A patient’s legacy: Researchers work to make phage therapy less of a long shot

The researcher couldn’t get Mallory Smith’s story out of her mind. Smith was a 25-year-old cystic fibrosis patient, and she was near death at a Pittsburgh hospital, her lungs overwhelmed by bacteria. All antibiotics had failed. As a last resort, her father suggested an experimental treatment known as phage therapy.

That meant giving her viruses known as bacteriophages — phages for short — which naturally parasitize bacteria. But not any phage would do. Smith needed one perfectly evolved to kill the microbes in her lungs. Urgent messages were beamed around the world, over email and Twitter, from one phage researcher to another. Was there someone, somewhere, who had the right virus tucked away in a fridge at the back of a lab?

That’s how Jessica Sacher heard about Smith. As a grad student experimenting on phages at the University of Georgia, she’d stumbled across a STAT article about the desperate virus hunt. She mentioned it to a friend she’d met through swing dancing, a tech consultant and developer named Jan Zheng. He knew there had to be a more efficient way to find the right virus when a patient’s life depended on it. “Using Twitter for this kind of stuff is ridiculous,” said Zheng. “It won’t scale to more than one or two patients.”

Over breakfast on Nov. 13, the two hatched a plan to create a Phage Directory to accelerate the search for a perfect match. That same day, scientists found a phage that could kill Smith’s bacteria, but she died two days later at the University of Pittsburgh Medical Center. The website was launched just two days after that.

The crazy, last-chance hunt for a phage to help Smith is a product of the experimental nature of the therapy. Because there have not been rigorous clinical trials of phages, they can be used only on patients for whom all other options have failed. By the time a medical team submits an emergency application to the Food and Drug Administration, the patient is usually in dire straits.

“The deck is stacked against phage therapy if we’re finding out that someone needs a phage and they are already facing imminent death,” said Steffanie Strathdee, the associate dean of global health science at the University of California, San Diego. In 2016, she helped revive her husband from a coma with a combination of phage therapy and antibiotics after he’d come back from Egypt with an untreatable bacterial infection, and she’s since become a kind of phage activist, helping others, like the Smiths, coordinate their own phage hunts.

The Phage Directory could help shorten the steps for those who are desperately looking for the right virus. Sacher and Zheng designed it as a one-stop shop where researchers could list the kinds of bacteria that might be fought with the different phages they have in their labs. Originally they were going to call it Phagebook, but the domain name was taken.

“I’m thinking of … how bone marrow transplant registries work, where you put yourself on the list: You may never be contacted, until there is a match,” said Sacher.

Scientists would still have to test the phages against a particular patient’s bacteria, and then purify the virus so that it doesn’t poison the person with remaining bacterial bits.

But the Phage Directory is better than starting a search from scratch. Sacher and Zheng have only begun recruiting scientists and spreading the word — and already, they’ve had phage requests for three other patients.

‘We were asking for miracles’

Two weeks ago, while Sacher and Zheng were eating lox and bagels in Atlanta and first talking about the Phage Directory, scientists at Adaptive Phage Therapeutics, a biotech startup in Maryland, were racing to find a virus that could kill Smith’s infection.

In collaboration with the Naval Medical Research Center, the team had already tested some 50 known phages, but none of them worked.

They turned to raw materials instead. The Navy collects water samples when ships are docked all over the world, and the team in Maryland had a box of about 100 of these vials. The water inside those vials is disgusting — grayish-brownish, full of particulate matter — and that’s good news when you’re looking for a phage. The grosser the sludge you collect, the better your chances that it’s full of bacteria, and the more bacteria there are, the likelier it is that it’s swarming with phages.

That Monday, they found a match. It had come from sludge collected in both Fiji and the Philippines. They told Smith’s parents they could have it ready by that Thursday. But that wasn’t soon enough.

“On Tuesday, it became clear to me that she wasn’t going to live until the purified preparation was there,” said her father, Mark Smith. “So I floated the idea of stopping the preparation in whatever stage it was in … just using it in its dirty form.”

The scientists promised they would have a makeshift, partially purified phage solution ready by 4 p.m. that day. The family just needed to figure out how to get the vial from Maryland to Pittsburgh. In the end, a plane was dispatched to pick up a Styrofoam box that held the hastily purified phage solution. The pilot remained on the ground just long enough to take the cargo and refuel before disappearing again into the cloudy sky.

When the plane arrived at the Allegheny County Airport, outside of Pittsburgh, a chopper was waiting to fly the phage to UPMC Presbyterian. The family watched its approach through the hospital windows, a dot of light that grew bigger and bigger out of the dark sky to the south. Someone began to sing, “Here Comes the Phage,” to the tune of the Beatles’s “Here Comes the Sun.” Someone pulled out a phone to film it. Their voices are hushed, excited. They could hear the growing noise of the rotors.

The phage arrived a few minutes before 6 that evening, and soon, they were inserting a tube into Mallory’s lungs to deliver a few milliliters of the phage solution.

“By that point, I think we were asking for miracles from a therapy that has a lot of promise, but the optimal time to intervene would have been a couple of weeks ago, before she became critically ill,” said Dr. Joseph Pilewski, co-director of UPMC’s cystic fibrosis program.

Smith’s father had gotten the idea to try phage therapy after reading about Strathdee’s husband. In that case, the patient had been unconscious by the time he was given phage therapy, only waking up 48 hours after the cocktail had been administered. “We expected it to take about that long to work,” Mark Smith said. But Mallory died a little before 5 p.m. the next day.

A legacy of helping other patients

A memorial service was planned in a school auditorium in Beverly Hills. The room sat about 500 people, but friends and scientists and admirers packed into the aisles and the hallways. There were more people who wanted to speak than could be slotted into two hours. They were friends from high school, friends from Stanford University, friends from the time she’d spent living in San Francisco after college. She had been an athlete, a writer, a radio journalist. She had written a book about an urban oasis in her hometown.

She had also been an advocate for cystic fibrosis patients. She chronicled the identity crisis she experienced as “the interests and characteristics that I thought defined me were ripped away by illness,” as she put it in a 2014 speech. She wrote about clinical trials, about administering her own IV meds throughout days of Stanford classes, about trying to keep herself buoyant even as her condition worsened. She took her IV pole outside in the rain to do lunges by the hospital fountain.

She gave lectures to drug companies. She often couldn’t meet other patients face-to-face, as they might exchange opportunistic infections, but she chatted with them through Facebook. Her father remembers hearing her typing to the patient in the next room, and then hearing that person composing a response, like prisoners tapping messages through a wall. She raised money for cystic fibrosis research.

While Smith was sick, her father’s curiosity was all being channeled toward keeping her alive. He’s not a physician or a microbiologist. He studied nuclear science and engineering in college, and he now works as a real estate lawyer. He’d first looked into phage therapy to see if it could get rid of his daughter’s infection to hasten a lung transplant, and then ended up trying it to get rid of her post-transplant pneumonia.

He hasn’t given up on phage therapy. He’s glad that Sacher and Zheng are starting the directory, saying it “is especially vital as long as phage therapy is an end-of-life, emergency treatment. That’s where we are today.”

But he’s hoping to get the field beyond that. He would like for phage therapy to be used long before all antibiotics have failed — before cystic fibrosis patients have even suffered much lung damage. The damage is caused by the immune response to bacteria. It’s a kind of vicious cycle: The mucus of CF patients is too thick and sticky for the tiny hairs inside the lung to get rid of it, and it becomes colonized by bacteria. Inflammatory cells rush to the scene, but they just make the mucus stickier, causing scar tissue, making it harder to breathe.

Smith’s plan is to convene a working group to figure out if phages could be used when a patient is first diagnosed with cystic fibrosis. Clear the bacteria before that cycle starts, he thinks, and maybe you could prevent some of the crises that his daughter had to deal with.

He isn’t starting to work on the idea immediately. He’s got other things on his mind. “But after we’ve gotten Mallory to rest, and managed the various different entanglements that that involves — moving out of our apartment in Pittsburgh, shipping the car home — I will start to devote more time to this,” he said.

Many cystic fibrosis clinicians hardly think about phage therapy. To them, it’s basic science, far from anything you might be able to prescribe. Smith and Strathdee are hoping that might change with further research. “I have a concrete vision,” he said, “of cystic fibrosis patients being counseled by their doctors that it is not a terminal condition.”