To save the life of a girl, researchers have injected her with genetically modified viruses | NOVA | PBS | NOVA

Even before Rebekah Dedrick unpacked the samples, the countdown had already begun.

Some 4,000 miles from her laboratory in Pittsburgh, in a London hospital, a 15-year-old girl with cystic fibrosis was battling a life-threatening infection. After undergoing double lung transplantation, the young patient received immunosuppressive therapy and an obstinate bacterium called Mycobacterium Abcessus had taken root. The microbes have resisted all the antibiotics prescribed by the girl's doctors and now spread throughout her body.

In a final effort, the London medical team sent Dedrick and his colleagues, microbiologists from the University of Pittsburgh, tubes containing a bacteria isolated from the patient. The samples contained an urgent – and radical – request: Identify a swarm of viruses that could be injected into the girl's body to kill the drug-resistant bacteria.

It was risky. This virus-based technique, called phage therapy, has never been used against the genus. Mycobacterium-a group that includes the bacteria responsible for tuberculosis and leprosy – which makes the method entirely experimental. But as Dedrick and his colleagues report today in the newspaper Medicine of nature, their bet seems to have borne fruit: one year after the first use of genetically modified phages against a mycobacterium microbe in the clinic, the patient is alive and well.

Until now, the procedure has been conducted only on one patient and will require verification and refinement through clinical trials before he is fortunate enough to have a clinical trial. enter into the traditional medical use. With these warnings, however, "this study is fundamental to the future of this field," says Marisa Pedulla, phage researcher at Montana Tech, who was not involved in the study. "All future studies on mycobacteria and phages will cite these essential works."

Although controversial in most parts of the world, phage therapy is not a new idea. Since the early 1900s, scientists have known that microbes have their own aggressors, in the form of viruses that divert molecular machinery from bacterial cells for reproductive purposes. As they invade and destroy their hosts, these "bacteriophage" viruses – bacteriophages or phages for short – can be a force for cataclysmic change for microbes, turning whole populations into periodic killings.

Phages, however, are also notoriously difficult: a strain that infects a species (or even a subspecies) will often sniff out another type of bacteria that strays even slightly from its preferred host. Combined with deadly viruses operating mode, this precision is exactly what gives phages such potential as a treatment. Unlike antibiotics, which operate quite indifferently, phages could, in theory, annihilate the sole responsible for the infection leaving all the rest intact; then, with their depleted targets, the phages would be quickly eliminated from the body.

Although the practice remains controversial and mainly experimental, phage therapy has not been defeated: in 2016, experimental phage therapy was successfully used as an emergency treatment for a drug-resistant drug. Acinetobacter baumannii infection.

It was the hope that drove the London medical team to speak for the first time to Dedrick and his advisor, Graham Hatfull, in the fall of 2017. The Hatfull lab at the University of Pittsburgh had the last ten years to stock a deposit of over 10,000 types of phage active against mycobacteria, most collected over the years by high school students and undergraduates from the Peach Hunters Science Alliance program for advancement of genomics and evolutionary sciences (SEA-PHAGES). If the phage the doctors needed existed, their best chance of finding him was here.

There was just a catch. It was known that all the phages of the Hatfull bank infected a non-infectious cousin of Mycobacterium abscessus, none had been tested on Mr. Abcessus himself. Given the complexity of the phages, this left Dedrick and his colleagues with many unknown candidates.

Steadfast, the team divided the phages into dozens of genetically distinct groups and began testing the representatives one by one. For weeks, researchers worked day and night, phage phage after phage on opaque films of Mr. Abcessus. Meanwhile, the clock in London continued to turn. "It was unclear," recalls Dedrick. "We worked as hard and fast as possible."

Every morning, Dedrick and his colleagues scoured the plates for revealing translucent spots where viruses had successfully killed the microbes below, but the bacteria continued to multiply.

Until the day they did not do it. In January 2018, Dedrick was stunned to discover that a phage named Muddy had produced a small but undeniable release in the otherwise thick lawn of Mr. Abcessus. "When we saw Muddy for the first time, we said to ourselves, 'Oh, God, we found something that infects that,'" Dedrick said. "We had so many disappointments before that."

But in the same way that bacteria can develop resistance to antibiotics, they can also become immune to their viral aggressors – and using a single phage would be too risky for such a severe case. In the following months, the researchers identified two other phages, ZoeJ and BP, which, with some genetic modifications, also infected the patient. Mr. Abcessus strain. The three active phage were then purified, suspended in a cocktail and shipped abroad.

In the meantime, however, several months had elapsed and the patient had become worse. After multiplying into her newly transplanted lungs, the bacterium had spread to infect the site of the surgical wound, her liver and more than 20 other spots on her skin. None of the dozens of antibiotics administered made a big difference and their chances of survival were reduced to 1%.

"It was clearly a very serious case," says Stacey Martiniano, a clinician from the University of Colorado's Faculty of Medicine specializing in pediatric pneumology, who did not participate at the study. "Few patients with cystic fibrosis have this disease Mr. Abcessus …but all researchers, as well as caregivers, have seen patients in these situations where we see the limits of our antibiotics. That's what led [these doctors] to try everything they could possibly. "

All other options were exhausted and no precedent was guided, the London medical team deployed its final weapon. A small dose of the viral mixture was applied to the infected areas of the patient's skin, while the remainder received an intravenous injection for the purpose of expelling the bacteria from its organs.

Nine days later, the patient came out of the hospital.

It was a year ago. In the following months, with continued phage therapy, the patient's wounds and infections healed, her weight increased, and she recovered her functions in the liver and lungs. The phages, it seems, have done their job.

"This illustrates something very important, namely that it is possible to administer phage safely and to achieve good clinical results," says Hatfull. "This has not been shown before for these types of infections. It means that there is hope … in a sense, we have shown that this can job."

It was not a cure, though – not exactly. Although a large part of the Mr. Abcessus Dedrick explains that his phage treatment is underway. We do not know yet when it will be enough.

And with only one patient waiting, there is no way to predict the future of this treatment, or even if it will be effective or safe for other people. "The case studies are very important and exciting. They help highlight treatments and rare cases and bring researchers together, "says Martiniano. "But we need other research strategies, such as clinical trials."

These should come, says Hatfull. One of the challenges is that this particular treatment is not generalizable – even among Mr. Abcessus infections. The same precision that makes phage therapy such a powerful tool could also be its greatest weakness: a given virus could serve only against a small number of bacterial strains. This rigor may require redeveloping the viral cocktail for each patient, as well as maintaining the maintenance costs of phage banks worldwide to meet the changing demands.

While this "personalized medicine" approach has benefits, many patients will not be able to afford the time needed to screen an extensive library of phages, isolate viruses, and prepare for treatment, says disease researcher Chidiebere Akusobi. infectious. studying Mr. Abcessus at Harvard University who did not participate in the study. "Individualized treatment takes time to individualize," says Akusobi. "The patient was probably lucky enough to be alive while preparing her cocktail."

The inconvenience of timing is not just a hypothesis. During the study, the researchers met another patient with a genetically distinct strain of Mr. Abcessus. But none of the phage they tested could fight the bacteria and the second patient died.

Even if they are identified in time to treat a patient, phages are not infallible. Bacteria are an ever-evolving target and can still develop phage resistance (and just about any other treatment, for that matter). And although they do not mean any harm to human cells, phages, like any other virus, can still invoke the anger of the immune system. As this patient did not seem to have any serious side effects, it does not seem that this is the case here, says Akusobi, but it is not surprising that "the injection of large amounts of foreign particles into a body can be dangerous for your health ". some."

The implementation of phage treatment on a larger scale will also require filling in huge gaps in knowledge. Phage far outnumber other biological entities on the planet (estimated at around 10 non-millions in the world, one to 31 zeros), and scientists are not yet aware of the diversity that exists. Even the few phages put aside by researchers remain mostly enigmatic, says Asma Hatoum-Aslan, a researcher on phages at the University of Alabama and not involved in the study. This uncertainty makes every injection of phages into a human body an almost literal shot in the dark.

Whatever the case may be, the new study is "very exciting and important," says Hatoum-Aslan, who remains optimistic about the future of phage therapy. Although the study procedure needs to be further refined, this early success suggests that such methods could one day improve, supplement or follow antibiotic treatment of these microbes and more.

And for the moment, even one victory remains a victory, especially for the patient. "See her right before treatment, and now after … I could see improvement with my own eyes," says Dedrick. "It makes me really proud."