Oct. 30, 2000 -- Deep in the wilds of your local sewer system, a microscopic drama is unfolding. Invisible to the naked eye, a virus with a bulbous head, spindly neck, and spidery legs glides toward a plump bacterial cell. After alighting, the bacteriophage punctures the cell's membrane and injects its own genes, which force the cell to mass produce viruses. In less than an hour, the victim cell explodes, scattering a brood of 200 newborn viruses. Each of them immediately begins prowling the sewage for more prey.
Bacteriophages, or phages for short, do nothing but attack and destroy bacteria. They thrive anywhere bacteria are abundant -- in sewage, on food, in water, even in your body -- and they've honed their killing technique for more than a billion years. Now some scientists in the United States and Europe hope to deploy these expert assassins to battle outbreaks of antibiotic-resistant bacteria.
For nearly 70 years, this approach, known as phage therapy, has been a standard treatment for bacterial infections in the former Soviet Union. In the West, phage therapy was dismissed as a failure decades ago. Now scientists in Europe and North America are turning once again to the tiny predators.
Prolific Killers
Around the world, patients are dying from bacteria that were once easily tamed with antibiotics. So scientists are scrambling for new treatments. Phages look promising for a number of reasons, starting with their prolific reproduction. With conventional antibiotics, the concentration in the blood peaks after each dose and then dwindles. Not so with phages -- their numbers actually keep pace with the number of bacteria, says microbiologist Mike DuBow, PhD, of McGill University in Montreal. "It's the only drug that makes more of itself."
Also, each kind of phage usually attacks only one species of bacterium. That means that phages are extremely unlikely to turn on us -- they don't have a taste for human cells -- and they won't mow down the helpful bacteria that live in our intestines, as antibiotics often do. This pickiness also explains why the phages within your body don't automatically kill off invading bacteria before you get sick. With so many kinds of phages around, you probably don't have the right kind to fight that particular bug.
Finally, phages can evolve along with the bacteria, so that the bacteria can't develop permanent resistance to them as they can to antibiotics.
Along with all these benefits come some risks. When doctors first tried giving phages to patients, they sometimes accidentally included poisons from the bacteria in the medicine, making patients sicker. In other cases, the phages may have done their work too fast, bursting too many bacteria at once, and releasing an overwhelming dose of poison from the bacterial cells. As a result, many patients given phage therapy died. So, except for occasional instances of "compassionate use" for dying patients, phage therapy has not been tried in the West for 60 years.
But long after European and American microbiologists abandoned phages, researchers in the Soviet Republic of Georgia kept working to overcome the dangers. Millions of patients in the USSR were treated with phage therapy for everything from diarrhea and burns to lung infections.
In one instance, workers building a stretch of railroad through Siberia in 1975 fell prey to a virulent strain of staphylococcus bacteria. Infections that began as skin lesions on the malnourished workers were invading their lungs, then spreading throughout their bodies. David Shrayer, MD, then a young microbiologist at the Gamaleya Institute in Moscow, was called in. Finding antibiotics useless, he arranged for the workers to receive phage therapy. Shrayer, now a Brown University oncologist, says they were quickly cured.
Phage preparations are still available today in Georgia and Russia. "I like to emphasize their safety," says Alexander Sulakvelidze, PhD, the former head of the state microbiology lab in the Republic of Georgia.
Cautious research
While the Soviet experience has encouraged Western scientists to take a second look at phages, they are proceeding cautiously. Soviet phage experiments lacked rigor, says geriatrician Joseph Alisky, MD, PhD, of the University of Iowa, who reviewed them for an article in the Journal of Infection. The studies did not include control groups and were vague about the methods of preparing phages and the criteria for successful treatment, he says.
In the West, only animal studies have been done so far because doctors here are still trying to answer questions such as whether a patient's immune system is likely to interfere with the treatment.
That hasn't deterred investors. At least three American startups and one government lab hope to launch clinical trials within the next 18 months. But it may take much longer to satisfy the stringent manufacturing and safety standards required by the Food and Drug Administration.
Then phages will have to pass another kind of scrutiny: Will doctors and hospitals embrace the treatment, given its tarnished history? Richard Carlton, MD, president and CEO of the Long Island startup Exponential Biotherapies, says he got an answer to this question when he approached several hospitals about hosting clinical trials: "They said, 'Hurry up!'"
Mitchell Leslie writes about science and health for New Scientist, Science, and Modern Drug Discovery.
