Eric Boodman, STAT
Eric Boodman, STAT
The word from the doctors came early this week: They had tried one cocktail of antibiotics after another, but Mallory Smith’s fever and chill and chest rattle were only getting worse. They were out of options.
Her father, though, had an idea. He wanted to infect Mallory with a virus — one carefully selected to kill the bacteria that had colonized her lungs. It was hardly foolproof, and it would require special emergency approval from the federal government, but it might just do what the antibiotics couldn’t.
First, they needed the virus. Mark Smith had read about a similar case from 2016. He’d already been emailing with the scientists involved. Now, he gave them the go-ahead.
The next day, a strange tweet went out from Steffanie Strathdee, the associate dean of global health science at the University of California, San Diego: “#Phage researchers! I am working with a team to get Burkholderia cepacia phages to treat a 25 y old woman with CF whose infection has failed all #antibiotics. We need lytic non-lysogenic phage URGENTLY to find suitable phage matches.”
In other words, she was on the hunt for a bacteriophage — literally, a bacteria-eater — that would attack the antibiotic-resistant Burkholderia cepacia in Mallory’s lungs. It couldn’t be just any old phage. It had to be a virus that would actually explode the bacteria, instead of peacefully nestling inside them for a while.
Strathdee had worked as a phage-wrangler before. Her husband, in fact, had been the patient Smith had read about. A combination of phage therapy and antibiotics woke him from a coma in 2016. After that, others began to seek Strathdee’s help in getting viruses to treat their superbugs. Most, but not all, had survived.
Now, she started the process again at Smith’s request.
For the family, it was another twist in what has already been a long road. They had fought to get a lung transplant for Mallory, who has cystic fibrosis, even moving cities to make the procedure possible. It took place in September, and seemed to have gone well. She’s 25, and an athlete, and was soon back on her feet, mixing and administering her own IV medications.
Like the organs that housed them, the opportunistic germs in her old lungs had been sent to the incinerator. But some of those Burkholderia bacteria, it turned out, were still clinging in the crevices of her upper airways. By late October, they’d migrated downwards into her chest, giving her pneumonia and landing her in the emergency room. Now, it looked like they might kill her, unless her father and the makeshift team of scientists he’d recruited could find the right virus and get it approved in time.
When the bacteria first invaded Mallory’s lungs 13 years ago, the news wasn’t as bad as it could have been. “They told us there are three paths: One is peaceful coexistence, one is immediate death, and one is slow decline over about 10 years,” said her mother, Diane Shader Smith.
The germs had nestled their way into the sticky mucus that fills the lungs of cystic fibrosis patients like Mallory, but it didn’t prevent her from doing anything. She joined the water polo, volleyball, and swim teams at Beverly Hills High School, studied biology and played club volleyball at Stanford, and made radio pieces about the environment. She even wrote a book about an urban oasis near Los Angeles full of verbena and mesquite.
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But when she was a college sophomore, Mallory’s lungs had started to deteriorate. She needed a lung transplant, but most hospitals would not take her case because of the species of bacteria in her chest. Their membranes naturally kept some classes of antibiotics out; their enzymes incapacitated others. And the germs could develop even more tricks to combat even more antibiotics after they encountered them.
“They really are built like tanks,” said Dr. John LiPuma, a professor of pediatrics at the University of Michigan, who directs a lab and repository dedicated to Burkholderia cepacia.
Mark Smith knew this. He knew that the bacteria made a transplant riskier for his daughter, but he also knew that she needed better lungs to survive.
He ended up emailing with George Church, the iconoclastic Harvard biologist who has translated one of his peer reviews into genetic code and whose lab is trying to resurrect woolly mammoths. Smith wanted to know about the possibility of using cellular scaffolds from pig lungs to grow Mallory’s own tissue in the lab. That way, he figured, the doctors wouldn’t have to worry about her body rejecting transplanted organs, and so wouldn’t have to suppress her immune system.
Church said that the technology wouldn’t be ready in time, and that they were better off trying to combat the infection with something called phage therapy.
Smith began to read up on the idea. It involved finding specific viruses that could hijack bacterial chromosomes, reproducing and reproducing until the microbe explodes.
But then, the University of Pittsburgh Medical Center invited Mallory for an evaluation. The hospital had performed lung transplants for a number of cystic fibrosis patients with the same kind of lung infection, and some had survived.
“We can’t deny young people like Mallory a chance at longer-term survival only because her chances of short-term survival are lower,” explained Dr. Joseph Pilewski, co-director of the UPMC cystic fibrosis program.
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The team was the only one in the country to offer Mallory a spot in their transplantation program. Pilewski warned the family that it was a high-risk operation, but that the alternative was death.
As soon as Mallory’s lungs stopped bleeding long enough for her to get on a plane, she and her mother left Beverly Hills and moved to Pittsburgh, where her father would soon join them, so that they could wait for a suitable pair of lungs.
The roller coaster of transplantation mostly put phages out of the family’s mind. There were three dry runs, in which Mallory was prepped for surgery but didn’t end up having it. Twice, the lungs in question weren’t viable; once, they went to someone else.
She finally got the operation on Sept. 11. The new lungs, her mother said, were pristine. Soon, Mallory was walking, doing physical therapy, making plans.
It was only this past weekend, after she’d been back in the hospital for two weeks on breathing tubes and feeding tubes, that her father revived the phage idea. He and his wife stay with Mallory at the hospital in 12-hour shifts; she’s there during the day, and he’s there overnight. When he isn’t on the pulmonary unit, Mark is home, sleeping, taking care of the dog, doing work for his legal practice, doing research for Mallory’s case.
He had found out that there were regulatory hurdles to get phage therapy in most of the U.S., and was now consulting with a doctor friend of his about potentially moving his daughter to a place where access might be quicker. He’d heard, for instance, that in the states of Oregon and Washington, naturopaths were allowed to use experimental therapies as a last resort if they’d been approved in other countries.
“What would be the protocol if we had to move Mallory to a jurisdiction where it was legal?” Smith recalled asking. “I had suggested to my friend Oregon, Washington, and the Republic of Georgia.”
That was when he read about the case of Strathdee’s husband, who was able to get an emergency investigational new drug application approved by the Food and Drug Administration for a number of phage strains, some of which had been isolated from a sewage plant and would help save his life. Smith emailed Strathdee and the doctor who had coordinated the effort, as well as any other scientists who might have the necessary virus on their shelves.
Strathdee was in. They just needed a doctor to agree to file an EIND. That wasn’t as simple as it might sound.
“Mark had already mentioned it to every doctor who had come through,” Diane Shader Smith recalled. “Nobody knew anything about it. Nobody was open to talking about it.”
Skepticism about phage therapy is not uncommon. The idea has been around a long time — long enough, said Kristin Parent, a phage researcher at Michigan State University, that there’s even a Sinclair Lewis novel about it. “Then, when antibiotics came around, phage kind of went by the wayside,” she said.
It didn’t disappear completely; the research just hid out in the labs of the Soviet Union, biding its time like a writer in exile. Over the last decade, as antibiotic resistance has become a worldwide crisis, the idea of using phages has become more and more appealing in the U.S. Still, it’s anything but mainstream.
“People that have been studying phages for their therapeutic use have been almost ridiculed,” said Strathdee.
Not all phage researchers agree with that statement — but just about everyone seems to agree that in the U.S., phage therapy is hard to get. While some clinical trials are underway, the idea remains experimental here, which means it’s often only accessible to patients like Mallory, for whom all other potential treatments have failed.
Part of the issue is that phages are alive, and continue evolving inside the body. “It’s one thing to have a chemical that you can control very easily. When you have a living organism, there’s less control,” LiPuma said. “The regulatory requirements for proving safety and efficacy are quite high.”
And the issue is not just about regulation. The science itself is hard. You need to find phages that perfectly match the strain of bacteria inside the patients. You need to make sure the immune system won’t go haywire because of the foreign agent. You need to make sure that the virus won’t make the patient sicker.
Years ago, LiPuma and his collaborators had funding to try to figure out phage therapy for Burkholderia. It didn’t pan out. As he put it, “The length of time that the idea has been around, and the fact that we don’t have it yet, tells us that it’s really tough to do.”
But the Smiths felt they had no other choice. As soon as Pilewski, the head of the UPMC cystic fibrosis program, got back to the hospital and agreed to give phage therapy a go, they began beaming messages across the country, which would end up bouncing across the globe.
Team Mallory was going to try to do in a few days what others had spent years trying to figure out.
The first thing they needed was to find out exactly what strain of Burkholderia is in Mallory’s lungs. On Wednesday, they collected a sputum sample and shipped it to LiPuma’s lab in Michigan so he could sequence it. Simultaneously, those microbes were being sent to phage labs around the country that had responded to Strathdee’s calls for help.
One of them is Carlos Gonzalez’s lab, at Texas A&M. He is in the department of plant pathology and microbiology, and he’s currently working on a treatment for a disease that affects grapevines, but preserved in refrigeration he has a library of some 350 different phages that all attack Burkholderia cepacia.
He’s no longer collecting new ones — “our phage hunts stopped probably 15 years ago because we weren’t able to get funding; it is what it is,” he said — but his library is one of many that will be tested against the bacteria in Mallory’s lungs over the next few days.
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Gonzalez’s colleagues had been involved in the phage hunt for Strathdee’s husband, and so they knew the drill. First, they reached out to any labs that might have samples worth testing. They got a phage offer from an institute in Finland. Other scientists offered to dig through collections of soil that contain Burkholderia, to see if there might be any phages lurking. Promising organisms will probably be shipped across borders before they are tested on Mallory’s germs, to avoid creating bio-hassles at customs.
So far, at least 300 phages are set to be tested.
To do that, Gonzalez and his team, among others, will immobilize Mallory’s bacteria in agar and incubate them at 37 degrees Celsius to mimic the temperature of the human body. They’ll pipette a phage preparation on top and then look for zones where the bacteria seem to be clearing out. Then, they will pick out a bit of stuff from those clear zones. They will examine the bacteriophages inside under an electron microscope, looking for the different kinds of tails that help identify different subgroups, and they will extract, sequence, and annotate the DNA.
It’s a painstaking process, but necessary to avoid injecting a virus that will hurt Mallory instead of helping her.
They don’t want phages that will happily take up residence inside the bacteria’s genetic material without killing the germs. Instead, they want species that will cause a Burkholderia bloodbath: After all, what’s bad for the bacteria will be good for Mallory.
Gonzalez hopes they will then have time to follow their usual regimen, which involves yet more tests. “We’re looking for the needle in the haystack,” he said. “We may or may not find the needle. That’s why we’re trying to get other laboratories involved, because they may have the phage that I don’t have.”
If one of the labs does find any viruses that fit the bill, they will be sent to the U.S. Naval Medical Research Center’s commercial partner, Adaptive Phage Therapeutics, in Maryland, so that they can be purified to FDA standards. That’s a crucial step: If any bacterial debris remains in the phage preparation, it could potentially send Mallory into endotoxic shock.
Emergency FDA approval comes next. Only then will Pilewski’s team be able to inject the viruses into Mallory.
“It’ll take a day to get the culture to Dr. LiPuma, maybe take him a day to confirm the genomic sequence, and then Dr. Gonazlez and Dr. Dennis can start on the testing, but that might take several days, or maybe up to a week,” said Mark Smith. “It takes a day to ship the phages to the Navy. It will take the Navy several days to grow them and purify them, so it’s tight on the time frame, which is why we’re really leaning on people hard not to do steps in sequence. We don’t have a day to lose.”
For Strathdee’s husband’s infection, some of the phages that were tested had been newly collected from bodies of water. She hopes, though, that these emergencies won’t always be relying on retweets and frantic email chains and trips out to the local pond. The couple is now writing a book about the experience, called “The Perfect Predator: An Epidemiologist’s Journey to Save Her Husband from a Deadly Superbug.”
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“My dream is to have an open source phage library,” she said. “If you have phages that are already characterized in a phage bank, they can be tested against a new bacterial threat, instead of having to go back to something like sewage every time.”
Diane Shader Smith likes that idea. “I want this to save my daughter’s life — but if it doesn’t, I sure as hell want to figure this all out so it can save others,” she said.
She and her husband are busy taking their usual shifts at the hospital, hardly seeing each other, communicating mostly through calls and emails and texts. “Let me tell you, the shift that’s difficult is the one at home,” he said. “The shift at the hospital, you’re with Mallory, so …”
Now, when he’s home, he’s focused on organizing paperwork and shipments of phages, coordinating sequencing and testing and culturing, counting the steps in each experiment, trying to eliminate any wasted time.
He hopes the right phages are out there, being pulled from fridge shelves and introduced to Mallory’s bacteria. “I can’t imagine a tragedy greater than the death of a child,” he said. “And we’re trying to avoid that tragedy.”
This article is reproduced with permission from STAT. It was first published on Nov. 10, 2017. Find the original story here.
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