A broad-spectrum look at the future of phages Antibiotic-resistant bacteria — superbugs — are medical monsters of our own design. Honed by years of antibiotic misuse and overuse, superbugs demand new weapons to treat them. Bacteria-hunting viruses called phages have emerged as potentially potent tools in this fight, successfully sicced on vicious infections in a psychologist who caught a superbug on vacation and a London cystic fibrosis patient. The cases are the most dramatic moments yet in a Western renaissance for phage therapy. Over a century since its debut, phage therapy is having a moment. And researchers are hoping that the moment lasts long enough for this to become not just a reliable weapon in our war against superbugs, but also potentially a tool that could do anything from delivering cancer drugs to parts of the body, to making our food supply safer. Just a few decades ago, phages were mostly forgotten in the West — but were still used frequently by doctors in the Eastern bloc. Alexander “Sandro” Sulakvelidze, a researcher from the country of Georgia first learned of the knowledge disparity during a fellowship at the University of Maryland in the 1990s. Sulakvelidze came upon his mentor, who had just lost a patient to a drug-resistant infection. When Sulakvelidze asked why the phages had not worked, his mentor asked him what he was talking about. “It was one of those moments in life when it really hit me,” Sulakvelidze says by phone. “Somebody’s father, brother, husband, friend just died in the most developed country in the world … has just died really unnecessarily, probably, from a simple infection that probably could have been treated in Georgia.” Nearly thirty years later, Thomas Patterson lived. The UC San Diego psychologist caught a vicious stomach bug on a vacation to Egypt. When he took a turn for the worse, bloodwork back in San Diego revealed he was fighting Acinetobacter baumannii, a bacterium nicknamed Iraqibacter for its proliferation in the Iraq conflict. Acinetobacter baumannii bacteria (Iraqibacter) as seen through a scanning electron microscope Iraqibacter is an example of a “superbug,” bacteria resistant to antibiotics. Desperate, his wife — epidemiologist Steffanie Strathdee — dove into the medical research and found papers on phage therapy. She promptly put out a call to other doctors around the world. The resulting assistance saved her husband’s life. Isabelle Carnell is alive, too. A cystic fibrosis patient in London, Carnell’s double lung transplant had led to an infection by Mycobacterium abscessus, another superbug. A team, led by Graham Hatfull of the University of Pittsburgh, began a phage treatment for Carnell as well. This was the first use of genetically modified phages for treatment, and the first time phages have been used against an infection of the genus Mycobacterium, which includes tuberculosis, one of the deadliest maladies on earth. Within six months, the infection had been beaten back. In 2010, Texas A&M University opened the Center for Phage Technology; the US Naval Medical Research Center began studying phages in earnest a year later. In 2018, inspired in part by Patterson’s recovery — detailed in a memoir Strathdee co-authored with Patterson called The Perfect Predator — UC San Diego founded the Center for Innovative Phage Applications and Therapeutics (IPATH). Strathdee is now co-director of IPATH. SUPERBUGS AND SCORCHED EARTH Phage therapy’s biggest obstacle, Strathdee believes, was its poor fortune to be discovered before penicillin, in 1917. (That phage therapies’ discoverer, Félix d’Herelle, was widely disliked did not help.) When the antibiotic first arrived, with its broad-spectrum, scorched-earth ability to eliminate vast swaths of different bacteria, the phage — which could only attack one specific bacteria at a time — was deemed less useful. The continued research and usage of phages in Eastern bloc countries like Poland and Georgia helped put the nail in the coffin; geopolitical bias made phage research for the Communists. The specificity which made phages once seem less desirable is now their greatest appeal. By overusing antibiotics, humanity unwittingly tipped the scales in an evolutionary arms race, leaving behind the strongest, most drug-resistant bacteria. The phage is now a potentially potent weapon against these so-called superbugs. Hatfull says that phages have been locked in an invisible war with bacteria for potentially 3 billion years, predating most forms of life we see today and predating bacteria just as long. The typical phage depicted in science books and as phage centers’ mascots are from the family Myoviridae. Looking something like the love child of a spider and a syringe, they feature a thin body topped with a “head” like a Dungeons & Dragons die, and end in a protrusion which injects their genetic material into the bacteria. The virus replicates inside the hijacked host, eventually destroying the bacteria as it escapes. This process is called the lytic cycle, and hunter-killer phages are called lytic to distinguish them from other phages which do not kill their prey. Working together as a phage cocktail, lytic phages can target and destroy superbugs. When the bacteria begin to resist the phages, biologists can genetically modify the phages to better attack the bacteria. The phages can even work in concert with antibiotics, applying evolutionary pressure from both sides. The bacteria must “choose” what to become resistant to, leaving them vulnerable to the other treatment method. “We don’t know enough about this kind of synergy,” Strathdee says. But further study can reveal which phages work best with which antibiotics, opening new methods of therapy. “Many of us don’t think that phage are ever going to replace antibiotics. We think they’re going to be an adjunct to antibiotics.” Mzia Kutateladze, director of the Eliava Institute in Tbilisi, Georgia, is excited to see phage therapy gaining traction and resources in the West. Whereas a few decades ago, Georgian scientists like Kutateladze and Sulakvelidze were viewed askance for their use of phages, they are now finding new acceptance. “I really proudly can say, together with the Georgians, that we have many international patients who are coming to us,” Kutateladze says. “And we have very nice results with very, very desperate and chronic infections.” Researchers at the Eliava Institute of Bacteriophages, Microbiology and Virology in Tbilisi BESPOKE BACTERIA KILLERS While promising, there are drawbacks to phage therapy. “The specificity is a double-edged sword,” Graham Hatfull says by phone. It’s advantageous for superbugs and for avoiding side effects. But that precision comes at a price: a phage that works for one strain of superbug in one patient may not work for another strain. Diagnosing the correct pathogen becomes absolutely critical, as phages not designed to attack the bacteria being treated are useless in said treatment. Strathdee believes that a giant, open-source phage library is key to making phage therapy valuable. Scientists and physicians can use the library to match phages and bacteria, ensuring quicker treatment. With enough genomic information about bacteria and phages — and a large enough training set — Hatfull imagines a world where machine learning enhances therapies. One could sequence the pathogen, plug the genomics into the algorithm, and be told which phages to mix together in the most effective cocktail. Jean-Paul Pirnay, a researcher at Queen Astrid Military Hospital in Brussels, takes this vision one step further. Pirnay believes synthetic natural phages, which are being worked on at Queen Astrid, may help alleviate the specificity problem. A system for producing custom-made iterations of natural phages would mean quick tailoring to particular pathogens and would remove the expense of storing massive stocks of phage. Eventually, Pirnay imagines a world where phages that do not exist in nature — truly bespoke viruses — are designed with the help of artificial intelligence to be as effective as possible, an infinite tool box. ONCE INSIDE THE BACTERIA, IT SHREDS THE BACTERIA’S DNA LIKE SO MANY BLUE GHOSTS Adding fuel to the fire is new investment by pharmaceutical companies, since genetically modified phages can be patented. Johnson & Johnson is in a partnership worth hundreds of millions with Locus Biosciences, a North Carolina-based company which specializes in using boutique phages to inject CRISPR-Cas3 into bacteria. CRISPR-Cas3 is often compared to Pac-Man: once inside the bacteria, it shreds the bacteria’s DNA like so many blue ghosts, killing it. Locus’ genetically modified phages help alleviate one of the challenges of phage therapy, which is that lytic phages do not always kill every bacteria. Locus can engineer the phages to have a more effective “depth of killing profile,” helping to ensure that everything the phage hunts is killed. There’s also potential in using phages as biological, targeted syringes. “In theory, you can deliver all different kinds of enzymes that do all different kinds of things,” Joseph Nixon, senior vice president of business development at Locus, says by phone. Nixon envisions phages being used to pinpoint cancer targets and — what he deems the “holy grail” — central nervous system targets. Theoretically, phages could be used to target bacteria in other ways — potentially increasing their pathogenicity instead of killing them. Luckily, that’s unlikely, Pirnay writes. He says there are more practical methods available for weaponizing bacteria, including CRISPR-Cas tools. A petri dish filled with bacteriophages PHAGES FOR THOUGHT (AND FOOD) Memories of the senseless death of his mentor’s patient stayed with Sulakvelidze. He went on to found Intralytix, a phage-focused company currently based in Baltimore, which today is perhaps best known for its food safety applications of the viruses. The phages, which target specific food-borne illness-causing bacteria, are not only effective at killing the pathogens, but are also certified kosher and halal, non-genetically modified, listed by the Organic Materials Review Institute, and are less abrasive than the chemical methods commonly used. The phages are sprayed onto the food, taking advantage of infrastructure which may already be in use, and cost slightly more than food safety chemicals, but are considerably cheaper than other non-chemical protections like irradiation and high-pressure pasteurization. For similar health conscious and anti-superbug reasons, phages have veterinary applications as well; targeted phage therapies to treat sick livestock may remove the overuse of antibiotics from animals’ food supply. According to Intralytix, the phages have applications in environmental sanitation and as probiotics — killing the bad stuff, keeping the good stuff. And the company recently announced a partnership with Ferring Pharmaceuticals and the Eliava Foundation, a Georgian nonprofit that is a separate entity from the Institute, to begin research for reproductive and women’s health. The researchers think phages could help with the management of bacterial vaginosis, Sulakvelidze wrote in an email to The Verge, and the treatment of pregnancy-related diseases. Once again, the specificity of phages is key; they could attack the “bad” bacteria without destabilizing the body’s invisible ecosystem. Sulakvelidze imagines a near future where phages — for food safety, or perhaps dietary supplements — are readily available in the West, perhaps even over the counter, like in his native Georgia. A doctor prepares a phage solution in France. BACTERIA HUNTER’S HURDLES All of the above work — the superbug bird-dogging, the research into and use of genetically modified phages, and their application in agriculture and OTC uses — are happening now, and will likely continue to grow as superbugs continue to kill, and novel uses for phages are discovered. And while all this is promising, there are real challenges facing phage research. We are entering an arms race which long precedes us, and will go on long after we disappear. The recent discovery of a CRISPR-Cas defense which robs the phage of the machinery it needs to replicate is just one of the many ingenious defenses we will no doubt encounter as we continue to fight superbugs. Phage therapy will need to find ways to overcome these bacterial defenses to remain effective. A current lack of basic knowledge needs to be addressed; the more information we have about the phages and their chosen prey, the better we will be able to utilize them, and the more applications we may find. Poorly run clinical trials have hamstrung the field before, and a headlong rush without more understanding could send it spiraling now. People that are using phages, Kutateladze says, should know how to use them, what phages are needed, and how they work in general. The biggest challenge of all, however, may be perception — but that is rapidly changing. Strathdee was invited to share her and her husband’s story at the annual meeting of the Infectious Diseases Society of America. Held at the very end of the conference on a Sunday morning, when many have usually gone home, hundreds of people packed the room to hear the harrowing tale. Many in the audience were crying, Strathdee said, and came up to her after to express their newfound interest in phages. “We’re seeing more excitement than we ever have before, because our back is up against the wall,” Strathdee says. Superbugs threaten the entire world; we have interfered in the delicate balance between humanity, viruses, and bacteria. “In my husband’s case, total strangers stepped up from around the world to donate phages to cure him. And if we can do it for one man, we can do it for the planet.” Source
