Phage Therapy: Concept to Cure

The development and mass-production of antibiotics ranks as one of the twentieth century’s greatest scientific achievements. For more than 60 years, antibiotics have comprised Western medicine’s primary defense against bacterial disease. But although antibiotics have saved millions of lives, our chemical shield has become increasingly leaky. Just last year, the director-general of the World Health Organization warned that “the world is on the brink of losing these miracle cures [antibiotics]” and that “in the absence of urgent corrective and protective actions, the world is heading toward a post-antibiotic era, in which many common infections will no longer have a cure and, once again, kill unabated” (Liljeqvist et al., 2012). Unfortunately, game-changing help from new antibiotics does not appear to be forthcoming. Over the past 30 years, the number of antibiotics newly approved in the United States has steadily declined, and despite increased awareness and redoubled efforts, the current R&D pipeline remains largely dry (Hughes, 2011). Even when effective antibiotics are available, it is becoming increasingly apparent that broadspectrum antibiotics can have sustained and detrimental effects on the body’s communities of beneficial bacteria (Buffie et al., 2011) which, according to a growing body of research, play a vital role in human nutrition (Yan and Polk, 2004) and immunity (O’Hara and Shanahan, 2006). Given the underlying economic factors that make antibiotic development unprofitable, (Nathan and Goldberg, 2005) and given that abuses of antibiotics continue to drive bacterial resistance, it seems unrealistic to assume that antibiotics alone will prove sufficient to counter the long-term medical threat posed by drug-resistant bacteria. Rather than continuing to focus solely on chemical solutions to drug-resistance, which are ultimately static responses d’Herelle’s expertise, and largely because of a poor understanding of basic phage biology, early returns from phage therapy were mixed. In 1932, one American health officer presciently warned, “Because of conflicting experimental observations, enthusiastic and poorly controlled clinical application and rapidly expanding commercial exploitation, a situation is developing which will, unless guided and checked, lead to the ultimate rejection of bacteriophage by all who make any pretense to the practice of scientific medicine” (Larckum, 1932). This rejection of phage therapy, which began with the misuse of phages, became complete with the emergence of antibiotics. Initially, antibiotics were cheap, widely available, and extremely effective against nearly all bacterial diseases, and because this golden age of antibiotic infallibility seemed like medicine’s new status quo, phage therapy was discarded throughout the West as an unnecessary approach to an already-solved problem. As has become uncomfortably apparent, though, bacterial diseases are not a solved problem, and scientists are now looking back to phages as a way to treat the most intractable bacterial infections. In the process, it has become clear that phage therapy holds some important advantages over traditional chemotherapy. Most importantly, phages are extremely precise: any given phage only attacks a very particular strain of bacteria. In d’Herelle’s time, this fact often confounded, rather than aided, effective treatment, but today, advances in diagnostic technologies, such as real-time PCR (Espy et al., 2006), 16s rRNA sequencing (Rhoads et al., 2012), and laser-induced breakdown spectroscopy (Mohaidat et al., 2012), seem likely to greatly facilitate the rapid selection of appropriate phages. From a therapeutic perspective, this means that phage therapy can eliminate an individual patient’s infection without affecting the to a dynamic system, we must also seek approaches that can keep pace with the bacteria they are designed to kill. This idea is not futuristic or even theoretical: we can tap into an ancient arms race between bacteria and their viral predators, bacteriophages, to combat drug-resistant bacteria. Phage therapy, or the use of bacteriophages to kill pathogenic bacteria, represents a potentially significant, if currently underdeveloped, weapon in our ongoing battle against bacterial disease. The purpose of this piece is not to provide a comprehensive history of phage therapy, but in order to understand its future prospects in Western medicine, some basic history is helpful. Bacteriophages, or “bacteria eaters” in Latin, were independently discovered by two microbiologists, Frederick Twort and Felix d’Herelle, in the late 1910s (Lederberg, 1996). Almost immediately, d’Herelle understood that these natural antagonists of bacteria represented a powerful new way of treating bacterial infections. The breakthrough came in 1919, when d’Herelle used phages to cure four patients of dysentery, and from there, phage therapy, when conducted by knowledgeable scientists like d’Herelle, met with significant success. D’Herelle used phages to halt outbreaks of cholera in India and plague in Egypt, and in 1923, two physicians from Baylor University’s College of Medicine, reporting successful results from one of the first phage therapy trials conducted in the United States, concluded that “the bacteriophage holds enormous possibilities as a new weapon for fighting infectious disease” (Ho, 2001). Despite (or perhaps because of) the heady enthusiasm for phage therapy, clinical results often failed to match the hype. Although phage products soon became commercially available in the United States, Western Europe, and the nascent Soviet Union, not every practitioner possessed