Features | Lysis to kill

How viruses could save your life

The assassins were born in Paris and kept a vacation home in Tijuana. They left calling cards and spawned countless imitators. Shunned by the West, the killers defected to the Soviet Union and were embraced by the Eastern Bloc. Now, lured by high-priced contracts, they’re back in North America with a long hit list. And they might just save your life.

The assassins, of course, are bacteriophages – viruses that infect and kill bacteria (the word is Greek for “eater of bacteria”). Researchers are working hard to find ways to use these tiny, lethal weapons as therapy against infection. And, with the future of antibiotics looking grim, the 007 of drugs may be just what we need.

As of mid-September, there had been 39 outbreaks of vancomycin-resistant Enteroccocus (VRE) in Montreal hospitals in 2011 alone. VRE is a “superbug” that causes blood infections and pneumonia. These bacteria are resistant to commonly used antibiotics and have become extremely common. Hospitals, with their weakened, antibiotic-dependent patients, are prime breeding grounds for these dangerous organisms. In 2006, 16 patients at a hospital in St. Hyacinthe, Quebec died after contracting C. difficile, another superbug.

Researchers are struggling to keep up, but they have proven too slow for the rapid evolution of superbugs. How can we respond to these superbugs as they grow more numerous, and as new antibiotics run out? Oddly, the solution to this crisis may be the same thing that causes everything from the common cold to AIDS: viruses.

Well, one kind of virus in particular. Just as bacteria infect us, bacteriophages infect bacteria. Resembling a space probe landing on the surface of the moon, the kinds of bacteriophages used in therapy plant their feet on the surface of a bacterial cell and inject their genetic information into their victim. The genetic material then hijacks the bacterium’s molecular machinery, turning it into an assembly line for more phages. When the new viruses are assembled and ready, they burst out of the cell, killing the bacterium, and drift off in search of new victims. As grisly as it sounds, bacteriophages can actually overcome bacterial infections in humans that do not respond to traditional antibiotics.

Phage therapy is nothing new. In 1919, only four years after the discovery of bacteriophages, the Montreal-born microbiologist Félix d’Herelle used bacteriophages to successfully treat dysentery in Paris. Over the next fifteen years, phage therapy enjoyed a boom in popularity worldwide and was even marketed by large North American pharmaceutical companies such as Eli Lilly. But this enthusiasm was short-lived: during the 1930s, the effectiveness of phage therapy was brought into question. In 1933, Margaret Straub and Martha Applebaum, researchers at Columbia University, published an investigation of the products of the three companies offering phage therapy in the US. They found that the products they tested had no phage in them, contained weak phages, or that the presence of phages varied from batch to batch. The following year, the American Medical Association’s Council on Pharmacy and Chemistry cast further doubt on phage therapy in a scathing report. “The lack of standardisation of phage preparations and the lack of criteria for purity and potency made it impossible to compare most of the studies that had been published,” the Council declared.

However, at the time, the world’s understanding of how phages work was very limited. Even though electron microscopy confirmed the details of these viruses’ structures in 1940, the discovery of penicillin and the rise in popularity of antibiotics caused phage therapy to be abandoned in most of the world. Rosemonde Mandeville, president and CEO of Biophage Pharma – a Montreal-based company founded in 1995 – spoke with The Daily about the PR campaign against phages. “It had bad press, mainly because of lobbying [by] pharmaceutical companies that [were] working with antibiotics.”

Although health authorities in the west were turned off of phages, many institutions in Eastern Europe continued to develop the therapy. In the 1920’s, Georgian physician and bacteriologist George Eliava met Felix D’Herelle, just as phage therapy was being born. In 1923, Eliava founded the George Eliava Institute of Bacteriophage, Microbiology, and Virology in Tbilisi, Georgia. The institute soon became the epicenter of phage therapy research and still exists today, treating patients and conducting research on phage therapy.

Surprisingly, very little research from Eastern Europe is being used in Western bacteriophage research. Although this may seem counterproductive, science cannot always transcend various linguistic, political, and societal borders. The lack of comparably strict guidelines in the testing of medical treatments in Eastern Europe may be the largest stumbling block when it comes to international scientific collaboration. “A lot of people [were] interested in phage therapy,” says Mandeville, “but phage therapy was used without the strict regulations that we have here in North America.”

While phage therapy attracted a large following in the former Soviet Union, only a small number of scientists in the West continued to test its effectiveness, and then only in treating animal infections. But, in these experiments, phage therapy often proved to be not only effective, but even more effective than antibiotics. Over the past thirty years, phage therapy has been tested on several different animals, and has been successful in treating numerous bacterial infections. One study found that phages protected mice from vancomycin-resistant Enteroccocus (VRE). Another study showed phages saving guinea pigs from a potentially fatal C. difficile infection.

These successes in animal treatment provided solid evidence, and allowed for a renewed interest in phage therapy. In 2006, the FDA approved a food spray – used to kill Listeria monocytogenes, a common food contaminate – that contained six different phages.

Now, ninety years after the height of the phage vogue, the list of antibiotic-resistant bacteria is growing progressively longer, at an ever more rapid rate. At the same time, the search for new antibiotics is getting more frantic, but less fruitful. It seems like the time of phage therapy has finally come.

“Especially now that a large number of bacteria are resistant to antibiotics, this could be a very good alternative,” says Mandeville.

Although bacteria can still evolve to develop resistance to bacteriophages, phages are also dynamic and able to evolve to overcome their victims’ defenses. Laboratory experiments have shown that, as bacteria develop resistance, new phages often rapidly emerge that are able to infect them.

In addition, a mixture of different phages with different characteristics, called a “cocktail,” is often used in treatments. This allows a number of harmful bacterial strains to be targeted at once, also making it more difficult for the bacteria to develop resistance. “There is very little resistance that develops because we use a cocktail,” says Mandeville. “If we use a cocktail, we are covering all the bases.”

(Still, a 2010 paper in the journal Applied Microbiology and Biotechnology warns of cocktails “efficiency is unlikely to reach 100%”).

Supporters of phage therapy were concerned at first that the use of cocktails would make it difficult for phage therapy to be approved by the FDA, which tends to prefer “one-size-fits-all” treatments. Surprisingly, this has not proved to be the case: in 2008, the first phage therapy product approved by the FDA for clinical trial in the US was a cocktail containing eight different phages for patients with ulcers.

Cocktails work because no two viral strains are created alike and, while bacteriophages are viruses, they are incredibly specific. They are only able to infect one species of bacteria, leaving our own cells untouched. And while some adverse reactions to the treatment have been produced by poorly purified specimens, the problem has been mostly eradictated by more careful sample preparation.

In addition to this, phage therapy may actually be safer than the antibiotics we have trusted for so long. Our bodies are ecosystems of microorganisms. There are actually more bacterial cells than human cells in our bodies and a large portion of these bacteria are beneficial, helping us digest our food and synthesize essential vitamins. Unlike bacteriophages, antibiotics kill all bacteria – both good and bad – leaving us open to opportunistic infections.

“There are no risks if you do your homework,” says Mandeville. “If you work well and you follow the guidelines of the FDA or Health Canada, if you prepare phages that are well characterized, have no toxins and no pyrogens in them and you are very sure that they are stable…you won’t have a problem.”

Currently, there are no authorized phage therapy treatments available to the public in North America, but companies like Biophage Pharma are pushing to begin clinical trials and get their products out to the public.

Mandeville says she hopes to have a product on the market in five years’ time. “The phages against MRSA and Pseudomonas are ready. We have well characterized phages and we are looking for the right partner. We do have some people that are interested, so we hope to get them on the market very soon.”

Even now, North Americans can easily receive phage therapy if they’re willing to travel. The Phage Therapy Center, recently bought by the American company Phage International, operates in Tbilisi, Georgia and Tijuana, Mexico and offers phage therapy to international patients. A clinic in Wroclaw, Poland is also licensed to conduct experimental phage therapy in cases where other treatments have failed. And one doctor in France uses phages purchased in Georgia to treat severe infections. (It’s worth noting that the quality of treatment in these places may not meet Canadian standards.)

The effect of phage therapy may go far beyond battling antibiotic resistance. Phage therapy could, in theory, offer a cheaper, more efficient method of dealing with common infections, especially in developing countries. For example, trials have been conducted in Bangladesh to see how phages fare at treating diarrhea in infants.

“One of the big killers of children is dysentery. In under-developed countries, this is the big factor,” says Mandeville. “We have the phages that can at least prevent or decontaminate and they’re not using them.”

This raises an interesting question: if phage therapy becomes a common alternative to antibiotics, what would it mean for drug companies? Since new strains of bacteriophages are constantly emerging in the environment, would it be possible for major pharmaceutical companies to hold a monopoly over phage therapies like they do over antibiotics?

Right now, we don’t have any way of knowing. But one thing remains certain: we are currently losing the battle against superbugs, and phage therapy is an option we cannot ignore.


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