Defeating Bacteria From the Inside Out
The world’s most ubiquitous organism could save millions of lives — if only they could get a new tryout.
Bacteriophages, a class of viruses that only attack bacteria, have been controversial ever since their discovery by a brash, young, self-taught researcher named Felix d’Herelle nearly a century ago.
In the 1920s and ’30s, before the advent of antibiotics, doctors using phage therapy reported near miraculous cures for infections, even at the critical stage. The treatments, however, didn’t work in every case, and after the discovery of much more reliable antibiotics, starting with penicillin in the 1940s, phage therapy was ushered off the medical stage in the United States and Western Europe.
Anna Kuchment, an editor at Scientific American, labeled phage therapy The Forgotten Cure in her recent book, in which she says the practice took up residence behind the Iron Curtain where antibiotics were scarce.
Alexander Sulakvelidze, who grew up in Tbilisi, Georgia, says phage therapy was there for him when he was a child. “Everybody took them when they got sick. It was just something you did.”
Although we now take penicillin and its host of antibiotic descendants for granted, scientists say with the emergence of more strains of antibiotic-resistant disease, it may be just a matter of time before we are forced to seek some alternatives, and researchers suggest that phage therapy may be just the ticket. And since the end of the Cold War, word has been trickling out that phage therapy still works.
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Forty times smaller than the bacteria they prey upon, each species of phage hones in on one specific type of bacteria. Finding its target, a phage attaches to its bacterial host and deliver a dose of DNA that converts the bacteria into a factory to make more phages — eating the germ from the inside out.
Phages can be found almost anywhere there is water (including the human nostril); they may be the most common organism on Earth. Mankind is awash in them, says Sulakvelidze, who grew up to be chief science officer for Intralytix, a Baltimore-based manufacturer of phage-based products.
For an effective therapy, proponents note, caregivers need to identify a pathogen precisely, then pick the exact species of phage that attacks it. (Antibiotics can work without knowing the specific bacterium because they attack a broad spectrum of bacteria.) The ability to identify the offending bacteria, although not foolproof, is much improved by genetic analysis and other means not available during 1930s.
Still, well-understood bacterial diseases like shigella, a disease of the digestive tract, make a good starting point for deploying phages. If phage therapy were more widely available, Sulakvelidze said, “and you saved just 10 percent of the 700,000 children killed each year by shigella, it would be mind boggling.”
And while they’re fast acting, beginning the process of breaking down targeted bacteria within minutes of application, when phages are done destroying bacteria they become inactive, he adds.
“There would be no downside to trying [phage therapy],” he argues, “The worst-case scenario would be that it did not work — it’s pretty well established that it could do no harm.”
(Because bacteria can be cagey opponents, Sulakvelidze says it would be best to use a variety of species of phage in a cocktail, to be sure to eliminate both the target strain and any closely related variants that might arise during an infection.)
Too good to be true? In a way.
Phage therapy is not a panacea, Sulakvelidze says. “Baseless claims” made by early enthusiasts helped to diminish phage therapy’s reputation in the past.
For instance, he contrasts shigella with tuberculosis, for which it’s “difficult to imagine” a phage-based treatment. That’s in part because the phage cannot get inside of human cells where TB takes up residence, nor can they easily pursue the TB bacterium to the various parts of the body where it hides out.
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The road to market is not an easy one, and experts say for a new antibiotic getting through the administrative hurdles can take years and cost in the neighborhood of $100 million, with the essential requirement of the double-blind clinical trial.
Dr. Glenn Morris, director of the Emerging Pathogens Institute at the University of Florida, co-founded Intralytix, Inc., with Sulakvelidze. While subsequent applications have gone more smoothly, he said, the U.S. Food and Drug Administration approval process for ListShield, the firm’s first phage-based product targeting listeria in food, took four years to reach the approval stage. Morris says that was “largely because there was no standard channel at the FDA for considering phage-based products.”
Phage preparations, by their nature need to be individualized in order to perform at their best. Ideally, Sulakvelidze says, an appropriate regulatory process would take a non-traditional approach, granting manufacturers the flexibility to mix and match phage combinations to address distinct outbreaks, or individual cases, without having to re-enact the entire clinical trial procedure every time they target a phage against a different bacterium.
Bill Egan, the former acting director of the FDA Office of Vaccine Research and Review, says he can see some logic in that approach. He envisions a process similar to the one used for approving annual influenza vaccines, which allows manufacturers to obtain approval based for new versions of influenza vaccines without the necessity for repeated large-scale clinical trials.
He says after first demonstrating that phage therapy can be performed with safety and efficacy, manufacturers of phage treatments would then need to be able to show they “have a procedure in place to handle the individual outbreak, that they have a way to determine the efficacy of therapy.” And finally they would need to demonstrate that when they put a phage preparation together “that it is effective.”
Although the FDA approval process can be arduous, Egan says, it’s flexible. The agency, “as much as anybody else, wants to see safe and effective products go out on the market.”
Ultimately, Egan says the test of phage therapy will be public acceptance. “The physicians will have their set criteria and patients will have theirs. That happens with any new thing, this happened when generics were first introduced; there was a lot of resistance. Now everybody takes them.”