In March of 1961, Elizabeth Taylor was in London filming her next blockbuster, Cleopatra, when she fell ill with pneumonia. She underwent an emergency tracheotomy, and for days the press followed every development in her increasingly dire situation. On March 7, a Philadelphia-area newspaper reported that a local company, Delmont Laboratories, had put several doses of an unusual antibacterial treatment on the next jet to London at the request of Taylor's doctors. With a touch of community pride, the paper reported that the treatment, "staphylococcus bacteriophage lysate," was exclusively manufactured by Delmont Laboratories, and that "Christopher Roos, laboratory director and formerly senior bacteriologist for Sharpe and Dohme, played a major part in its development."
It's not clear what impact the treatment had on Elizabeth Taylor, but Christopher Roos, my great-grandfather, didn't doubt its efficacy. My mother recalls that during her childhood visits to his house, he would treat her colds with a dose, administered as a nasal spray. Staphylococcus bacteriophage lysate is a form of antibacterial therapy based on phages, viruses that are the natural predators of bacteria. Discovered early in the 20th century, decades before modern antibiotics, phages have an obvious therapeutic potential that doctors and scientists were quick to explore. In the 1930s and '40s, bacteriophage preparations were manufactured by major drug companies like Eli Lilly, and used to treat everything from cholera to wound infections.
Aside from the technological advances, there is now a major medical and economic reason to reconsider phages: the growing crisis of antibiotic resistance. The number of antibiotic-resistant bacterial infections is growing rapidly, while the drug pipeline of new antibiotics is drying up.
But the hype got a bit ahead of the science. The biology of these viruses was not well understood, and phage treatments were difficult to prepare consistently. The effectiveness of the treatments varied widely, and while there were some clinical studies of phage therapy, many weren't particularly rigorous by rapidly modernizing, post-World War II standards. In the mid-1940s, penicillin, cheap and obviously effective, began to be mass-produced in the U.S. By the time that Liz Taylor's doctors called my great-grandfather, phage therapy was on the wane. Knowing that, the story sounds like the familiar scenario of the celebrity doctor who peddles some unproven alternative treatment to his famous patient.
But that characterization isn’t accurate. Despite the lack of rigor in the early studies, there is a long record of substantial evidence showing that phage therapy holds genuine promise. After phage therapy was superseded by antibiotics in the West, researchers in the Soviet Union and Eastern Europe—where antibiotics weren't as readily available—continued to work on phage therapy, with encouraging results. Some occasional studies continued in the U.S. and Western Europe as well. And now, phage therapy is in the limelight again, drawing the interest of researchers, governments, and biotech companies.
What changed? As my Washington University colleague Jeffrey Gordon and his co-workers wrote, we're experiencing "the incipient rise of a phage biology renaissance," thanks to modern DNA analysis technologies. Discovered before we knew that genes were made of DNA, we now know that phages are highly efficient gene-delivery machines. They inject their genomes into bacteria, hijack the bacterial machinery to make new DNA copies of themselves, and repackage those copies into protein capsules, bursting open the bacterial cell in the process. The capsules then diffuse away in search of new bacterial prey. By scouring oceans, soil, and our own bodies for phage DNA, researchers have discovered an enormous world of viruses with a tremendous bacterial-killing capability—according to one review, "phage predation destroys an estimated half of the world bacteria population every 48 hours." The diversity of the world's bacteriophages is an essentially inexhaustible source that we can trawl for potential anti-bacterial treatments, with the aid of today's highly effective biotechnological tools. And researchers like Gordon and his lab members are exploring how phages operate in their natural habitats, such as the human gut.
Aside from the technological advances, there is now a major medical and economic reason to reconsider phages: the growing crisis of antibiotic resistance. As the Centers for Disease Control reported last year, the number of antibiotic-resistant bacterial infections is growing rapidly, while the drug pipeline of new antibiotics is drying up. Two million people acquire antibiotic-resistant infections each year in the U.S., leading to over $20 billion in health care costs. And antibiotics themselves pose a major burden, accounting for 20 percent of all emergency room visits for adverse drug events.
Phage therapy has the potential to avoid all of these problems. While bacteria can become resistant to any one strain of phage, there are many different phage strains out there that could be combined into an effective, multi-strain cocktail treatment. And unlike chemical antibiotics, phages have their own genomes that can evolve to circumvent the defenses of resistant bacteria. Phage therapy also would not destroy the important community of healthy bacteria in our guts. Antibiotics wipe out these healthy gut bacteria, leaving people vulnerable to opportunistic infections by Clostridium difficile, a bacteria that the CDC reports is responsible for 14,000 deaths each year in the U.S.
The need is there, but will phage therapy actually work in humans? The answer is a cautious yes. The biomedical research community is certainly ready to try, bringing new funding, technology, and rigor to this old-fashioned approach to infections. A clinical trial of phage therapy for infected burn wounds is underway in Europe. The FDA has already approved phages to kill contaminating bacteria in food, and phage treatments for infections are being tested for efficacy in some animal studies, as well as for safety in a few human studies (PDF). Phage therapy may or may not become the major solution to our crisis of antibiotic resistance, but it is very likely that we'll soon see a variety of limited but successful applications of phage therapy in humans.
Delmont’s product was a federally-approved drug in the 1950s, but as the FDA revised its approach to regulation in later decades, the small company struggled (PDF), and, in the 1990s, it stopped selling its bacteriophage treatments for human use. The company continues to make a USDA-licensed phage therapy to treat recalcitrant skin infections in dogs. When my great-grandfather sent those doses of phage lysate express to Liz Taylor, the time wasn't quite right for phage therapy, scientifically or economically. But times have changed, and this old-fashioned treatment may become cutting-edge.