But the phages can be finicky and unpredictable. Each strain of phage is highly targeted and has evolved to home in on specific bacteria, which means a precise match between prey and predator is necessary for any phage-based treatment to be effective. At first, in the 1920s and ’30s, doctors didn’t know about this specificity, so sometimes the preparations worked, and sometimes they didn’t. Also, people occasionally became sick after ingesting the tiny microbes because the treatments weren’t purified properly. Western physicians discarded them once the more reliable antibiotics became widely available after World War II.
However, Soviet scientists figured out how to make phages more effective — advances in molecular biology techniques allowed biologists to identify better matches between phages and their intended prey — although their less rigorous studies in Russian journals were ignored by cold warriors in the West.
Phages are still routinely used in Eastern Europe and, more recently, in Asia. The muddy-looking serums are often sold over the counter in glass vials and dabbed on wounds or taken orally. A handful of desperate Americans — struggling with treatment-resistant infections, diabetic ulcers or other chronic wounds — have journeyed to a clinic in Tbilisi, Georgia, for the “phage miracle cure.”
“I have used phages — almost everyone I know has used phages,” says Sulakvelidze, who was a rising scientific star in his native Georgia and became a director of the then-republic’s version of the Centers for Disease Control and Prevention at age 27. He conducted phage research until the collapse of the Soviet Union in 1991. Twenty years ago, when he arrived in the U.S. as a postdoctoral fellow at the University of Maryland, he was shocked to find that this therapy was virtually unknown here. But the tremendous progress in phage research of the past 10 years and the urgency to find alternatives to antibiotics have made physicians more willing to look into phages, he says.
Putting Phages to Work
In 1998, Sulakvelidze helped found the biotech company Intralytix, which has successfully devised a number of food safety products, including a spray that uses phages to eradicate Listeria, Salmonella and E. coli in foods before they reach stores. “When we first formed, people would simply laugh at us, and told us there is no way this can be commercialized,” says Sulakvelidze. “It took a long time — more than four years to get our first product approved — but it did happen.”
Along with other scientists, he now focuses on human cures. He’s currently working with the U.S. Army’s Research Office on a project to fight shigellosis, a form of dysentery that kills almost a million people a year, mostly young children.
Preliminary studies show phages are effective in fighting antibiotic-resistant ear infections and chronic ulcers, and some researchers suspect they might work on acne outbreaks. Phages even neutralized the deadly MRSA (methicillin-resistant Staphylococcus aureus) superbugs that are resistant to most antibiotics and have become a serious problem in hospitals, nursing homes and intensive care units. “The food safety preparations, the possible acne treatment, these are all potential icebreakers — incremental steps toward acceptance of phage therapeutics,” says Graham Hatfull, a biology professor and co-director of the University of Pittsburgh Bacteriophage Institute.
On other fronts, Camilli’s lab is busily figuring out how the cholera-fighting phages — called ICP1 — did their genetic sleight of hand. Researchers aren’t sure how these tiny viruses got a chunk of DNA from a bacterium’s immune system, but they’re looking into how the viruses transformed this adaptive immune system into a weapon against the deadly pathogens. “We don’t know how this happens, although we do have some clues,” says Camilli. Unraveling the underlying mechanism could help pave the way toward making phages a targeted therapy for diseases like cholera.
Still, numerous stumbling blocks remain before phages could become part of our infectious disease arsenal. To gain regulatory approval, a drug is normally tested in costly large-scale trials encompassing a large number of people — with about half getting a placebo, or dummy pill — to prove the treatment actually works. But since phages need to be targeted to specific bacteria to be effective, mixing and matching phage preparations to fight infectious disease outbreaks isn’t optimal for the one-size-fits-all approach that regulatory agencies like the FDA require for marketing approval. In contrast, antibiotics kill off a broad spectrum of bacteria, making them easy to test in standard clinical trials.
Phages would require a less traditional approach to get official approval, such as the annual process for influenza vaccines in which manufacturers secure approval of new formulas based on the flu bug that is going around that year, instead of conducting big clinical trials every time. Big Pharma is also leery of investing millions in the capricious microbes. The key question, Hatfull says, is when do we hit the turning point?
“How bad does antibiotic resistance have to become that it initiates a full-blown global initiative and we relax regulatory procedures? We haven’t quite gotten there yet — but when we do, phages will be waiting in the wings.”