In 1915, British scientist Frederick Twort saw something weird happening to the bacteria that had invaded his viral cultures: They were disappearing, a sign they had been destroyed. Two years later, French-Canadian microbiologist Félix d’ Hérelle observed the same phenomenon in his own lab.
Both researchers, working independently, concluded that the viruses they had been growing were killing the bacteria. It was an astonishing discovery, because no one had any idea that viruses had that kind of power.
D’ Hérelle called them “bacteriophages,” or “bacteria eaters.” That was a misnomer, because the viruses don’t actually eat the bacteria. Rather, they infect them, then blow them apart. But the name stuck.
A century ago, bacteriophages were difficult to isolate, purify and administer to people, so they offered little prospect as treatments against bacterial infections. Moreover, antibiotics soon would come along and prove to be plentiful, potent and easy to use. Researchers continued to study bacteriophages, but there was scant motivation to use them for therapy.
Today the world faces an alarming public health threat from multi-drug-resistant infections. The World Health Organization calls bacterial resistance “one of the biggest threats to global health, food security, and development today,” and says it is rising to “dangerously high levels” everywhere, with many infections difficult or even impossible to treat. There are more than 2 million cases and 23,000 deaths from antibiotic-resistant infections annually in the United States, according to the Centers for Disease Control and Prevention.
As a result, scientists are taking a fresh look at what is called phage therapy.
“They are starting to dust off their old laboratory notes and re-explore the use of bacteriophages as a ‘new’ way to treat serious, life-threatening infections,” says William Schaffner, medical director of the National Foundation for Infectious Diseases.
Increasingly, specialists in infectious diseases believe phage therapy holds promise against bacterial diseases, especially in cases where antibiotics have failed. In 2016, the approach saved a San Diego man who otherwise would have died. (See sidebar.) Several similar successes have been reported since then.
“We desperately need something to treat infections resistant to antibiotics, so we are turning back to these viruses, but with new knowledge and new technology,” says Carl Merril, a retired National Institutes of Health scientist who has been studying bacteriophages for 50 years. Initially, they probably will be used in life-threatening situations or as an adjunct to antibiotics, “but I do see them in the future as being a first-line defense,” he says.
Phage therapy is not licensed by the Food and Drug Administration for humans, although the agency has granted permission to use it in at least four life-threatening situations,including the 2016 San Diego case. The agency also is studying the issues related to possible future widespread human use. These issues include the design of clinical trials, which are necessary for approval. The agency has scheduled a public workshop to discuss the scientific and regulatory issues.
Nevertheless, “the data on efficacy of bacteriophage are limited, particularly due to a lack of well-controlled clinical trials,” says Cara Fiore, a microbiologist in the FDA’s Center for Biologics Evaluation and Research. The agency is aware of the growing interest in phages among researchers and “recognizes the potential importance of bacteriophages for therapy,” she says.
(What is the plural of “bacteriophage” — “bacteriophages” or “bacteriophage”? Fiore uses both words, as many do. See sidebar.)
Bacteriophages are ubiquitous. They are found in sewage and wastewater, soil, marine water, the intestines of animals, even in the human gut. In fact, there are more bacteriophages than any other kinds of viruses. There are believed to be more than 10 million trillion trillion, more than any other organism on Earth.
“Our GI tracts are loaded with millions of them that are merrily trying to kill the bacteria that live in our GI tract, bacteria that are constantly evolving to avoid the phages that are coming after them,” says Robert T. Schooley, chief of the Division of Infectious Diseases at the University of California at San Diego. “Darwin would be proud.”
Several academic institutions and the U.S. Navy are collecting phage samples. The Navy, which has been researching phages for nearly a decade, sees them, among other things, as a potential treatment for infections cause by battlefield wounds.
Naval researchers collect phage specimens all over the world, from places most people avoid.
“We go where there is water humans have used, whether to flush toilets or to take a shower with or brush your teeth,” says Michael Stockelman, deputy director of the Naval Medical Research Center’s infectious-diseases directorate in Silver Spring. “We go to wastewater treatment plants and cities with open sewers. They’re easy to find because phages are fairly stable in the environment. They have to linger long enough to find their next host.”
Antibiotics typically kill all bacteria, including beneficial ones. But phages are bacteria-specific, attacking only a single species of bacteria. Phages enter bacterial cells, where they replicate, causing the cells to rupture. This releases additional phages into the body, making the treatment more potent.
The key is matching the right phage to the right bacterium. Scientists say it is likely that every bacterium has a phage — or many phages — that can kill it.
This involves taking a patient’s multidrug-resistant bacterium, growing it on a “lawn” of agar (a jellylike substance used to culture microorganisms) with an overlay of phages, then looking for “holes” in the lawn where the phages have killed the bacteria. Once identified, the phages are plucked, grown in large batches and purified. Depending on the site of the infection, they are then delivered orally, topically, intravenously or into the respiratory tract by aerosol administration.
This process can take five to 10 days. A critically ill patient might die during that time, but researchers say they believe that eventually they will be able to streamline the method.
“There are some things that ultimately might make this easier,” Schooley says. “For example, as we learn what receptors a given phage uses to get into a cell, one could see if the bacterium has that receptor — if not, the phage won’t work. Also, as it becomes more automated, it is possible that one could cut this to 48 to 72 hours. But for now, it’s going to be a ‘show me what you kill’ vetting process.”
Although phages are not yet approved for people, most experts say they believe they are safe. “We are awash with phages already, and administering a purified phage or [combination of] phages is unlikely to cause problems,” Schooley says. “We’re exposed to them all the time.”
It is possible that people will develop antibodies to the viruses, but this should not diminish the phages’ efficacy, according to Merril. “Antibodies could react to parts of the virus but wouldn’t affect how they kill the bacteria,” he says. Also, a phage will bind quickly to the bacteria, “whereas it takes longer for antibodies to develop and act,” he adds.
Bacteria can develop resistance to phages, as they do to antibiotics. But because millions of genetically different phages can attack a specific bacterium, it’s possible to create phage “cocktails” to prevent resistance, an approach similar to that used by AIDS clinicians with antiviral drugs to treat HIV.
“Because there are so many of these viruses on the planet, it assures we will be able to find the right virus, or combination of viruses, to treat any infected individuals,” Merril says.
Some phages are able to pick up genetic material from bacteria and, during replication, transfer it to other bacteria. This raises the possibility that phage progeny could spread harmful genes — for example, genes that could produce dangerous toxins. Viruses with this quality are called lysogenic phages.
But it’s possible to screen for such phages by “sequencing the viruses we identify and analyzing them,” Merril says. Lysogenic phages would not be used in humans, he says.
Most phage researchers see none of these challenges as insurmountable. Moreover, they say that the growing urgency posed by multidrug-resistant bacteria underscores the need to find effective alternatives, including the greater use of bacteriophages.
“Antibiotics are becoming a limited option, and new ones are not coming along when we need them,” says the Navy’s Stockelman. “We are very excited about phage therapy. It shakes up the old paradigms, but we believe in it.” And, unlike antibiotics, he adds, “we will never run out of them.”