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The Return of the Phage
As deadly bacteria increasingly resist antibiotics,
researchers try to improve a World War I era weapon.
Amid the din from street musicians, panhandlers and
baby-toting moms along Baltimore’s Inner Harbor, a petite woman
wearing surgical gloves squats down on an embankment wall. She
dips a sterile white bucket into the water, pulls it up, then
peels off her gloves, and in seconds vanishes.
Few onlookers would guess Ekaterine Chighladze is a mercenary
in a microscopic war. She marches the unsavory water past Camden
Yards, the Baltimore Orioles’ playground, and ducks into a lab
of the University of Maryland.
She repeats this process every two weeks. So even before her
analysis, she knows the bucket is chock-full of naturally
occurring predatory viruses called bacteriophages — phages for
short. After more than a half century of neglect in the West,
these tiny viruses are gaining new consideration as slayers of
so-called superbugs — those often deadly bacteria ever more
resistant to conventional drug treatment.
“Modern medicine could be set back to its pre-antibiotic
days,” Alexander Sulakvelidze, who runs the lab, says from
behind a lab bench piled high with agar dishes of bacteria. In
1998 the professor of medicine cofounded a Baltimore company
called Intralytix to manufacture phages. “All the advances that
we take such pride in, from transplants to chemotherapy,” he
says, “may become impossible when bacteria develop resistance to
antibiotics.”
According to a recent World Health Organization (WHO) report,
nearly all gonorrhea strains are unchecked by penicillin in
Southeast Asia. In India, typhoid species have developed
resistance to three drugs commonly used against them.
Drug-resistant tuberculosis has invaded one in ten TB patients
in Estonia, Latvia, and parts of Russia and China. In Thailand,
the top three antimalarial drugs have been rendered useless.
“The phenomenon isn’t just happening in developing nations,”
says Richard Honour, president and CEO of Phage Therapeutics
International, a fledgling company in Bothell, Washington. “More
American lives are lost each year to antibiotic-resistant
bacterial infections than were claimed by the entire Vietnam
War,” he says. The WHO reports that some 14,000 people die each
year just from drug-resistant infections picked up in U.S.
hospitals. Worldwide, up to 60 percent of hospital-acquired
infections turn out to be drug-resistant.
Phages are among the simplest organisms on the planet. About
a millionth of an inch in size, a fraction of most bacteria,
phages become visible only under an electron microscope. A
milliliter of water can contain up to a trillion. They thrive
anywhere bacteria can exist — in raw sewage, open water, humans
and practically everywhere else, says Carl Merril, chief of the
biochemical genetics lab at the National Institute of Mental
Health (NIMH). Some phages reproduce by invading a bacterium and
forcing it to manufacture copies of the phage until the host is
overwhelmed, he explains. Eventually, the progeny either
dissolve or burst the cell wall, destroying the host bacterium,
and move on, ready to prey on surrounding bacteria. A single
phage can produce tens of thousands of offspring in an hour,
growing exponentially from there. Other phages reproduce by
becoming a part of the bacterium’s genome. When the bacterium
reproduces, so does the phage.
Human phage therapy is hardly new. Before the discovery of
penicillin, pioneering doctors around the world employed phages
as healers, giving them by potion or injection. These stalkers
of bacteria were discovered during World War I by British
bacteriologist Frederick Twort and independently two years later
by the French-Canadian Felix D’Herelle, a self-taught medical
maverick then at the Pasteur Institute in Paris. Both observed
mysterious activity that produced clear areas in agar plates
otherwise cloudy with thriving bacteria. Something was killing
the bacteria. D’Herelle identified the microscopic marvel as a
new type of parasite. “In a flash I had understood what caused
my clear spots was in fact an invisible microbe...a virus
parasitic on bacteria,” he wrote. He named it bacteriophage,
derived from two Greek words and meaning “bacteria devouring.”
Early on, phages held much promise in conquering many of the
world’s scourges. D’Herelle went on to set up an institute with
microbiologist George Eliava in Tbilisi, the capital of Georgia.
There, they harvested phages from the nearby Kura River for
culturing. Though D’Herelle left during the Stalinist era and
Eliava was executed, the Eliava Institute of Bacteriophage,
Microbiology, and Virology flourished. In the late 1930s, it
churned out phages by the ton. Patients threw back their heads
and swallowed a solution of the phages. Several major U.S.
pharmaceutical companies — Eli Lilly, for one — entered the
field.
But the advent of sulfa drugs and antibiotics in the 1940s
relegated phages to the backseat — at least in Western
countries. While phages frequently and inexplicably failed,
antibiotics, it seemed, were fail-safe. Physicians preferred the
new class of drugs because they were relatively easy to use,
killed a broad spectrum of bacterial infections and didn’t pose
the risk living organisms do.
Later on, because of their structural and genetic simplicity
and ease of growth in the lab, Western researchers tapped
bacteriophages as model systems to study the molecular basis of
genetics, spawning the science of molecular biology. The lab
techniques that made the revolution possible were largely
advanced through research on phages and their bacterial hosts.
“If you look at the early Nobel Prizes in molecular biology,
half of the awards went to researchers using phages,” NIMH’s
Merril says. The work also helped researchers understand the
shortcomings of phage therapy of the past. Some of the
preparations were contaminated. On top of that, early
researchers didn’t realize that each phage type is highly
specific for a given bacteria species, more finicky than Morris
the cat.
Back in the Baltimore lab, Chighladze painstakingly isolates
phages from harbor water by culturing them with sundry strains
of bacteria. Modern technology can decipher which type of phage
kills which type of bacteria. For a broad spectrum assault,
purified phages can then be combined in cocktails.
Over time, bacteria naturally develop resistance to phages,
as they do to antibiotic drugs. Drug resistance, however, has
been accelerated by global misuse of antibiotics. Phages, in
contrast, can adapt to keep up with the bacteria, matching their
prey mutation for mutation. “It’s a biological arms race,”
explains Sulakvelidze, a former Georgian lab director who worked
extensively with the Eliava Institute. Back in Tbilisi, phages
never fell out of fashion. They’ve been in use in humans for 70
years with claims of miraculous results. Phages offer other
advantages over antibiotics. For starters, they don’t harm
benevolent bacteria living in symbiosis with human hosts. But
even with such positive traits, phages do have their downside.
Rather than kill bacteria, some phages make them even more
lethal. This happens, for example, with the bacterium that
causes cholera.
In the mid-1980s interest in the West was renewed when
British and Polish researchers studied phage success against
microbes in animals. But burgeoning cases of
antibiotic-resistant bacterial infections really prompted the
surge in Western research.
Today Intralytix and Phage Therapeutics, like a handful of
other companies, are developing phage catalogs to sequence the
genetic code of a select hundred or so of the inestimably large
number of species of bacteria-killing viruses found in nature.
Although Intralytix has opted to use only naturally occurring
species for now, other companies are attempting to genetically
engineer phages so that they overcome bacterial resistance.
The first human clinical trials in the United States are
slated to begin within a year. Possible applications include
impregnating artificial skin or other materials with phages to
heal infected wounds, intravenously medicating patients
suffering from bacterial infections of the bloodstream, and
culturing custom phage therapies from infected patients.
Psychological barriers to phage acceptance remain. “Some
people worry about getting treated with a virus,” Merril says,
“but they don’t realize that many of today’s leading vaccines
are made with live virus.” Yet even Merril doubts phages will
ever be a panacea or more than an adjunct to antibiotics.
Whatever the future, phages have already earned a respected
place in the annals of medicine. We shall see how much larger
their entry becomes.
By Julie Wakefield
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