimating a colony of bacteria. As a health officer with the League of
Nations a decade later, he traveled through India and the Middle East using
the viruses to treat everything from simple infections to bubonic plague.
Pharmaceutical titan Eli Lilly listed phage liquids in its product catalog
in the 1930s, and Sinclair Lewis's Pulitzer Prize-winning 1925 novel Arrowsmith
featured a d'Hérelle-like doctor who used phages.
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- But failures were far too common. D'Hérelle
and his peers lacked the technology, such as high-speed centrifuges, to
rid their preparations of biological debris, which can render solutions
toxic. More important, they didn't understand phages' extreme pickiness.
"An advantage of antibiotics is that they're broad spectrum, against
many different species and genera of bacteria," says Richard Carlton,
president of Exponential Biotherapies, a New York-based biotech firm that
is trying to develop phage-therapy products. But each phage has a taste
for a very specific targetsomething that pre-World War II researchers didn't
know.
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- Although Western medicine largely abandoned
phage therapy, work continued in the former Soviet Union. In 1934, d'Hérelle
had traveled to Tbilisi, capital of present-day Georgia, to help found
the Eliava Institute of Bacteriophage, Microbiology, and Virology. Researchers
there slowly figured out which phages kill which bacteria, and new technology
allowed them to purify their concoctions. The institute claims impressive
success ratesaccording to one 1985 study, for example, the institute's
phages are 80 percent effective against enterococcus, which can spur fatal
heart-valve infections.
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- Few of the studies done in Tbilisi have
been scrutinized by Westerners, and the former Soviet Union's less rigorous
approach to clinical trials troubles U.S. researchers. But many feel that
there must be some merit to the Georgians' work. "One can't propagate
a myth forever without having some results," says Ian Molineux, a
phage biology researcher at the University of TexasAustin.
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- Entrepreneurs. The encouraging tales
from Georgia have motivated some stateside researchers to once again try
to develop therapeutic applications of phages. Next year, for example,
Exponential Biotherapies hopes to begin clinical trials on a phage product
that attacks a strain of enterococcus resistant to vancomycin, the current
antibiotic of last resort. Phage Therapeutics, a Bothell, Wash., start-up
developing a treatment against Staphylococcus aureus, also aims to launch
clinical trials in 1999. Evergreen State's Kutter estimates that phages
might be used in American hospitals "when nothing else works"
within three to five years.
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- Though modern know-how may help scientists
avoid d'Hérelle's mistakes, most of them are not ready to declare
phages the ultimate remedy. "There has been too much hyperbole and
far too few well-controlled experiments," says Molineux. Jim Bull,
an evolutionary geneticist at the University of TexasAustin, has worked
with Bruce Levin, a biology professor at Emory University, to treat mice
infected with fatal doses of E. coli. In one experiment, infected mice
treated with phages had a 92 percent survival rate, compared with 33 percent
for those receiving the antibiotic streptomycin. Still, Bull doesn't mind
calling himself skeptical. "It sounds simple to let a phage attack
something," he says, "but the complexities of infection inside
our bodies may get in the way of making that as easy as we'd like to think."
For instance, bacteria can "hide out" inside cells where phages
can't reach.
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- As in d'Hérelle's time, phage
finickiness is also problematic. Even though researchers may now know which
phages attack which bacteria, life-threatening illnesses usually allow
precious little time to culture and identify the strain causing the infection.
"If we're expecting a series of infections due to a single bacterial
strainif there's one strain sweeping through a hospitalwe may be able to
treat that without diagnosing the bug," says Bull. Otherwise, tests
to determine which phage is needed might take too long.
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- Another big question regarding the treatment
is whether phage-resistant bacteria will develop. Phage advocates concede
that resistance is a concern, and many supporters preach moderation, pointing
out that overuse was antibiotics' downfall. "This could be an extremely
valuable tool," says Carlton, "and it should be used only as
a tool of last resort."
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- Carl Merril, chief of the Laboratory
of Biochemical Genetics at the National Institute of Mental Health and
a collaborator with Exponential Biotherapies, believes that resistance
is inevitable. But he adds that given medicine's current crisis, future
roadblocks do not justify a slowdown in research. "Bacteria will mutate
and become resistant to anything you do," he says. "In the meantime,
we'll save a hell of a lot of lives."
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- Superbugs, superenemies
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- Phages might soon be used against antibiotic-resistant
strains of these deadly bacteria.
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- Enterococcus. Vancomycin-resistant strains
can infect the bloodstream, skin, wounds, and heart valves.
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- Staphylococcus. The nation's No. 1 cause
of hospital-acquired infections.
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- Pseudomonas. Highly adaptable, it attacks
the respiratory tracts of cystic fibrosis, burn, and cancer patients.
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