In February, an exciting threshold in medical history was crossed: a team of scientists at the University of Pittsburgh used contemporary gene editing tools to alter a bacteriophage. The phage — a tiny organism that preys on bacteria — was then used to treat a young English woman, Isabelle Holdaway, who was suffering from a previously untreatable bacterial infection.
One of the scientists to identify this moment as historic was Steffanie Strathdee, an infectious disease epidemiologist at the University of California San Diego (where she heads up a phage research and treatment program called IPATH) and the author of The Perfect Predator: A Scientist’s Race to Save Her Husband from A Deadly Superbug (Hachette Books, 352 pp.).
That titular race played a key role in sparking the recent wave of renewed interest in phages. Strathdee’s experience was, as her book’s title suggests, horrific. Her husband contracted a superbug infection while travelling in Egypt and was saved by an eleventh-hour intravenous phage treatment. But — as she put it when we spoke to her about her book, phage technology, and the looming superbug crisis — “it wasn’t really until my husband’s case hit the news” that phages caught the interest of the medical mainstream again. “He was treated with phage therapy in March of 2016. In April of 2017, the results were presented at the Pasteur Institute for the 100th anniversary of the discovery of bacteriophages.”
This wider medical recognition is long overdue, in Strathdee’s opinion. “Phages,” she told us, are “actually the oldest and most ubiquitous organisms around. It’s estimated that there are ten million, trillion, trillion phages on the planet. They’re in soil. They’re in water. They’re on our skin. They’re in our guts.” Despite this ubiquity, their potential use as an anti-bacterial agent was not discovered until 1917. A French biologist and entrepreneur, Felix d’Herelle, managed to isolate them and use them to treat dysentery. While d’Herelle’s discovery soon fell into the shadow of the discovery of penicillin, phages went on to enjoy a robust medical use in the Soviet Union and in some European nations. However, the medical uses of phage, Strathdee explained, were largely ignored in the U.S. and elsewhere — even as the tiny organisms proved to be foundational for much of modern microbiology. “About half of the Nobel Laureates in the 1950’s and 60’s won because of their work on phages,” she points out. “But they were seeing phages as a tool. They were never really forgotten in basic biology, but they were forgotten in medicine. Even with CRISPR [a powerful contemporary gene-editing tool], phages were used as a tool to discover it. CRISPR is really a form of the bacteria’s immune system that they equipped themselves with to protect themselves from phages.”
These organisms have taken on new significance in what Strathdee frighteningly called our “post-antibiotic” age. She describes her husband as its “poster child,” a sobriquet she bestowed because the bacteria infecting him had “acquired a resistance gene to Colistin — the last resort antibiotic — right around the time a paper was first published in Lancet reporting the appearance of this gene in pigs in China. By the time people looked to see if it was other places, it was already in 30 countries. It was mindblowing, to be honest. We’re at a time now where simple scrapes and surgeries are leading to infections that are increasingly untreatable. It’s not universal, but we’re seeing more and more people coming in to hospitals for a knee replacement, or a pacemaker replacement, or appendicitis, or bariatric surgery. And they’re acquiring superbugs. I know because they’re calling us at IPATH. They’re calling every day.”
How did we get here? “We were complacent as a society,” Strathdee says. “New antibiotics were being developed. We thought that we could stay ahead of the bacteria. We were shocked to realize that they were way ahead of us. But this is not only due to our overuse in people, it’s due to our overuse in livestock and agriculture. Seventy-five percent of all antibiotics used in the U.S. are actually used in livestock to make pigs and cows and chickens grow fatter faster. In hospitals poor infection control can lead to the spread of antimicrobial resistance as well. About 15 percent of inpatients in hospitals in the U.S. these days acquire a superbug while they’re there — often MRSA or C. diff. Worse still, many of these superbugs are not reportable at the national level in the U.S. My husband’s infection was reportable in Germany at the national level. But it wasn’t reportable in California. We’re not monitoring antimicrobial resistance very well, either.” She cites a frightening anecdote about the bacteria that almost killed her husband: she herself, when working towards her Ph.D. in the late 1980’s, used to plate it on Petri dishes with no fear. Since then, it has become a nearly unstoppable killer.
It’s important to put emphasis on that nearly. Strathdee titled her book The Perfect Predator to reflect her view of phages. They generally function in a simple but deadly way: by entering bacterial cells and using their internal biological machinery to reproduce more and more phages. “When given the kill signal,” she told us, “these baby phages burst out of the bacterial cell and then they, in turn, go to attack more bacteria until there’s none left.” This is what makes them so potentially powerful as treatments: they are the last organisms left capable of taking on bacteria adapted to the flood of antibiotics inundating the modern world. And not only can they work as a form of direct therapy. They have powerful applicability as a secondary treatment as well. As Strathdee points out, they can sometimes make antibiotics efficacious again against superbugs previously resistant to them: “The bacteria are faced with a genetic decision when they’re being attacked by those phages and antibiotics at the same time. They need to evade both attackers at the same time, and in some cases they modify themselves so that they’re susceptible to the antibiotics again.”
When it comes to longer-term risks associated with phage therapy, Strathdee is blunt. “We haven’t seen any so far. And we’ve been injecting phages into people.” She also points out that because each phage is specialized to attack only certain bacteria, when they have done their work they are excreted “almost magically by the body, without hurting any of the other friendly bacteria.”
There is, however, a short-term hurdle. Phages, while in many cases ruthless killing machines, can sometimes be “temperate,” to use the current term of art. This means that instead of hijacking the bacterium and changing it into a phage-production facility, they instead enter the bacterial cell and become dormant. Strathdee calls this “hitting the snooze button.” These phages “integrate their genetic material into the genetic material of the bacterial cell. And with it they can integrate other parts of their DNA — toxin genes or even antibiotic resistance genes. Often they have a defense mechanism whereby they make the bacterial cell impervious to new attacks from other phages. So they are not only not killing the bacterial cell in this situation, but actually causing potential harm.” This is why the phage developed by the Pittsburgh team had to be gene-edited in order to be effective: Isabelle Holdaway was infected with Mycobacterium asepsis, a member of the same genus of bacteria as those that cause tuberculosis. The phages that attack mycobacterium belong to the “temperate” category, and they required the deletion and addition of genes in order to realize their potential as perfect predators. There is an element of poetry in all this, grim as it is: consider Strathdee’s observation that CRISPR itself comes from phage work against bacteria and is now being used to edit phages to make them still more effective in the fight.
And effective they are. They saved Tom Patterson’s life, and appear to be saving Isabelle Holdaway’s. The young woman is, Strathdee notes, still under treatment — her infection is a difficult one to get rid of, even with phage therapy. But, says Strathdee, “Isabelle was in hospice and now she’s emailing me, texting me, sending me pictures of her cat, and asking when we’re coming to visit so that she can make cupcakes. She’s learning how to drive, she’s taking her A-level exams. She’s just a happy teenager.”
Nonetheless, work remains to be done. “We need to know a lot more about phage biology,” Strathdee says, before the question of temperate phages can be conquered fully. “The lab scientist who did the genetic modification of the phage to treat Isabelle says, basically, ‘Let’s not run before we walk. Let’s do carefully controlled studies, rigorous controlled clinical trials, and do them right. And publish and work together as a field, globally, because this is a global health problem.’” This work is all the more necessary because, as Strathdee pointed out, a number of major pharmaceutical companies are making strategic exits from the antibiotic development market. “New antibiotics take 10 to 15 years to develop, and at least a billion dollars. And most pharmas are getting out of the industry because they’re too expensive and because they’re being told the shelf life of these antibiotics is short. We need a new incentives model for antibiotics.”
But that alone, in Strathdee’s opinion, won’t be nearly enough. Phages are important precisely because they offer a powerful complement or even an alternative to existing anti-biotic therapies. “It’s generally believed now,” she says, “that phage therapy is probably the best alternative to antibiotics that we have. And this isn’t just a problem in the U.S. or the U.K. It’s a problem everywhere. By 2050 one person every three seconds is going to be dying from a superbug infection, unless something drastic turns this around.”