If you were dying of an intractable bacterial infection and your physician offered to shoot you up with a virus, would you say yes? You just might.

As antibiotic-resistant microbial infections proliferate, health care providers are turning to a century-old biological remedy, the phage. Also known as bacteriophages, these are tiny viruses that infect bacteria and use them to replicate, killing the host in the process. Nothing new here: phages and bacteria have been at war on the Darwinian battlefield for literally billions of years.

Phages were a bit later in coming to our party, of course. They were first used as medicine in humans nearly a decade before the discovery of penicillin, and their application retained a small but loyal following — particularly in the former Soviet Union, where medical researchers were often inclined to march to a different drummer. But in recent years, research on phages has moved to the fast lane.

Driven by multiple factors, there’s been a surge of peer-reviewed papers on phages along with a boomlet in biotech start-ups with phage-based remedies in mind. For one thing, the demand is there: antibiotic-resistant bacterial diseases kill about 700,000 people a year, a number expected to grow to 10 million by 2050 as overuse of the current portfolio of antibiotics makes treatment of bacterial infections increasingly problematic.

For another, developing special-purpose phages is a relatively low-cost endeavor. The biology is well understood, and the FDA regards them as safe to ingest or inject. Moreover, they can be harvested from natural sources, including pond water and raw sewage. And the above-mentioned biotechs may soon be able to engineer more potent phages that specifically target human scourges.

But there’s a big qualifier: the Catch-22 that has stymied traditional antibiotics development applies to phages as well. Existing drugs usually work well enough, and cost so little — pennies a pill — that established pharmaceutical companies are loath to spend the $1 billion it can cost to bring a new antibiotic to market. Venture capitalists are in turn loath to fund start-ups pursuing antibiotics. And here’s the kicker: even when new companies do get funded and new antibiotics do get approved, they often go unused because hospitals keep them on the shelf as a last resort.

Phages, moreover, face some caveats of their own. Although they have been spectacularly successful in some individual treatments over the decades, there has never been a large double-blind clinical trial of the sort required to gain FDA approval for a new drug. Meanwhile, small trials with phages have failed in treatment of burns, urinary tract infections and childhood diarrhea. Consider, too, that phages are specific to a particular strain of bacterium, which is good from the standpoint of not killing nearby beneficial microbes, but self-limiting when real-world patients face multiple bacterial threats. Nor are individual phages immune to diminishing efficacy as bacteria evolve and develop resistance.

Stalin’s Miracle Cure

Phages were first discovered in 1910 by the French biologist Felix d’Herelle at the Institut Pasteur. D’Herelle found them in locust diarrhea (no kidding) while working in the Yucatan. Back in Paris, he studied stool samples taken from soldiers stricken with dysentery and found similar viruses attacking the bacteria. A dysentery patient was first cured with phages in 1919, and many more followed. The French biologist subsequently traveled the world treating bacterial infections from plague to cholera — and with some success.

But d’Herelle’s attempt to start a company to isolate and commercialize phages in France failed. A dedicated Communist, he accepted an invitation from Joseph Stalin to come to Soviet Georgia in 1934, where a friend and fellow scientist, George Eliava, had founded the Tbilisi Institute. D’Herelle worked there for about a year and a half and wrote a book, The Bacteriophage and the Phenomenon of Recovery, which he dedicated to Stalin. Alas, Eliava was very unlucky in love. He courted a woman also fancied by Lavrenti Beria, the psychopath who would soon head the predecessor organization to the KGB, and was promptly executed. D’Herelle fled the country.

D’Herelle returned to France where he died of cancer in 1949, largely forgotten by modern science. The success of penicillin, discovered by Alexander Fleming in 1928 but first used in humans in 1942, put an end to phage therapy in much of the world — though phages did become an essential research tool in molecular biology. But the Tbilisi Institute continued its work, cataloging thousands of samples. And it became a global pilgrimage site for the desperately ill, many of whom were saved from amputations or death.

Following a restructuring in 1988, the Tbilisi Institute was renamed the George Eliava Research Institute of Bacteriophages. Fresh interest — and, as important, funding — followed a BBC report in 1997, allowing the institute to rebuild. And the work there continues. The institute’s primary asset remains its library of thousands of natural phages, kept frozen and often used in combination as phage “cocktails” as first suggested by d’Herelle.

“When patients go for therapy there, they basically have a big bank of isolates they try,” explained Michael Wittekind, former chief scientific officer of the ContraFect Corporation, which is currently in Phase 3 clinical trials for use of a phage-derived protein to treat antibiotic-resistant Staphylococcus aureus infections. “It’s hard to get a universal phage that’s going to cover every variant of the agent causing the disease. But there are extreme infections where it would be the first thing to try. These people making the pilgrimage to Russia are in pretty bad shape.”

Phage Are All the Rage

That’s the title of a 2021 article in the Journal of the Pediatric Infectious Diseases Society co-authored by Pranita Tamma and Gina Suh, of Johns Hopkins and the Mayo Clinic, respectively. They note that phages are the most abundant organisms on Earth, with a trillion of them for every grain of sand on the planet. Their therapeutic utility is based on the lytic cycle: in the process of hijacking a bacterial cell’s reproductive mechanism, phages “lyse,” or destroy, the cell. And happily, lytic phages inject their DNA only into bacteria, ignoring the patient’s genome.

“The ability to characterize and test phage as antibacterial therapies has advanced immensely,” pointed out Suh. In addition to resistance, infections associated with increased use of medical devices, such as prosthetic joints, pacemakers and defibrillators, are also driving interest in phages. “Once those become infected, they are very difficult to treat with antibiotics,” she said.

All the phages used to treat infection so far have been wild types found in nature — not the product of genetic engineering. But the tools of biotechnology will soon be applied.

“We are way better off now than we were in 1950 or 1919 in terms of being able to make this work,” Suh explained. “We know more about what makes a certain phage bind to a certain bacterium, and we’re able to use that information to do all sorts of things.” In the not-too-distant future, artificial intelligence “will be very relevant to developing further phage technologies. We’ll be able to create designer phages.”

Molecular biology and machine learning are a heady mixture for young scientists, driving attendance at conferences like Phage Futures Europe, the first to focus on moving the technology into commercially viable therapeutics. “What stands out to me is the degree of enthusiasm and passion that people have for phages,” Suh said. “It’s also striking how youthful the audience is, like 25 years old, which reflects how aware this younger generation is of antibiotic resistance … These younger folks have fewer residual negative thoughts and feelings about phage therapy from decades past.”

The Perfect Predator

An apparent miracle cure landed phage research in People magazine. When Steffanie Strathdee and her husband, Thomas Patterson — both professors at the University of California, San Diego — took a dream trip down the Nile in Egypt, Patterson was struck by a virulent infection. Flown to a hospital in Germany and already drifting in and out of consciousness due to septic shock, he was found to be infected with Acinetobacter baumannii, a so-called superbug. None of the 18 antibiotics in common use could kill the Egyptian strain — not even colistin, a drug of last resort.

Patterson was subsequently flown to a hospital at UC San Diego, where he entered a coma and was deteriorating rapidly. Desperate, Strathdee combed the peer-reviewed literature and came across phages. Researchers crafted a cocktail of the bacteria-eating viruses, some harvested from sewage. Three days after Patterson’s first treatment, he regained consciousness, only to relapse. But subsequent treatments with other phages seemed to clear the infection from his body.

Patterson also received other medical treatment, though the timing of his recovery suggested that the phages played a crucial role. It led to a book by Strathdee and Patterson, The Perfect Predator, a TED talk and a flurry of grants.

The case sparked international attention and led to more interventions with phage therapy. Another prominent case: a 15-yearold cystic fibrosis lung transplant recipient infected with Mycobacterium abscessus, a bacterium distantly related to the ones that cause tuberculosis and Hansen’s disease. After receiving a three-phage intravenous cocktail, she improved markedly. In recent years, other patients have been successfully treated with phage for bacterial infections of the lung, wounds and prosthetic joints.

Old Cures, New Company

While Felix d’Herelle and the Eliava Institute feature in any history of phage therapy, the record should also show the contributions of Carl Merril and the U.S. Navy. Merril started working with phages in 1966 after taking a course at the private Cold Spring Harbor Lab on Long Island, and he continued his research at the National Institutes of Health.

But his work was considered quixotic — other scientists at the NIH had little regard for phages — and Merril was ultimately let go. Nevertheless, the U.S. Navy saw the potential and in 2010 quietly began applying Merril’s concepts to assemble its own phage library. Indeed, the Navy’s Biological Defense Research Directorate supplied the phages used in Patterson’s recovery.

Following that success, the Navy turned to Merril to help commercialize its collection. With his youngest son, Greg, a veteran medical technology entrepreneur, Merril started a new company, Adaptive Phage Therapeutics, that has exclusive rights to the Navy’s phage library. Adaptive has created its own phage bank of potent viruses and has teamed with the Mayo Clinic to commercialize it on a global scale. (Suh is a consultant to Adaptive.)

Nonetheless, brand-name investors weren’t interested; nor were pharmaceutical companies. So Merril raised money privately. He, by the way, is not starry-eyed about the prospects for phage therapy. With nearly six decades in the field, he’s seen other periods of enthusiasm for phages — and plenty of phage failures.

“A lot of people are starting new companies and they do experiments in test tubes, and the experiments work, but they don’t realize that’s not what happens in the human,” Merril muses. “You can’t just think you’re going to solve this thing with one enzyme. You’re going to have to have a large library, and you’re going to have to continually monitor the patients. It’s going to have to be an adaptive approach.”

Adaptive’s new facility was purpose-built for manufacturing therapeutic phage products and is strategically located in Gaithersburg, Maryland — close to the FDA, Walter Reed Military Hospital, Johns Hopkins and the National Institutes of Health. Now the company is attracting investment, so far raising over $100 million from Deerfield Management Company, the Mayo Clinic and the AMR (Antimicrobial Resistance) Action Fund. The latter comprises a consortium of major biopharma companies, the World Health Organization, the European Investment Bank and the Wellcome Trust.

But Merril remains circumspect. “I don’t see a quick way to do this; I don’t see a magic bullet,” he said. “The number of bacteria on the planet is 1030th [that’s 10 followed by 29 zeros]. There isn’t even a name for that number.” Over three billion or so years, bacteria have “developed all kinds of defense mechanisms and the phage interact with each other, too. It’s going to take a real effort, it’s not going to happen overnight.”

Fresh Out of Yale

Paul Turner wanted to do phage research when he joined the faculty at Yale University in 2001, but there was no money, he said. “We would submit grants and they would be rejected. Now that has changed so dramatically, and I think it is the nimbleness of phage genomes to be engineered and used for a lot of things. Now it’s a matter of proving that they’re safe and effective, proving to investors that they’re viable.”

Today Turner is the director of Yale’s Center for Phage Biology and Therapy, where he has his own eponymous lab. The lab made headlines when a phage culled from a local pond was successfully used to treat a New Haven ophthalmologist who had become seriously ill following an otherwise routine coronary bypass operation. He had been infected with a common species of bacteria called Pseudomonas aeruginosa, which is usually harmless for healthy people but can be deadly for those with weakened immune systems.

Yale is conducting an early-stage clinical trial of inhaled phages to vanquish Pseudomonas aeruginosa in patients with cystic fibrosis. CF patients lack an essential enzyme for clearing the lungs of mucus, making them vulnerable to infections and typically requiring long-term antibiotics use, which all too often leads to resistance. One serendipitous aspect of phages’ own susceptibility to bacterial resistance is that in mutating to resist the phage, the bacteria often become less resistant to chemical antibiotics — a boon for CF patients, who will likely be on such drugs for life.

In addition to his work at Yale, Turner is a co-founder of Felix Biotechnology, a South San Francisco company named for d’Herrelle (of course). Robert McBride, Felix’s chief executive, said cystic fibrosis is a good first disease to tackle from a strategic as well as medical perspective because it is chronic, thus creating a recurring revenue stream. And because it is typically treated in outpatient settings, so it is not impacted by hospitals’ hard-core opposition to high-priced drugs.

Lest that seem mercenary, it is also mindful. Mindful of companies like Achaogen, whose first drug, plazomicin, received approval in 2018 to treat urinary tract infections, one of the most common drug-resistant diseases. But hospitals balked at using it, and plazomicin’s sales totaled less than $1 million in its first year — not nearly enough to recoup its development costs. Achaogen was forced into bankruptcy.

Felix has filed a preliminary application with the FDA to launch a commercial clinical trial of the same phage used in the Yale investigation. But long term, Felix intends to move beyond phage libraries and cocktails to engineering purpose-built phages. “We have technology to make phages more broad, and to manage evolution,” Broad explained. “Engineering lytic phage traditionally has been very, very difficult. … We have a platform that allows us to generate large data sets [digitally] in silicon and then implement them in biology.”

Not To Rain on Anyone’s Parade

Felix and Adaptive are two of the more consequential start-ups chasing phage. Some of the others are less so, with founders and claims direct from the notorious dietary supplement business. There was a surge of new phage companies 20-odd years ago, too, perhaps driven by the seminal report “Bad Bugs, No Drugs,” published by the Infectious Diseases Society of America. But most of those companies have left the planet or, at any rate, have left phage research.

“Two things are really appealing about phages,” said Dean Scholl, who worked at one of those companies before joining Merril at NIH. “It makes complete sense; you’ve got something that kills bacteria, and it’s really easy to work with. The entry to phage research is undergraduate level. One person can isolate a brand-new phage.”

But getting from here to there is still problematic, to say the least. The antibiotics market is difficult for everyone. And phages present some unique challenges, explained Scholl, who is now vice president for research at Pylum Biosciences, a company developing antimicrobial protein-based drugs. “There’s just way too much biology there getting in the way. … Everything biological that you can think of can go wrong.”

Phages can be tested on humans in one-off situations by applying for so-called compassionate use, where the FDA and related medical regulators permit the use of a new, unapproved drug to treat a seriously ill patient when no other treatments are available. The process sometimes saves lives, but it never leads to drug approvals. “Doing compassionate- use trials on people who are dying is really not a good route into the market,” said Scholl. “What would that product even be?”

And yet, many of biotechnology’s current home runs spent decades delivering disappointing results — even killing patients, as in one infamous gene therapy trial. Scientists stuck by such long shots despite the naysayers, and they have since accounted for many lives saved and many billions of dollars in revenue for investors with fortitude. That could happen to phage therapies, too.

“Are phages going to have their day in the sun like nucleic acid vaccines just did, or Tcells, or monoclonal antibodies, which nobody thought were going to work?” asked Scholl. “Probably they will. But I wish I knew what that could be.”