The patient was a healthy 30-year-old woman who had survived a nightmarish terrorist attack. Shrapnel in her leg left her vulnerable to infection with one of the world’s most drug-resistant bacteria, rendering antibiotics useless. Even after emergency surgery to save her leg, a partial hip amputation, and bone grafts, the infection stubbornly returned.
Finally, a team in Belgium stepped in with an experimental treatment: phage therapy. Phages, the most abundant organism on Earth, are bacteria-killing viruses. Harmless to humans, they can be found virtually everywhere — on your skin, in your throat, in lakes and ponds, rivers, soil. What makes them so potent is their four billion-year history engaged in an eternal war with bacteria: Every phage has evolved a laser-like ability to vanquish specific bacterial strains. The trick is finding and matching up the right phage — or cocktail of phages — to the bacteria causing a given infection.
The Belgian medical team obtained a sample of the woman’s bacteria and studied it in the lab using an approach called directed evolution: they observed how it mutated and selected phages –sourced from a sewer sample — that would neutralize subsequent generations. Then the team created a phage cocktail to anticipate these mutant strains. Combined with antibiotics, the phage therapy cured the woman’s infection, and three years later, as reported in Nature Communications, she is now walking and even participating in sports.
Drug-resistant infections killed 1.27 million people globally in 2019 and played a contributing role in another 3.68 million deaths, according to a study published last year in The Lancet. In total, researchers estimate that nearly five million deaths could have been prevented that year alone in the absence of superbug infections. The urgency of finding effective therapies for these infections is critical, while at the same time the market for new antibiotics is broken.
Setting aside the economic hurdles, antibiotics face an existential challenge: bacteria are constantly evolving — they divide every ten minutes. This means that no matter how sparingly we use a new antibiotic, it will always, eventually, lose efficacy.
Fortunately, phage therapy offers promise for a tool that can evolve along with the pathogen itself and act as a complement to fortify our much-needed antibiotics.
A Second Life
Phages were discovered in 1915, but there was no way at that time to manufacture them. Less than fifteen years later, the Scottish doctor Alexander Fleming discovered penicillin, the first broadly effective antibiotic, which could also be chemically mass produced. It proved to be one of medicine’s greatest leaps, saving millions of lives each year. Phage therapy in the West fell to the wayside.
Then, in 2016, a man Tom Patterson got very sick with a life-threatening superbug infection, and his wife helped to change history. Steffanie Strathdee, who happens to be an infectious disease epidemiologist, embarked on a now-famous mission to save his life with phage therapy alongside an international team of researchers — and succeeded.
Tom and Steffanie’s story, recounted in their book The Perfect Predator, sparked a phage renaissance a century after its discovery, drawing attention to important research that had been quietly ongoing. In 2018, the Center for Innovative Phage Applications and Therapeutics opened at UCSD under Steffanie’s co-direction, marking the first location of its kind in North America. Several other academic centers have since followed, in addition to a program at the Mayo Clinic and centers in Canada, Belgium, Australia, France, Sweden, Switzerland, and the UK.
Testing and Scaling Up
Phage therapy remains experimental in the West (although its use in Russia, Republic of Georgia and Poland has persisted for decades) while the trials collect data. For patients to access it today, they must either receive it from a company sponsor with FDA permission for compassionate use or participate in a trial.
Adaptive Phage Therapeutics, a biotech company based in Gaithersburg, Maryland that was born out of Steffanie and Tom’s story, receives several requests every day for compassionate use, but only has the capacity to handle one or two per month. To date, APT has treated over 60 patients who have failed standard-of-care antibiotics and “almost every time we’re able to show microbiological or clinical improvement or resolution with this approach” says CEO Greg Merril. “It’s been really inspirational.”
APT has developed a bank with thousands of phage samples and is now prioritizing which ones to large-batch manufacture based on which bacteria are making people sick.
“Surveillance is the key,” Merril says. “By testing a patient’s bacteria against the phage we have in order to provide them with their personalized treatment, we are getting a double benefit — not only matching to the patient but we’re also doing surveillance to see what bacteria is out there, and if we don’t have coverage, we have an entire team dedicated to taking that bacteria and discovering new phage that can be added to the collection.”
In that sense, broader use of APT’s phage bank will result in better coverage of bacteria, not worse — a reversal of the current paradigm with antibiotics.
APT is one of the leading companies in this space thanks in part to an investment from the AMR Action Fund, which launched in 2020 to fund to best of innovation in antimicrobial therapies. (Bayer is one of the investors in the Fund.) Their story is featured in a new BBC Storyworks documentary about the global threat posed by superbugs.
Since last October, APT has launched three randomized, double blind, placebo-controlled trials in the U.S. to test phage therapy across several types of patients: those with diabetic foot infections, those with cystic fibrosis suffering from lung infections, and those with chronic infections following hip or knee replacements. The company has placed phage inventory at more than 40 clinical sites around the U.S., so once a patient’s bacterial isolate is tested and identified, Adaptive can direct the pharmacy at the hospital to the phage vial that is expected to be most effective.
The trials are expected to read out next year and could pave the way for commercialization in 2027.
Part of the allure of phage therapy is its speediness to develop: “It takes just 2.5 weeks on average for APT to find a phage that covers a bacteria we previously couldn’t cover,” Merril says. Add in genetic sequencing, manufacturing, quality control, FDA assessments, and distribution, and theoretically, within just a few of months, the world has an answer available to a previously drug-resistant bacterial strain. By contrast, the development of a new antibiotic takes anywhere from eight to 20 years.
Of course, phage therapy needs to be cost effective to manufacture, and regulators will need to broaden the scope of what can be considered an off-the-shelf medicine. Developers anticipate that the FDA may eventually approve a vast library of phage that can be continuously expanded, once efficacy data is available, rather than a single phage at a time.
Anthony Maresso, associate professor of molecular virology and microbiology, leads another biotech leveraging new technologies to solve the problem of scale and widespread resistance. Phiogen is a spinoff of Baylor College of Medicine’s TAILOR LABS, which has a library of about 400 unique phage samples and has treated 25 patients under compassionate use, many in collaboration with Strathdee’s phage center at UCSD. Their success rate approaches 75 percent. In the absence of treatment, Maresso says, such patients improve only 10 percent of the time.
The Science Leaps Forward
New viruses, bacteria, fungi, and parasites will continue to emerge forever. Until now, we have had only fixed medicines to fight them. Penicillin in 1928 is still the same penicillin on pharmacy shelves today.
“But now we are going to make medicines that are changing at paces that meet how fast the disease changes, and that is the groundbreaking realization,” Maresso says.
Our increasingly sophisticated tools, like gene editing and machine learning, are further accelerating those changes for the benefit of patients in need.
For example, in 2019, the first genetically modified phage cocktail to be successfully used in a human was reported in Nature Medicine. The patient was a 15-year-old with cystic fibrosis who was in hospice with a chronic infection after a double lung transplant. After treatment with the genetically engineered phage cocktail, which was tolerated without significant side effects, the patient was discharged with healing wounds and improved lung function.
“The advent of personalized medicine, phage therapy, and synthetic biology with CRISPR-Cas are all coming together and that’s creating this incredibly exciting space whereby we are confident saying that phage therapy is the most important alternative and adjunct to antibiotics that’s out there,” says Strathdee.
Importantly, she says, phage can be synergistic with antibiotics, so even if a certain phage doesn’t directly kill the bacteria, it can put selective pressure on the bacteria to mutate in such a way that it becomes sensitive to antibiotics again.
The beauty of biotech is that we are learning how to harness nature’s own biological power for the benefit of humanity.
“It’s estimated there are more different phages on earth than all the stars in the knowable universe,” Maresso says. “And we haven’t even made the slightest indentation of tapping into this power. That’s where the next few decades of remarkable, groundbreaking research will go.”
Special thanks to Kira Peikoff for her additional research and reporting on this article.
The article was initially published on Forbes.com on September 13th, 2023