Genetically altered viruses save life of infected teenager

Teenager recovers from near death in world-first GM virus treatment

Teenager recovers from near death in world-first GM virus treatment

This treatment used a cocktail of three phages: viruses that exclusively attack and kill bacteria.

The background: Isabelle Holdaway had been given less than a 1% chance of survival after a lung transplant, carried out to combat the symptoms of her cystic fibrosis, left her with an antibiotic-resistant infection.

Her skin was covered in lesions and her liver began to fail, she lost weight and could barely breathe. For eight years, she had been taking antibiotics to control two stubborn bacterial strains. Afterward, one of the infections spread throughout her body, and there weren't any antibiotics that could treat it. "The bacteria was just coming through her skin, there was nothing they could do to make her comfortable, it was horrific".

The science behind this incredible story has been published in the journal Nature Medicine.

Professor Graham Hatfull, a microbiologist at the University of Pittsburgh was sent samples of Isabelle's infection along with samples of another infected patient. Such a treatment could offer a personalized approach to countering drug-resistant bacteria. "That's really at the root of the problem of [not] having a broader and more generalizable therapy", he said.

"The idea is to use bacteriophages as antibiotics-as something we could use to kill bacteria that cause infection", Hatfull says in a Howard Hughes Medical Institute press release.

Different phages target different bacterial strains, however.

When she was 16, she needed a double lung transplant, but the bacteria were still hiding in her body. Hatfull and colleagues identified dozens of phages known to infect bacterial relatives of the patients' strains, and tested thousands of combinations of them in petri dishes to see which wiped out the patients' bacteria.

But maybe something else could help.

"Cocktails of phages were used therapeutically in Europe and the United States during the pre-antibiotic era, and they are still prevalent in Russian Federation and Central and Eastern Europe today, for wound infections, gastroenteritis, sepsis and other ailments", wrote Charles Schmidt, a science writer, in a related article published in the journal Nature Biotechnology. Phages can also be toxic. His phage collection - the largest in the world - resided in roughly 15,000 vials and filled the shelves of two six-foot-tall freezers in his lab.

Hatfull had a lot of phages to choose from.

There are more than a nonillion (that's a quadrillion times a quadrillion) phages in the dirt, water, and air. (M. abscessus primarily lives outside cells.) Others say there could be ways to ferry phages into the infected cells.

"This program engages beginning students in real science", says David Asai, HHMI's senior director for science education and director of the SEA-PHAGES program. "You just need to have a scintilla of curiosity and you can come discover something new". "Now the phage collection has actually contributed to helping a patient".

While the therapeutic use of phages remained largely unexplored for decades, the field "sputtered back to life" in the early 2000s due, in part, to "the rise of modern sequencing technology", Schmidt wrote. Several weeks later, a scan of her liver showed a significant drop in signs of infection, and it didn't seem that the bacterial strain causing the infection was developing a resistance to the phage cocktail. But until recently, there wasn't much data about the treatment's safety and efficacy. "So, a phage designed for bacteria in one person may not work in another".

Phages work by infecting bacteria cells and killing them, but they are very specific in which infections they can target.

But to use phage more widely would require careful matching of phages to a patient's infection.

Isabelle admits she found it "gross" that one of the phages came from a rotting eggplant. But they were too late, Hatfull says.

In the nine months after the transplant, Spencer watched her patient go from a sociable teenager to one who spoke only in monosyllables, if she talked at all. "These really are severe, life-threating infections", he says.

When it came to identifying the phages that may be able to help the 15-year-old patient, the search was not so smooth.

They found three candidate phages in soil-dwelling mycobacteria that don't infect people. By removing a single gene, they were able to increase the efficiency of these two phages, making a cocktail that they believed could kill the infection. Spencer made a decision to take a gamble on what seemed like a far-fetched idea: phages, viruses that can destroy bacteria and have a long-if checkered-history as medical treatments.

Isabelle is not completely cured and still receives infusions of the treatment twice a day.

Hatfull and his team spent 3 months searching for phages that could kill M. abscessus isolated from Isabelle's wounds and sputum.

"If we wanted to use more than one phage, we needed to do something to convert some of the miserable-looking guys into something that would work efficiently, and we have engineering tools and strategies we can use to do genetic manipulation", Hatfull explained.