The Return of the Phage

As deadly bacteria increasingly resist antibiotics, researchers try to improve a World War I era weapon

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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.


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