When Genean Hixon was twelve, she was admitted to a Denver hospital with a bone infection that was known to be fatal. Doctors there treated her with a “miracle drug” derived from mould and only used experimentally on civilian patients. It was 1943, and the drug, penicillin, cured her. Hixon didn’t die until this past March, two days shy of her eighty-third birthday, during the very same week that a case of antibiotic-resistant tuberculosis was reported in a Los Angeles hospital—just the latest chapter in an ongoing global superbug crisis.
Alexander Fleming, who discovered penicillin, was a good enough scientist to foresee this disaster. “There is the danger,” he said in 1945, “that the ignorant man may easily under-dose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.” The ignorant man did indeed, but he didn’t stop there; he under-dosed his livestock, too. As a result, superbugs have colonized hospitals around the world. Eighteen strains of bacteria are now recognized as a threat by the Centers for Disease Control and Prevention in Atlanta. In Canada, an estimated twenty-two patients die every day from hospital-acquired infections, while many more are left with chronic illnesses that destroy their quality of life. Less than a lifetime after Hixon’s recovery, the miracle cure is no more, but has an alternative—bacteriophage therapy—been waiting in the shadows all along?
If the history of antibiotics is fast paced and simplistic, a Die Hard kind of narrative, the story of phage therapy, which predates the discovery of antibiotics by about ten years, is a complex, tortured European noir. Our protagonist, Félix d’Herelle, was an iconoclastic French-Canadian scientist with socialist leanings and an adventurous, peripatetic past. Possessing only a high school diploma, he was hired in his twenties to distill whisky from banana pulp in Guatemala, where he was attacked at knifepoint and shot his assailant dead. He went on to Mexico, Argentina, Algeria, and Tunisia to combat plagues of locusts by using their own diseases.
In 1917, his research into dysentery revealed the existence of bacterial viruses called bacteriophages. These resemble tiny lunar landing modules, and they attach to the surface of bacteria and inject them with DNA, which multiplies within, destroying the host in the process. Unlike broad-spectrum antibiotics, which swiftly and indiscriminately wipe out both helpful and harmful bacteria, phages target precisely but work over a longer period of time.
Phage therapy prevented thousands of deaths from dysentery in Brazil and cholera in India, and pharmaceutical companies such as Eli Lilly began to investigate its possibilities. In 1933, d’Herelle was invited to continue his research at a Soviet lab in Tbilisi, Georgia. He accepted, and worked there on and off for two years, until his lab partner was arrested and killed by the secret police. D’Herelle, spooked and disillusioned, returned to the West. He died in France in 1949, overlooked for the Nobel Prize, which was awarded in 1945 to (you guessed it) Alexander Fleming.
Penicillin, after all, was one of the heroes of World War II, saving many American soldiers’ lives, and in subsequent decades it became ubiquitous. Meanwhile, the Soviets, whether out of Cold War stubbornness or economic necessity, continued to use phage therapy in conjunction with antibiotics.
The Eliava Phage Therapy Centre is one of two clinics in Tbilisi actively soliciting international patients afflicted with resistant infections. “There was a news article in a Norwegian newspaper, and we got a patient from that,” says Naomi Hoyle, manager of international relations for Eliava. “There was a show on Swiss television, and we got several patients from that.” Anna, a sixty-nine-year-old from Montreal, was also one of the clinic’s patients. After routine surgery for kidney stones seven years ago, she contracted resistant E. coli and Klebsiella, and she has had a chronic bladder infection ever since. “I’m Russian,” she says, “so I knew phages have been used in Russia since about eighty years, with good results.”
She had her first treatment in 2011, followed by two more a year later, and she is now free of Klebsiella. An unrelated condition has made the E. coli especially difficult to eradicate. “I strongly believe in phages,” she maintains, “but you have to be living there to be treated successfully, or be very rich, to afford to go back and forth.” Andrew Kropinski, a microbiologist and professor who studies phages at the University of Guelph, in Ontario, explains that isolating effective phages, then engineering them in sufficiently large numbers with optimal shelf lives is tricky and time consuming—and even when they work in the lab, they don’t always work in the clinic. “Let me put it this way,” he says. “Is phage therapy the next magic bullet? No, it isn’t. Is it worth investigating? Yes, definitely.”
Yet Canadian research in the field so far has been limited to livestock, with mostly positive results. Rosemonde Mandeville runs BioPhage Pharma, a company in Montreal that develops phages for food safety, but also has a library of viruses effective against various resistant bacteria, including S. aureus. Every month, she says, people contact her asking for help, but she has to turn them away. In Georgia, she explains, “anecdotally they have spectacular remissions, but you need more than that. You need clinical trials, and clinical trials cost a lot,” between $30 million and $50 million.
Add to that the fact that phages are live and potentially unstable, and they have the ability to adapt in tandem with evolving bacteria. How do you regulate a product that is constantly morphing? Still, the urgency is undeniable. “I think that phage therapy will come, no matter what,” says Kropinski. Indeed, last year the US Army paired with American company AmpliPhi Biosciences Corporation to take the first steps toward bringing phage therapy to scale.
For now, sick Canadians must rely on expensive international travel to find relief. It is an irony to which wary socialist Félix d’Herelle would have been exquisitely attuned.
This appeared in the July/August 2014 issue.