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.”