Phage Therapy Making A Big Comeback
By Deborah Borfitz
February 10, 2020 | A resurgence of interest in phages over the past few years—in basic and translational research, as well as animal agriculture and aquaculture—is closely tied to the global rise in antimicrobial resistance, rendering once-standard treatments ineffective. In the newly declared “post-antibiotic era,” more than 35,000 people in the U.S. are dying each year from a drug-resistant superbug. By 2050, drug-resistant diseases could claim the lives of 10 million people worldwide.
That makes microbial-resistant infections a bigger cause of death than cancer and motor vehicle accidents, and a more immediate threat to human health than climate change, according to Steffanie Strathdee, associate dean of global health sciences and professor of medicine at the University of California, San Diego (UCSD) as well as co-director of its Center for Innovative Phage Applications and Therapeutics (IPATH).
Phage therapy is a century-old approach to treating infections that uses bacteriophages (aka phages), a type of virus that infects and, in some cases kills, disease-causing bacteria. “States in the former Soviet Union were highly active in discovering phages, and Eastern Europe still has a large number of laboratories working on bacteriophages,” says IPATH researcher Bernd Schnabl, professor of medicine and gastroenterology at the UCSD School of Medicine and director of the San Diego Digestive Diseases Research Center.
With the advent of antibiotics, phage therapy quickly fell out of favor in the U.S., says Strathdee. It is now making a comeback due to a confluence of factors, not the least of which was her husband’s nine-month ordeal with a deadly superbug that in March 2016 was quickly resolved with a highly refined cocktail of phages procured from a large bacteriophage program run by the U.S. Navy and Texas A&M. The emerging field of metagenomics and scientific advances such as high-throughput sequencing have also enabled a new era of research where phages can be matched to the culprit bacteria with greater precision.
The seemingly miraculous cure of Tom Patterson, professor of psychiatry at the UCSD School of Medicine, was by many accounts a “watershed moment” in the strange history of phage therapy, says Strathdee of her now-healthy spouse. It was the catalyst for the launch of IPATH, the first dedicated phage therapy center in North America and one of the only nonprofit phage centers in the world, as well as Adaptive Phage Therapeutics (APT).
The phages injected into Patterson came from a PhageBank program of the U.S. Department of Defense, which granted APT worldwide exclusive rights to the collection in 2017 to broaden their commercial use. In conjunction with a companion diagnostic, the ever-expanding phage library seeks to give more people with recalcitrant bacterial infections their best shot at a permanent cure.
Strathdee discloses that she and her husband own stock in APT.
“What people have not realized until recently is that phages are the gatekeepers of our microbiome”—an idea that holds widespread appeal, says Strathdee. “They’re nature’s own living antibiotic… even those in the anti-vaccine community are pro-phage.”
Patterson is the first known person in the U.S. to successfully undergo intravenous phage therapy to treat a systemic, multidrug-resistant infection, and it became the subject of a 2019 book The Perfect Predator authored by the couple recounting Tom’s unlikely rebound from a strain of Acinetobacter baumannii after teetering close to death. His phage therapy protocol was led by Robert “Chip” Schooley, chief of the division of infectious diseases at UCSD Health and the other co-director of IPATH.
Naval researchers were able to quickly match phages to Patterson’s bacterial isolate and injected billions of them into his system, one billion per dose, and in less than two weeks he was off life support, says Strathdee. The story went viral and the book was recently optioned by a major Hollywood producer.
After calls began to pour in from around the world, Strathdee and Schooley spearheaded the June 2018 establishment of IPATH at UCSD to selectively take on compassionate-use therapy cases and begin doing clinical trials. It remains one of only a handful of U.S.-based academic institutions working on the clinical application of phages.
“Traditionally, many people have been involved in phage biology but now more of them are moving toward translational medicine and how to apply phages to patients in model systems of disease,” says Schnabl. These include his collaborators at Texas A&M University and the J. Craig Venter Institute.
IPATH has to date treated 10 UCSF patients with phage therapy and consulted on dozens of other cases internationally, says Strathdee. These have predominantly been compassionate use cases as allowed through U.S. Food and Drug Administration’s (FDA) Emergency Investigational New Drug application as well as its standard IND process—a move that “in and of itself shows there has been a sea change” in the agency’s thinking about phage therapy.
Phages in the lytic stage of their life cycle are ideal for therapeutic applications because that’s when they shoot their genetic material into bacterial cells, turning them into “phage manufacturing plants,” explains Strathdee. When given the signal, these baby phages burst out by the hundreds, selectively killing the host cell while leaving other bacteria in the microbiome unharmed. They go on to kill other bacteria they match to and they’re then removed by the body, mostly through the liver and spleen.
Temperate phages go through many of the same paces, but their genetic material instead gets integrated into the DNA of bacterial cells, she continues. The process effectively hits the “snooze button” on the replication or expression of phage DNA.
Not only do temperate phages not immediately kill bacterial cells, but they often carry undesirable genetic material from previous hosts—including antibiotic resistance genes—and can collude with the bacterial cells to make them resistant to attack by other phages, says Strathdee. “So, we generally don’t want to use them for phage therapy.”
For unknown reasons, temperate phages are generally the ones found to fight certain bacteria, including Clostridioides difficile and Borrelia burgdorferi (causing Lyme disease), says Strathdee. When a 15-year-old girl from the UK named Isabelle was famously treated with phage therapy for a Mycobacterium absessus, a tuberculosis-related organism, half of the phages used were the temperate variety. They therefore had to be genetically engineered to force the sleepy phages to complete the lytic cycle, causing bacterial cells to expand and burst like overfilled water balloons.
It was the first-ever genetically modified phage cocktail to be used in a human being, she says.
The challenges encountered with phage therapy tend to be organism-specific, says Strathdee. Twenty to 30 phages are thought to cover most circulating staph strains in the world, although that could change over time as phage and bacteria continue to co-evolve. A phage cocktail might therefore cover the majority of Staphylococcus and Pseudomonas infections, which some phage companies are banking on, she adds.
But phage cocktails tend to be “highly personalized,” so the combination that conquers a pathogen in one patient may be wholly ineffective in another, says Schnabl. Phages might recognize the same drug-resistant strain only at certain times and can be thwarted by even a small change on a bacteria’s surface.
To treat anyone infected with the A. baumannii pathogen, which includes many veterans coming back from the Middle East, requires phages that match the bacterial genus and species as well as the bacterial isolate specific to an individual patient, Strathdee says. But gene editing could potentially broaden the host range of a phage so it will attack a broader variety of A. baumannii isolates.
Schooley was part of the care team for Isabelle, who has cystic fibrosis, and co-authored the paper (DOI:10.1038/s41591-019-0437-z) that published last May in Nature Medicine detailing her successful phage treatment following a double lung transplantation. Strathdee says she and Isabelle’s mom were “united through phage” and are now friends on Facebook. “It’s a little surreal.”
It’s also notable that the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK agreed to let the experimental treatment proceed, Strathdee says, given the nearly 200 lives lost in the last mad cow disease outbreak that some people blamed on genetic tinkering. The agency’s rationale, in part, was that the phages were being “helped along” to do what they might eventually do on their own—drop the repressor gene keeping them in sleep mode. It was also convinced that the phages were not genetically modified organisms, she adds, since they had a gene removed rather than added.
“Tom’s protocol informed Isabelle’s, with Dr. Schooley advising on that process,” says Strathdee. “She was out of the hospital within a week and she had been in hospice. Almost no one thought she was going to live. Is she entirely cured? No, but it’s a slow-growing bacterium.” Isabelle continues to receive phage therapy, and no one knows for sure when, or if, it can be safely discontinued.
Isabelle’s case was “big if not bigger than Tom’s case,” says Strathdee. The biotech sector is particularly excited to see that a bioengineered phage, which is easier to patent than one found in nature, could successfully treat a human infection.
“We don’t want to have a market on this,” Strathdee says of IPATH. “Our top priorities are to disseminate knowledge about the clinical application of phages and to try to conduct rigorous clinical trials… and to provide phage therapy on a compassionate basis to patients while we wait for the trial data to emerge.”
The growing number of collaborators in this endeavor include not only research institutions but also pharmaceutical companies and government agencies. IPATH has been working closely of late with the Walter Reed Army Institute of Research, says Strathdee, which is somewhat ironic given that the Army refused to get involved in her husband’s case.
Locks and Keys
Multiple collaborators are needed because no centralized, open-source phage bank currently exists, a situation Strathdee says she’d like to change. “That is how to make a dent in this global antimicrobial resistance crisis.”
The number of phages on the planet number “ten million trillion trillion,” she says, an almost infinite number that is “both a blessing and a curse” when it comes to precisely pairing them to the bacterial pathogens they will attack. “It’s like having a million locks spread all over the world and not knowing which keys match.”
Even if a bacterium subsequently become resistant to a phage, rendering it useless, a phage bank would provide a potentially endless supply of other phages that might suppress the bacterial mutant, Strathdee says. It was pure luck that the Navy team that assisted with Patterson’s case was able to come up with a second-generation phage cocktail when he needed it.
“I have taken on phage therapy as a mission because of my husband’s case and after seeing how it has helped people since,” says Strathdee. “Tom and I feel like this is the reason we’re on the planet.”
Her dream, she says, is finding the resources to build a phage bank “to make phages available to whoever need them, including the developing world where the majority of people who die from superbugs live.” No one knows how many individual phage libraries are out there, proprietary or otherwise, or their size.