Molecular Medicine Israel

Viral Soldiers

Phage therapy to combat bacterial infections is garnering attention for the second time in 100 years, but solid clinical support for its widespread use is still lacking

n July 2011, a 43-year-old woman walked out of the National Institutes of Health (NIH) Clinical Center in Bethesda, Maryland, after a month of battling a serious bacterial infection. Three weeks later, two more patients tested positive for the same bacterial strain after checking into the clinic. Over the next four months, the pathogen, a multidrug-resistant form of Klebsiella pneumoniae, continued to spread; approximately one clinic patient acquired the infection every week.

Clinicians threw up walls—both physical and chemical—to contain the pathogen. All patients were kept isolated and under surveillance; after the fourth case, infected patients were placed in a separate section of the center and tended to by a dedicated staff using dedicated instruments. Visitors wore caps, gowns, and gloves, surfaces were routinely washed with bleach, and the intensive care unit was regularly gassed with hydrogen peroxide to decontaminate the rooms. Still, patients in the hospital continued to become infected. At the end of the months-long outbreak, 18 patients had suffered Klebsiella infections; 11 had died. As the researchers reported later, bacteria isolated from many of these patients were resistant to most known antibiotics, “leaving no effective therapeutic options for some patients.”1

In the last decade, antibiotic resistance has grown from a concern to a crisis. In addition to the deadly incident at the NIH, a multidrug-resistant form of methicillin-resistant Staphylococcus aureus (MRSA) in a UK neonatal unit infected 12 babies in 2011. And just last year, carbapenem-resistant enterobacteriainfected seven people and killed two at a Los Angeles, California, hospital. Even when antibiotics do work, they’re not always the best option, as they wipe out beneficial bacteria as well as pathogenic ones, with potentially long-lasting health consequences.

Researchers on the hunt for more-effective therapies that preserve a healthy microbiome are taking a closer look at the many different viruses that attack bacteria. Bacteriophages (literally, “bacteria eaters”) punch holes through the microbes’ outer covering and inject their own genetic material, hijacking the host’s cellular machinery to make viral copies, then burst open the cell with proteins known as lysins, releasing dozens or hundreds of new phages. The cycle continues until there are no bacteria left to slay. Phages are picky eaters that only attack specific types of bacteria, so they’re unlikely to harm the normal microbiome or any human cells. And because phages have coevolved with their bacterial victims for millennia, it’s unlikely that an arms race will lead to resistance. This simple biology has led to renewed interest in the surprisingly long-standing practice of phage therapy: infecting patients with viruses to kill their bacterial foes.

While most research is still in the preclinical phase, a handful of trials are underway, and a growing number of companies are investing in the treatment strategy. Phage therapy is receiving as much attention now as it did in the pre-antibiotic era, when it flourished in spite of the dearth of clinical tests or regulatory oversight at the time. “Bacteriophage therapy will have its day again,” pathologist Catherine Loc-Carrillo of the University of Utah told The Scientist last year. “It sort of had one, before antibiotics came along, but it wasn’t well understood then.”

But with lingering questions about phages, which are often dubbed “viral dark matter” because so little is known about their biology, their use in mainstream medicine still faces many hurdles. And the consequences of moving phage therapies forward without more concrete evidence could be devastating, adds phage biologist Ryland Young of Texas A&M University. “If we have more poor data like we did in the 1920s, it’ll really set applications back in the long term.”

A century of cures

The roots of phage therapy stretch back more than 100 years, even before the discovery of bacteriophages. In 1896, British bacteriologist Ernest Hankin tested water from two Indian rivers, the Ganges and its tributary the Yamuna—locally believed to have curative properties—and found evidence of antibacterial activity. He used porcelain filters to strain the river water, removing bacteria and larger organisms while retaining a suspension that could kill Vibrio cholerae. He suspected some unknown substance or agent in the water played a part in limiting the spread of cholera epidemics in the area. Over the next few years, reports of natural waters with similar antibacterial properties trickled in from Russia and other parts of the world.

Two decades later, another British bacteriologist, Frederick Twort, found a bacteria-killing agent while working with Micrococcus cultures, although he hesitated to hypothesize that it was a virus.2 In the 1910s, French-Canadian microbiologist Felix d’Herelle was testing fecal filtrates from soldiers infected with Shigella, a causative agent of dysentery, when he uncovered evidence to support Twort’s discoveries. After a few days of applying the fecal samples to Shigella cultures, d’Herelle saw kill zones on the culture plates where something had decimated the pathogen. Conjecturing more boldly than Twort, d’Herelle suspected he was observing the work of viruses that infect bacteria, and he coined the term “bacteriophage,” from the Greek word for “to eat,” to describe the disease-fighting agents.3 “In a flash I had understood: what caused my clear spots was, in fact, an invisible microbe, a filterable virus, but a virus parasitic on bacteria,” d’Herelle recalled in a 1948 article.4

D’Herelle conjectured that the sick soldier whose fecal sample had killed the bacteria in culture would probably also recover, thanks to the same microbe-killing virus—and he was right.5 Four years later, in 1919, d’Herelle used these same phages, isolated from the fecal samples of dysentery  patients who’d recovered, to successfully treat children suffering the same infection.

No one had actually seen a phage; it would be another 20 years before scientists captured the earliest electron micrographs of bacteria-infecting viruses.6 But phage therapy began to be used around the world to treat a dizzying array of infections. Belgian researchers reported injecting phages isolated from various sources to cure staphylococcal skin infections; intravenous phage therapy was used to treat cholera in India and streptococcal infections in France; studies in the U.S. reported treating septicemia and meningitis.

The rapid growth of the field was characterized by “an early, enthusiastic period during which claims were excessive and often unrealistic, while at the same time little was understood of the viral nature of phages or their strengths and limitations,” Elizabeth Kutter of Evergreen State College in Washington and colleagues wrote in a 2011 review of phage therapy’s history.7 Despite the fact that some pharmaceutical companies began standardizing and marketing the therapies as early as the 1920s, the US Food and Drug Administration was not overseeing their development, and few were subjected to controlled clinical testing.

In 1934, a three-part JAMA report provided the first objective evaluation of phage therapy. The authors assessed more than 100 studies and concluded that the treatment was only reliable for some staphylococcal infections. Without double-blind trials and clinical research to test its effectiveness and safety, phage therapy fell out of favor in the West. Attention turned to antibiotics, which had been discovered in 1928 and were easier to manufacture and standardize.8 But phage therapy stuck around in many parts of the world, particularly in Eastern Europe, where modern drugs are expensive and often hard to come by………

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