Helpful Viruses

Thomas Kessler’s phage research stems from a chance meeting and an intriguing lead. Telling the tale, Kessler, senior physician for neuro-urology at Balgrist University Hospital, describes how a modern twist on an almost-forgotten therapy could revolutionize the treatment of urinary tract infections. If all goes well, it would be a major victory against a disease which affects around 150 million people worldwide every year. Currently, such infections are treated with antibiotics, but resistances are on the increase and in many cases the problem returns after a short time, becomes chronic, and can end up damaging the kidneys.

But let’s start the story at the beginning: when picking up his daughter from daycare, Thomas Kessler gets chatting with a fellow parent who happens to be a microbiology expert. As they discuss their work, the daycare dad mentions to Kessler that in Tbilisi, Georgia, you can buy medication for urinary tract infections which does not contain antibiotics. Instead, the pharmacies in Georgia sell bacteriophages. Bacteriophages, or phages for short, are viruses that attack and kill only bacteria. They are seldom used in Switzerland because a lack of high-quality studies means they have not been legally approved for use as medicinal products. And yet, phage therapies were already successfully tested more than 100 years ago. Once penicillin was discovered and antibiotic use became widespread, phages fell into oblivion in Western Europe. Not so in Georgia, Poland and Russia.

The scientific name for bacteriophages comes from the Greek and means bacteria-eater. But the name is not entirely accurate: the phages do not eat their prey. Rather, they inject their genetic material into the bacterial cell, where it multiplies and, after further molecular processes, causes the bacterium to decay, at which point the phages leave the cell.

The possibilities of phages so fascinated Thomas Kessler that he secured SNSF funding to carry out a research project in Tbilisi. His plan was to test the effect of phages in a randomized study. Kessler was keen to find an alternative for the standard treatment with antibiotics used in Switzerland, because they don’t kill just the infection-causing bacteria but also many others – including bacteria that are important for the human body. In addition, he was concerned about increasing antibiotic resistance.

The study participants in Tbilisi were treated with bacteriophages that could be bought in local pharmacies. The treatment was composed of a cocktail of different phages. The study divided the test subjects with urinary tract infections into three groups: one group had bladder irrigation via a catheter, another group received antibiotics, and a third group were given the phage cocktail. In 2021, Kessler and his team published the first-ever randomized study on phages and urinary tract infections. Their findings caused a stir in the scientific community – all three treatments had the same effect: the phages worked just as well as antibiotics, as did the bladder irrigation.

“We were astonished – that was not what we were expecting,” recalls Kessler. Especially surprising was the efficacy of the irrigation. The findings encouraged the team to take their research further with another question: what if they modified the non-specific phage cocktail and created tiny bacteria-eaters that would specifically target urinary tract bacteria?

A new character enters the story here: the research group of Martin Loessner at ETH Zurich had recently managed to genetically modify phages in the lab, making it possible to engineer the viruses so that they could target the bacteria in the bladder and urinary tract. Two new projects arose out of the cooperation between the research groups, CAUTIphage andImmunoPhage. By the end of 2024, the research should be ready to start the clinical phase in which patients with urinary tract infections will be treated with phages that can precisely attack and destroy the bacteria in the bladder. “We hope the treatment will have a positive long-term effect,” says Kessler, “as urinary tract infections are often recurrent.”

He suspects that the reason for recurrent infections could be due to bacteria remaining concealed in the cell walls of the bladder undetected by the antibiotics or phages. “We used to think that the urine in the bladder was sterile, but today we know that the bladder also has a microbiome. In healthy individuals, the microbiome prevents infections,” says Kessler. Since summer 2023 he has been working on another project funded by The LOOP Zurich called mTORUS (short for Microbiome-Based Therapeutic Options for Recurrent Urinary Symptoms). They have adopted a push-pull strategy: genetically modified bacteriophages are used for localized elimination of pathogens and in addition a healthy microbiome is transplanted into the bladder to restore a stable local immunological status.

Study participants include patients currently suffering from urinary tract infections, people with bladder cancer, asymptomatic patients and healthy individuals. “By carrying out many tests we’ll be able to collect a great deal of data,” says Kessler. “These data in combination with highly developed computer models will form the basis for our research into bladder health.” This is the groundwork needed to create precision medicine treatments.

Kessler hopes that in the future, the knowledge gained about the bladder microbiome, the efficacy of phages and the accompanying diagnostics could help patients in Zurich and around the world escape chronic dependence on antibiotics and maybe even prevent infections before they take hold or become severe. “These findings could also be used to find treatments for other bacterial infections as well as systemic inflammatory diseases and possibly bladder cancer. But before the phages and the insights into the bladder microbiome can be used to help patients, further research is required,” Kessler concludes.