New NIH-funded center at Pitt explores ‘natural predators of bacteria'

For more than a century, antibiotics have been medicine's go-to weapon against bacterial infections.

But as drug-resistant bacteria become increasingly common, researchers are looking to an oft-overlooked ally: viruses.

At the University of Pittsburgh, scientists are helping lead a national effort to advance phage therapy, a promising treatment that uses naturally occurring viruses, called bacteriophages, to target and destroy harmful bacteria. In phage therapy, doctors administer these naturally occurring viruses - found in our bodies and environment - to patients who are suffering from infections that cannot be treated by antibiotics.

The work recently received a significant boost when the National Institute of Allergy and Infectious Diseases awarded funding for the Pitt Center for Accelerating Phage Therapy, one of three new centers focused on ESKAPE pathogens - a group of bacteria responsible for many of the multidrug-resistant infections seen in hospitals worldwide.

The initiative is the first coordinated U.S. research network dedicated to developing the tools and testing methods needed to bring phage therapy closer to routine clinical use, according to a late May press release from Pitt. Because the center was already up and running when it received notice of the award - up to $1.2 million annually for direct costs for up to five years - there was no lag in beginning work on the project; it was immediate, said Daria Van Tyne, the center's co-director and an associate professor of infectious diseases in Pitt's department of medicine.

For Daria Van Tyne, co-director of the Pitt center and an associate professor of infectious diseases in the university's department of medicine, the expanded use and study of phages are necessary and very timely.

"Phages, very simply, are viruses that infect bacteria," Van Tyne said during a video interview. "The word phage actually comes from the Greek word phagos, which is ‘to eat,' so phages are basically bacteria eaters."

Phages don't infect humans. Instead, they naturally prey on bacteria and can be found almost everywhere.

"They exist naturally in the environment, and sort of all around us," Van Tyne said. For example, "in the guts of people, or in the soil outside, there are phages that are living there. They're basically like the natural predators of bacteria."

"Phages, very simply, are viruses that infect bacteria," explains Daria Van Tyne, co-director of the Pitt Center for Accelerating Phage Therapy.(Alexandra Wimley/Post-Gazette)

That ability to selectively attack bacteria has made phages increasingly attractive to researchers and doctors as antibiotic resistance grows into a global health crisis.

According to Van Tyne, antibiotics and phages operate very differently.

"The metaphor I use is: Antibiotics are basically like an atomic bomb," she said. "They're very broadly active, they can kill lots of bacteria, both the good ones and the bad ones, and so it's like napalm, or like a very broad bomb."

Phages, by contrast, are much more precise.

"Phages are like a drone. They're like a precision-guided missile that's trying to target one specific kind of bacteria."

That precision may offer advantages beyond simply killing dangerous bacteria. Many patients with severely drug-resistant infections require powerful antibiotics that can cause serious side effects, including ototoxicity, which destroys a patient's hearing, or nephrotoxicity, which severely damages the kidneys.

Phages appear to avoid many of those concerns.

"Phages are remarkably safe," Van Tyne said. "They don't infect human cells. They can't infect us and make us sick."

Researchers believe part of that safety may stem from the fact that humans encounter phages constantly.

"They're in the food that we eat, they're in the water we drink, they're in the air that we breathe. We're kind of surrounded by phages all the time," she said.

The concept of phage therapy is actually older than many antibiotics.

Scientists first described bacteriophages in the early 1900s and began exploring their potential as treatments for bacterial diseases like typhoid fever and cholera well before the widespread adoption of penicillin in the 1940s, according to a February article in the journal of American Society of Microbiology.

Phage therapy largely disappeared from Western medicine after World War II. Researchers at the time struggled with issues such as poor phage purification and a limited understanding of how highly specific phages are to their bacterial targets.

At the same time, the discovery of penicillin and the rapid development of antibiotics offered a simpler, more reliable way to treat infections. While phage research continued in parts of Eastern Europe and the former Soviet Union, antibiotics became the dominant approach in the U.S. and much of Europe, the article stated.

Several developments have renewed attention in recent years, including growing antibiotic resistance and advances in modern genetics and imaging technologies, all of which have helped drive the field forward, Van Tyne said.

Pitt professor Daria Van Tyne works with lab technician Nathan Wallace in Van Tyne's Oakland lab on June 4.(Alexandra Wimley/Post-Gazette)

Close to home

One source of potential treatments lies beneath Pittsburgh's streets.

"A lot of the phages that we work with in our laboratory are fished, literally fished, out of wastewater that we've collected from various places around the Pittsburgh area," Van Tyne said.

Researchers collect wastewater samples because many of the bacteria they hope to target naturally live in the human gut.

"We found that wastewater - literally, raw sewage - is a very rich resource for finding these phages," she said.

Those locally discovered phages have already been used to treat about two dozen UPMC patients, she said.

Standardizing phage use

The Pitt center's role in the national network differs from the other newly funded centers, both of which are in California. Pitt researchers will focus on creating standardized testing methods and laboratory procedures that can be used across the field.

Gladstone Institutes' Center for PhAIge Therapy in San Francisco will use artificial intelligence, high-speed lab testing and miniature human tissue models to understand exactly how phages work and try to predict which phages will be most effective against specific bacteria. Stanford University's Center for Phage Pharmaceuticals will focus on learning how phages behave inside the body once they're given to a patient and determine correct dosing and delivery recommendations.

Right now, Van Tyne said, phage therapy remains highly individualized. Physicians seeking treatment for a patient often must work with one of only a handful of specialized laboratories, each using somewhat different methods.

"One of our main goals in this project is to develop standardized assays and protocols," she said.

Many of the patients receiving phage therapy today have exhausted conventional options for conditions including chronic urinary tract infections, infected joint replacements, lung infections in people with cystic fibrosis and infections affecting organ transplant recipients.

"In all of these cases, it's usually an organism that's evolved resistance," Van Tyne said, "and where the available antibiotic options are either not great, because they might make the patient go deaf or destroy their kidneys, or they literally have no other antibiotic options, because the bacteria have become resistant to literally everything."

Currently, most patients receive phages through intravenous infusions, often combined with additional delivery methods such as inhalation therapy for lung infections or direct injections into infected joints.

Looking ahead, Van Tyne hopes phages eventually become another option available to physicians treating bacterial infections.

"My goal is that we add phage to the toolbox," she said.

She does not envision phages replacing antibiotics. Instead, she sees them as an additional weapon in an increasingly difficult battle against drug-resistant bacteria.

"We don't want to replace antibiotics," Van Tyne said, "but we think in this fight, the war that we have with antibiotic-resistant bacteria, the more weapons that you have, the better off you are."

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