Phages: Bacteria-Killing
Viruses May Fight For
Humankind Again

By Brendan I. Koerner
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.
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.
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."
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.
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.
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.
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.
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.
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.
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.
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.
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."
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."
Superbugs, superenemies
Phages might soon be used against antibiotic-resistant strains of these deadly bacteria.
Enterococcus. Vancomycin-resistant strains can infect the bloodstream, skin, wounds, and heart valves.
Staphylococcus. The nation's No. 1 cause of hospital-acquired infections.
Pseudomonas. Highly adaptable, it attacks the respiratory tracts of cystic fibrosis, burn, and cancer patients.