Isabelle Carnell-Holdaway, 17, has faced not one but two unrelenting threats to her life. Diagnosed at 11 months of age with cystic fibrosis, the progressive genetic disease that causes lung infections and breathing impairment, Isabelle has also combated an on-again, off-again infection caused by antibiotic-resistant bacteria since age 8.
"Children with cystic fibrosis are very prone to picking up all sorts of nasty infections," said her mother, Jo Carnell-Holdaway.
By the time she was 14, Isabelle's lung function was about 25% or 30%, according to her mother. In September 2017, at 15, she underwent a double lung transplant, as recommended by her doctor Dr. Helen Spencer, a respiratory pediatrician and lead for the lung transplant service at Great Ormond Street Hospital in London.
Though the operation was "uncomplicated," luck was not on Isabelle's side in the days after the procedure, according to a case study published Wednesday in the journal Nature Medicine that describes a first-of-its-kind experimental treatment.
When her doctors discontinued the intravenous antibiotics that caused Isabelle severe side effects, the bacterial infection that had plagued her for years returned with a vengeance. Her surgical incisions turned vibrant red.
By January 2018, "her liver really started to fail," and Isabelle ended up back in the intensive care unit with acute liver failure, he mother said.
Spencer described her prognosis at this point as "very poor."
"I know that because of the experience that I've had with other patients who have had a transplant and who were infected with MB," Spencer said. "All of those patients went on and died."
MB, or Mycobacterium abscessus, the bacterium causing Isabelle's infection, is a type of antibiotic-resistant bug that, though commonly found in nature, does not usually cause sickness in healthy people.
One of the hospital consultants told Isabelle's mother that her daughter wouldn't be leaving and gave Isabelle "less than 1% chance of survival," Carnell-Holdaway said. "We were totally devastated by that."
Dire circumstances led Spencer to consider experimental treatments for the teen, which resulted in a cocktail of genetically engineered viruses that altered the course of Isabelle's recovery.
"It was actually the patient's mum, Jo, who asked me about phage therapy," she said.
Creating a one-of-a-kind treatment
Bacteriophages or "phages" are viruses that can infect and destroy bacteria. The natural enemy of bacteria, phages are ubiquitous on Earth -- found in soil and seawater -- and in our own guts.
"Cocktails of phages were used therapeutically in Europe and the United States during the pre-antibiotic era, and they are still prevalent in Russia 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. "In the West, phage therapy was abandoned after broad-spectrum antibiotics came on the scene."
Luckily, Spencer said, "one of our microbiologist consultants here did his thesis on phage therapy 20 years ago." Offering advice on Isabelle's case, "he, by chance, knew a phage scientist in the [United] States, Graham Hatfull."
A conference call between Spencer's and Hatfull's teams included Robert Schooley, an infectious-disease specialist who heads a phage translational research center at the University of California, San Diego, who "happened to be visiting Graham on the same day, so he came in on that same conversation."
"We sent a sample of our patient's bacteria over to that lab, and Graham and his team did an amazing job finding the phages that would kill her bacteria," Spence said.
To create a phage therapy, it is necessary to correctly characterize phage biology and the genetic interactions that will occur between the phage and the target bacterium -- no easy feat, according to Schmidt, who notes that the function of as much as 90% of the phage genome remains unknown. "Despite the fact that phage have been a subject of research for nearly a century, very little is known about them," he wrote.
Additionally, the creation of Isabelle's therapy, which combined three separate phages, required Hatfull and his team to genetically engineer one of the phages to more efficiently kill the target bacterium.
Isabelle's experience with the treatment
When Isabelle was sent home from the hospital in April 2018, she was "not eating, had severe weight loss, had abnormal liver function and skin nodules were popping up -- one or two every week," Spencer said.
Isabelle had spent months in bed and lacked strength, her mother recalled: "We were doing everything for her. She had to be carried here; she had to be carried to the toilet; she had to be carried to bed. She just could not walk."
About two months after returning home, Isabelle was given her first dose of phage treatment, both intravenously and applied directly to her wounds, while continuing on IV antibiotics and the usual course of immunosuppressive drugs that are necessary to prevent rejection of a transplanted organ.
Spencer said that "a big lesion" by Isabelle's liver "disappeared, and then we've seen the wounds on the skin just gradually -- gradually -- just slowly start to heal."
Her mother noted that "within weeks, this amazing treatment from Mother Nature was having this incredible effect on her body. Her appetite improved. She's had weight gain."
Isabelle also returned to school in September and, for the first time in her life, has been attending classes "every single day with no problems, no issues, at all," her mother added. "She's just loving her life. And she's even got herself a Saturday job, starting this weekend."
Spencer is also hopeful, if more guarded: "We are dealing with microbacterium, and in treating it, we know this is a long game; it's not a short fix. I think we're looking at several more months, if not years, of treatment for her.
"We haven't cured her," Spencer said, adding that that today, 11 months since the start of Isabelle's treatment, the bacterium is still causing skin lesions "on occasion. I hope with time, eventually, she'll clear the infection. If it will happen or not, I don't know."
The future of phages
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.
Hatfull, a professor of biotechnology at the University of Pittsburgh, believes that this accomplishment "represents a number of firsts: the first genetically engineered phage treatment ... and the first treatment of a mycobacterium," Schmidt said. The proof-of-concept treatment, he noted, also bodes well for "the future of synthetic-biology approaches to the vexing problem of antibiotic-resistant bacteria."
Schmidt notes that pharmaceutical companies, including Johnson & Johnson, have begun to invest in potential phage therapeutics, while scientists believe the field is better positioned today with faster, cheaper genetic screening and greater understanding of phage pharmacology. Still, production costs "pose a major hurdle," and much remains unknown about phage biology.
"Even as companies move toward clinical trials, they're confronting entrenched biases against phage therapy by physicians inclined to view it as an old Soviet technology that was never backed by reliable evidence," he wrote.
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