In October 2017, Graham Hatfull received an urgent email from across the pond. A microbiologist colleague of his named James Soothill was desperately looking for a way to help two patients at the Great Ormond Street Hospital in London. The pair of teenagers, a girl and a boy, had cystic fibrosis, a genetic condition where the lungs can’t clear mucus or disease-causing bacteria. And they had both recently received double lung transplants as a result. The surgeries had gone well. But shortly after, infections long simmering inside their young bodies erupted from their sutures. And as Soothill noted in his message, the bacterial strains now spreading across their skin and through their tissues were impervious to all the hospital’s antibiotics.
With no more drugs to try, they were put on palliative care plans. But maybe Hatfull had a hail mary in his freezers. Since the late 1990s, the University of Pittsburgh microbiologist had been enlisting students to help him amass the world’s largest collection of bacteriophages—viruses that prey solely on bacteria—from around the world. Perhaps a phage or two among those 15,000 vials sitting at –80 degrees Celsius might overpower the bacterial assaults on the lives of the two British patients.
In the end, there were four. By January, Hatfull’s team had identified one phage that could attack the boy’s strain. But they were too late—he had succumbed to his infection earlier that month. The girl, though, has been receiving a cocktail of three phages from Hatfull’s lab since June—including two that were genetically modified to better attack her bacteria.
Though she's still recovering, her skin lesions have mostly disappeared, and her liver and lungs are back from the brink of organ failure. She’s also back to more normal teenage things, like posting silly cat photos to Facebook and baking cupcakes. The results of this drastic intervention, published today in the journal Nature Medicine, represent the first-ever use of engineered phages in a human patient. The success offers hope that the emerging field of synthetic biology might reboot the 100-year-old Soviet science of phage therapy to arm doctors with a potent new weapon against superbugs.
“At first we were just excited to have two more strains to test on our phages,” says Hatfull. But as his team’s search for viral predators with a taste for Mycobacterium abscessus began to turn up promising leads from deep within the phage library, it became an all-consuming quest for the young research associates in his lab. “Once they smelled blood in the water, they worked tirelessly to turn this thing from a hypothetical to something we could put in a box and ship to London.”
The University of Pittsburgh researchers dug up three phages that could successfully invade the female patient’s strain of M. abcessus: Muddy, ZoeJ, and BPs. (Because most of Hatfull’s phage library is collected and characterized by undergraduate research volunteers, the names can get pretty funny: ChickenNugget, TGIPhriday, and IAmGroot are among the recent additions.)
But Muddy, which was scraped off the underside of a rotting eggplant by a student in Durban, South Africa, in 2010, was the only phage that has what’s called a lytic lifecycle. It hijacks a bacteria’s machinery to make millions of copies of itself, eventually bursting the cell apart and killing it. ZoeJ and BPs, on the other hand, could get inside the bacteria. But once there, they just curled up inside its DNA and went dormant. To make them useful for a patient, Hatfull’s team needed to toggle their snooze button into “phage rage” mode, as Steffanie Strathdee, coauthor of The Perfect Predator, calls it.
Using a form of genetic engineering pioneered in his lab, Hatfull’s group removed the repressor gene that sent ZoeJ and BPs to virus dreamland. With that stretch of DNA gone, they could now blow apart bacteria too. And because the scientists hadn’t added any genes, merely deleted some, the phages weren’t subject to the European Union’s regulations around GMO therapeutics. The team still faced regulatory hurdles, including getting permission to use the unapproved phages as an experimental treatment. But by June, the hospital had received the cocktail and prepared dosages to begin dripping into the patient’s arm.
While her recovery is perhaps nothing short of remarkable, Hatfull is quick to point out that the treatment does not generalize. The phages were tailored for one isolate of a single strain of M. abcessus; they won’t work in most other cases of infection from that bacterium. “Phages are a double-edged sword,” he says. “Their tremendous specificity gives you safety—they won’t touch human cells or the rest of the microbiome. But they’re so specific that you wind up with a personalized medicine that can’t be applied to other patients.”
Still, as the global crisis of antibiotic resistance deepens, commercial interest is growing in engineered phages as a potential solution. In January, Johnson & Johnson struck a deal worth upwards of $818 million with Locus Biosciences to develop Crispr phages for treating lung infections. The startup joins nine other companies in the US and Europe currently developing phage-based therapies.
The Cystic Fibrosis Foundation recently committed $100 million to better detect, prevent, and treat the chronic lung infections that often develop resistance as a result of antibiotic escalation. As part of that effort, the organization says it is pursuing research into the safety and efficacy of phage therapy. “We are particularly interested in approaches that intend to follow a path that includes achieving regulatory goals, so that ultimately new treatments could be available beyond unique situations and conditions,” says J. P. Clancy, senior director of clinical research at CFF.
Those sorts of rigorous trials will soon be underway. The nation’s first phage translational research center, which launched last year at the University of California, San Diego, is currently planning two clinical trials, including one for patients of cystic fibrosis. It will enroll 30 patients, likely starting later this year, and test Pseudomonas-fighting phages isolated by the Walter Reed Army Institute of Research in Texas.
The goal of the trial, backed by the National Institute of Allergy and Infectious Diseases, is to figure out the best dosing strategies to minimize any negative potential impacts of the therapy. “It’s the same method we’ve used to evaluate antibiotics for 80 years,” says Robert “Chip” Schooley, who is leading the UCSD study and also advised Hatfull’s group. Except that unlike antibiotics, phage therapy is more than just a new class of drugs, says Schooley. “It’s a whole new approach that opens the doors to treating multidrug-resistant superbugs. With phages we’re really going back to the future.”
Science has come a long way since Felix d’Herelle first treated Parisian schoolchildren with a phage he isolated from the stools of soldiers in his care at the Pasteur Institute in 1919. But with an estimated nonillion phages never catalogued in libraries like Hatfull’s, out there stalking their bacterial prey through the soil, water, and air, there’s still plenty left to learn.