Félix had died long ago, and Carl had been put out to pasture. There seemed to be relatively few phage researchers left in North America who believed in its therapeutic potential. If there were any working on phages active against A. baumannii, I had to find them. Now that we had the science and the technology to see and study phages, tweak their genes, and tailor their appetites, maybe it was time for their comeback.
On the way to the hospital a few hours later, I called Carly and then Frances to tell them what I had in mind. How do you tell your stepdaughters that you want to inject live viruses into their dad to try to cure him of his bacterial infection? It sounded ludicrous, but I gave it my best shot. Both had listened attentively and were encouraged that Chip was supportive.
“So, basically, this is like a green alternative to antibiotics, right?” Carly asked when I reached her at home. Carly lived about ten hours away, in a Victorian farmhouse just north of San Francisco, where she and Danny had moved shortly before their wedding. I could imagine the pastoral setting with song sparrows trilling in the background. Tom would have identified them—Meliospeza melodia—if he were here. If he could talk.
“I never thought about it that way, but yeah, I guess you could say that,” I replied. I was on my speakerphone, sitting in bumper-to-bumper traffic on I-5. “And over millions of years phages have co-evolved with bacteria, even those that have become superbugs.”
“Love that Mother Nature,” said Carly wryly. “But where are you going to find the phages?”
“That’s the six-million-dollar-question. Haven’t figured that part out yet,” I admitted.
“But where there’s a will, there’s a way.”
I was relieved she was on board. One down, one to go. I reached Frances while she was out doing fieldwork under contract for a biological sciences project.
“Have you watched too many reruns of Forensic Files, Steff?” She was teasing me. I knew she detested the show. In an episode that I’d forced her to watch with me when she had visited last, a scientist had used swamp plankton to solve a murder that was decades old.
“At least I am not a black widow trying to finish off her husband with succinylcholine,” I countered, referring to what often turned out to be the murderer’s preferred poison. “Besides, your dad’s illness belongs on another show: Monsters Inside Me.”
After I explained the idea behind phage therapy, she gave it her blessing: “That there is some cool shit.”
Truer words had never been spoken. Since phages are plentiful in the guts of humans and animals, billions of them are excreted into the environment every day in fecal waste. So the first places to start looking for Tom’s cure would be locations with a high concentration of that particular organic matter: feces. This meant that one of the best places to find them in was in raw sewage. In other words: shit. No, I thought, that detail could be explained later, if and when the time came. I could see the National Enquirer headline now: MAN CURED OF DREADED SUPERBUG WITH PURIFIED SEWAGE.
16
SEMPER FORTIS:
ALWAYS FAITHFUL, ALWAYS STRONG
February 21–26, 2016
The evening of February 21, intent on finding a clue that could lead to phage sources, I spent the night with PubMed and half a bottle of 7 Deadly Zins. Newtie and the kittens made a nest along my side in the blanket that covered my lap, each jockeying for a position that would reward them with a scratch under their chin or on the belly. By eleven p.m., I had finished scribbling down a list of the top phage researchers who made any mention of Acinetobacter baumannii in their published papers. I highlighted the ones that were based at US institutions, knowing that time was of the essence. The AppleTV connected to our surround-sound speakers was set on random play, and I clicked it on to fend off the painful quiet. The room filled with one of my favorite songs, “Courage,” by the Tragically Hip. We were living the through line: sometimes all we can do is stay upright through the worst of times, make the best decisions we can, and live with the consequences, never knowing what they’ll turn out to be.
My mind wandered. It had now been over a month since I had last heard Tom’s voice. I took a deep breath and hit the answering machine button, just so I could hear his deep baritone: Hi, you’ve reached Tom and Steff. We’re not here right now…
“OK,” I announced to the kitties. “This is no time to feel sorry for myself.” I thought of Tom fighting for his life against this superbug that I’d once dismissed as wimpy. He’d made the decision to fight, and we’d made our pact to do it together. As I sang along with the chorus to “Courage,” I summoned whatever strength was left in me to get the job done.
My search had turned up only a handful of people in the US who could maybe—just maybe—help find the right A. baumannii phages for Tom, and were close enough to possibly beat the clock. I stared at the blank email page. It stared back. I would have to make cold calls, emailing someone out of the blue. I was used to that, since I often contacted leading researchers for their expertise. But this felt weird for a few reasons. First, although I had an undergraduate degree in microbiology, phage research was far afield from the discipline I knew best and for which I was known by others. Second, this wasn’t a professional query. It was as personal as it gets. I was about to ask a group of strangers to help me save my husband’s life. A proverbial shot in the dark, with Tom’s life hanging in the balance. But if Tom died despite my efforts, at least I’d know that I’d tried my very best.
In fifteen minutes, I’d written a generic email that I tailored slightly for each of the researchers on my list. The first one was to Dr. Ryland Young at Texas A&M University, director of the Center for Phage Technology. He had been quoted in a news article in a top scientific magazine, where he claimed that finding phages to target a specific bacterium is “relatively easy.” Could this possibly be true?
Dear Dr. Young,
I learned about your phage research in a commentary in Nature. As an infectious disease epidemiologist, I find this approach to treating clinically resistant ESKAPE pathogens fascinating. However, I also have a personal interest, as my husband has a serious case of gallstone pancreatitis, which is complicated by a pan-resistant Acinetobacter baumannii infection that he probably acquired in Egypt, where he fell ill. After three months of acute illness, he is now being treated at a UCSD hospital by my colleagues, some of whom are top infectious disease experts. However, his condition is deteriorating because the infection cannot be controlled, and we are considering less conventional approaches. I recognize that your lab primarily does in vitro research, but I am wondering if you have any suggestions for us in terms of phage treatment. Many thanks for considering this unusual request.
As I tailored each letter and hit the Send key, I could feel my desperation rising. Would he even read my email? Tom and I got so many phishing emails every day, junk disguised as urgent messages, or predatory journal editors offering to publish a research paper—for an astronomical fee. He and other researchers did, too, no doubt. Even if they opened my note, how could I expect a total stranger to respond to such an unusual request—and do it right away?
The next morning, I had a hundred or so emails waiting for me, as usual. Most were routine; others were junk. I scanned them briefly, triaging some of the work-related ones for later and deleting others. Several were from phage researchers I had written the night before who had sent regrets about my situation. A few explained politely that they had no A. baumannii phages. Others said that their approach was not yet ready to be tested in humans.
The last email I opened was from Ryland Young at Texas A&M. As I clicked open the message, I braced myself for yet another rejection. Like the other researchers, he wrote that he was sorry to hear about Tom’s condition and the desperate circumstances, that Tom’s case was heartbreaking. But unlike the others, he offered to help locate appropriate phages that might be able to treat Tom. He suggested we talk by phone ASAP and sent me three phone numbers where he could be reached. He signed it Ry. I wa
s electrified.
I called Ry and we spoke for nearly two hours. It was as if I’d dropped like Alice down the rabbit hole. He proceeded to give me a crash course in phage biology, picking up where my virology class had left off thirty years ago.
I jotted down some notes outlining what we were up against. Unlike some phages, such as those active against MRSA, those that are active against A. baumannii are type-specific. This meant that we would need to match specific phages not just to Tom’s bacteria’s genus and species, but to Tom’s actual bacterial isolate. In other words, it wasn’t enough to know that they needed a phage match for A. baumannii. They would need to get a sample of the specific A. baumannii that was growing so successfully in Tom. Then they’d be able to turn to screening the phages they found to find a match. Did we have a sample of his isolate on hand so that any phages Ry or others found could be appropriately matched? We did. I would ask Sharon Reed in the UCSD microbiology lab to ship it to them right away.
Next, Ry asked me whether I happened to have any soil or water samples from Egypt, even soil from our hiking boots. If Tom’s superbug was acquired in Egypt, Ry explained, environmental samples from the region would be potential sources for identifying phages, because in nature, they coexist. I recalled how dry the earth was when we visited Saqqara and Dahshur, and doubted that we would have any dust on our boots that would meet his needs. We didn’t. No help there.
Last, Ry explained that we needed to find not just one phage active against Tom’s isolate but, ideally, several. “As you know, bacteria have an uncanny ability to mutate,” he explained. “Even if we are lucky enough to find a phage that we know matches Tom’s isolate—and I have to warn you, we will be extremely fortunate if we do—if we treat him with a preparation based solely on this one phage, his bacteria will likely become resistant to it, almost immediately. To make it perfectly clear what we are up against, our lab has only collected a few A. baumannii phages in the last seven years. But I’ll have them tested against Tom’s bacterial culture as soon as we get his sample, and we will know if we have a match in a day or two. I’ll also ask my team to plate out his bacterial culture against our environmental samples. You know what that means, right?”
I’d done my homework.
“Sewage,” I replied.
“Yeah, these samples come from sewage runoff, swamp water, farms—basically anywhere you can find poop,” he said.
“How many phages do we need to find, then?” I asked, with a growing sense of alarm.
“No one really knows,” he replied. “Phage therapy is virgin territory in North America. The Georgians and the Poles both have centers, so they have the most hands-on experience. But they haven’t collected enough empirical data to convince the FDA and other regulatory bodies that phage therapy can work. And most of their cases are more garden variety: Staph, Pseudomonas, and Klebsiella. Iraqibacter has become so virulent and resistant, it stands out, even among superbugs. My guess is that we’d need even more phages to cure a patient like Tom, who is fully colonized. Let’s aim for three or four that we can grow here and send back to you in a phage cocktail.”
“That would be amazing,” I told him, my voice wavering. “I am so touched that you are willing to go out on a limb to help a total stranger.”
“I’m the same age as your husband,” Ry replied. “An old fart. About to retire. Maybe that’s why his story struck a chord. And I’d like to see some real-world good come from this research and the career I’ve spent on phage biology.”
Self-effacing humor aside, there was nothing retiring about Ry’s style, and his old-fart status only meant that he knew a helluva lot about how phage therapy had developed—and stalled—through the years.
“There are a handful of researchers around the world who have kept plugging at the notion of a rebirth of phage therapy, but in many cases, they’ve been pushed to the margins of the phage community, some treated like pariahs,” Ry said. “Remember, phages were discovered long before Watson, Crick, and Rosalind Franklin figured out the mystery of DNA’s double helix, so the early research had its flaws. But I truly believe it’s time for phage therapy to come of age, now that even the best antibiotics are becoming increasingly useless against superbugs. An effort like this, if successful, would give them credibility—and perhaps more funding for phage therapy research.”
Ry brought a born-again fervor to this quest as an opportunity he saw to advance phage therapy research, as he’d spent much of his earlier career as a self-professed “anti–phage therapy” guy. As he told it, in his grad school days in the early 1970s, he’d been persuaded by the prevailing prejudice within the molecular biology community that regarded phage therapy as a “bizarre chapter” in medical history that should remain closed. That camp held that phages had been and still were very powerful as tools or models for discovering fundamental aspects of molecular biology, but their practical use in clinical applications—treating patients—amounted to quackery. Pipette dreams.
But, in 2002, at a national microbiology conference he’d been swayed by a very different vision of a modern approach to phage therapy, put forth by an internationally respected biotech scientist-entrepreneur from India. Thus enlightened, Ry became an advocate for a broader approach to phage science that included phage therapy. He eventually won the support of the higher-ups at Texas A&M, and in 2010 they established the Center for Phage Technology (CPT), providing faculty positions and a base research budget. It became one of the pioneering phage centers in the US. And it was this body of work by Ry and the CPT since, published in the ranks of influential peer-reviewed journals that had once deep-sixed phage therapy, that had caught my attention in my online search.
“If this works, it will be a game changer,” Ry said.
“In any case, we have our work cut out for us,” he said. “With your permission, later today I’ll forward your email to everyone I know who might have some A. baumannii phages. With any luck, they’ll have some they can send to my lab, where we’ll test their activity against your husband’s strain. Ship me his isolate hasta pronto. And email me any other information you think could pull at their heartstrings as you did mine. I’ll set up a Google drive so we can share files.”
I hung up, exhilarated. My heart felt like it was beating out of my chest—if I’d been hooked up to Tom’s cardiac monitor, it would be sounding the alarm. I immediately sent Ry the photo of Tom I had taken with his Iraqibacter T-shirt, along with a photo of Tom from 2012 when he was in perfect health. I added Tom’s academic bio and his curriculum vitae, which was over a hundred pages.
Chip was just getting to his office at the university when I caught him on the phone to share the good news.
“You won’t believe this, but Ry Young from Texas A&M already responded to my email and offered to head up a phage hunt. So I guess I should ask you formally—if they find at least one phage, will you be the principal investigator of the protocol?”
This was a critical question. There were two reasons why I couldn’t be PI of the protocol myself. First, I’m not an MD, and clinical protocols required one. Second, I was the wife of the patient, which meant I had a major conflict of interest.
I could hear a whoosh as Chip sat down in his office chair.
“Wow. That is quite a feat,” he said. “And sure, of course I can be PI. I’ll get hold of my contact at the FDA to get paperwork started for a compassionate use request. We need to have our ducks lined up so we’re ready to go if they find a phage.”
Chip wasn’t surprised to learn that Ry needed to match phages to Tom’s bacterial isolate and that they’d need to find more than one to overcome resistance. Chip chaired an NIH review panel that adjudicated research proposals focused on antimicrobial resistance, so he was also well aware of the regulatory challenges that lay ahead in the FDA’s review process for an eIND—experimental investigational new drug. These are treatments of last resort, not yet FDA-approved and used only when someone is dying and all conventional treatments
have failed. Tom qualified on both counts. And there couldn’t be a more qualified clinician than Chip to shepherd this project. The question was, could the approval process move quickly enough to get any phage they happened to find sent in time to save Tom?
“This might be a stupid question,” I said, “but why do we need an eIND from the FDA? Phages aren’t medications.”
“The FDA doesn’t have any other mechanism for approving new therapeutics,” Chip explained. “That’s part of what discourages developers from testing new treatments like phage therapy. The FDA needs a new regulatory model, but the odds of that happening any time soon are nil. Though if we can cure Tom with phage therapy, that might be an impetus for them to make some changes.”
The next morning, my inbox had more emails than usual. There had been a flurry of activity overnight, thanks to time zone differences. Ry’s email had been persuasive. Phage researchers in India, Switzerland, and Belgium had all agreed to send A. baumannii phages to Ry for testing. Dr. Jean-Paul Pirnay, the head of the Belgian team from the Queen Astrid Military Hospital in Brussels who collaborated on the paper I had found by Dr. Merabishvili, wrote that his team had some phages active against A. baumannii that they were hoping to use topically to treat soldiers with burns. Incredibly, he offered to send their phages in a diplomatic pouch.
Chip had news to report, too. He had called his contact at the FDA, Dr. Cara Fiore, prepared to explain what phage therapy was and why it was needed for compassionate use in Tom’s case. But Dr. Fiore, a microbiologist with the agency’s Center for Biologics Evaluation and Research, knew all about it and was familiar with all the main labs in the US that were working with phages. She even offered to provide contact information for a couple of labs that weren’t on our list.
This was so much better than either of us had even hoped for.
The Perfect Predator Page 17
