This was puzzling on two fronts. First, I found articles on phage therapy dating back to the 1930s and ’40s. There were case reports of its use to treat Salmonella infections, published in one of the world’s most prestigious medical journals, Journal of the American Medical Association. Second, my Google search quickly identified that phage therapy was being used regularly in some former Soviet bloc countries, like the Republic of Georgia, Russia, and Poland. A Buzzfeed article from March 2014 described the desperate attempts of patients with superbug infections who had flown to Eastern Europe, where the Eliava Phage Therapy Center in Tbilisi, Georgia, had existed for decades.
In most countries, phage therapy had fallen out of favor after penicillin came to market in the 1940s. Understandable, since antibiotics were true miracle drugs until antibiotic-resistant bacteria began to surface as a significant concern in 1959. The alarm over a coming pandemic of deadly antibiotic-resistant bacteria threatening human life had been sounded the world over with no apparent effect. Outdated ideas, ignorance, and plain prejudice had hobbled the scientific and medical community. Although phages were studied extensively by basic scientists in molecular biology and genetic engineering experiments, relatively few scientists had persisted to research phage for its therapeutic potential, most of them laboring in obscurity at universities or a few small biotechs.
As much as some phage therapy proponents were eager to see it embraced as a potentially “new” way of treating antibiotic-resistant bacteria, bureaucratic hurdles and the lack of empirical data on efficacy had thwarted attempts to advance its clinical use in the Western world for more than a century, and that muddled past had muddied prospects ever since. Phage therapy clinics in Tbilisi and Wrocław advertised treatment and there were online accounts of some success stories, but few rigorous studies in humans had been published in English journals.
I could not find a single article describing phage therapy to treat humans infected with Acinetobacter baumannii. It had been done in Petri dishes. In mice. A few rats. It seemed promising, but could I really justify turning my husband into a guinea pig? If things went sideways, how would I explain my decision to inject him with a legion of viruses to his daughters?
Using viruses to chase bacteria reminded me of the children’s song about the old lady who swallows a spider to catch a fly:
She swallowed the spider to catch the fly
But I don’t know why she swallowed the fly—
Perhaps she’ll die.
It was after eleven p.m. and I was starting to fade, but heard a ping from Facebook messenger—my colleague Maria Ekstrand in San Francisco who knew both Tom and me well wrote to tell me about a friend of hers who had flown to Tbilisi to have her MRSA infection treated at the Eliava Phage Therapy Center. It had worked. Another cosmic coincidence? Some might call it a sign, and maybe it was, but I needed more than a sign. I needed a path forward, even if I had to build it myself. I fired off an email to Chip, attaching a research paper on A. baumannii phages I had found by Dr. Maia Merabishvili, a phage researcher from the Eliava Center who was now based in Brussels. I could just imagine Chip’s eyebrows twitching as he read my email.
Dear Chip, I know that we are running out of options to save Tom, so I have been exploring alternatives to antibiotics. What do you think about phage therapy? I know it sounds a little woo woo, but it might be worth a shot.
If I was going to try to obtain an experimental treatment to save Tom’s life, it was going to take an act of God, a lot of luck, and more energy than I might be able to muster. But just thinking about phage therapy gave me an adrenaline surge. I’d loved my undergrad virology class years ago, and now the challenge was anything but academic. I couldn’t help but find it profound that I had to return to my own past, my training, to bring an obscure thread of science forward to find a cure for Tom. And that the potential answer could have been there all along without me or anyone seeing it until now—I could feel the excitement building in my gut. And it wasn’t the knot of fear that I’d been learning to live with since Luxor. Could this really be it?
I checked my email again before going to bed. Chip was burning the midnight oil, too. He had already replied to my message.
It’s an incredibly interesting idea that would be worth thinking about—although it might be slightly ahead of its time… If you can find some phages with activity against Acinetobacter,I will give the FDA a call to see if they will issue an eIND for compassionate use.
Chip’s positive response should have been nothing but exciting. But at first, I could only focus on two words: “compassionate use.” I stared at those words for a full minute. So, there we had it. Even Chip was admitting now that Tom was dying.
I could just hear him reviewing Tom’s situation with Connie through his most objective lens. Chip was deeply empathetic, but he’d told me once how, as a physician, you have to compartmentalize. You can’t let yourself get so emotionally wound up that you can’t function as your patient’s physician, or it means they don’t have a physician, and that’s worse. You have to be able to make scientifically and medically sound, pragmatic decisions. And the truth was, despite everyone’s hard work and hope, there was no way you could convince yourself that Tom was getting better. He was barely communicating. His kidneys were barely holding on. He needed pressors to maintain a livable pulse and he needed the vent to get enough oxygen. And the superbug wasn’t the only thing killing him. His underlying issues—the pancreatitis foremost—and the collateral damage meant that his body was breaking down, bit by bit. His organ systems were failing.
Our best hope now was that the FDA would decide that because he was going to die anyway, an experimental therapy was worth the risk.
It had been a long-running joke between Tom and me that wherever we traveled, Tom “collected” local parasites or weird infections, always returning home with some malady or another. Like Cameron and his Pokémon cards. Tom had even quipped once, after our MRSA experience, that it was his goal to collect all six of those deadly ESKAPE pathogens. It had seemed funny at the time: “Gotta catch ’em all!” Now his next acquisition—after Acinetobacter—could be an entirely new character from a new deck of cards, one with protective powers, maybe the ace up his sleeve.
At the hospital the next morning, I strode through the atrium feeling bathed in the light and the energy of possibility. The ride up to the TICU wasn’t the usual discouraging descent into fear. And when I reached Bed 11, I was ready for a painful but important conversation. Tom and I needed to have another “life or death” talk. The first talk we’d had like this was in the Frankfurt ICU, more than two months before—two months of this “near-death” experience. Whatever I’d said that day had triggered his fight response. Granted, today the trach vent made it a one-way conversation, but we had to do our best.
I leaned close and took his hand in mine, hating the gloves I had to wear. I thought I detected Tom’s lips move at my touch, which was a good sign. Maybe he was just conscious enough to hear me.
I told him the truth. The docs were now out of ammunition. They were all out of antibiotics, and he was not a candidate for surgery. So, if he wanted to live, he’d need to fight again. This would be a fight for time, while I looked for an alternative treatment I didn’t know if I could find. And a fight against the continuing deterioration of his body, beginning to trigger organ shutdowns. No guarantees of anything, except certain death if we both stopped trying.
“Remember we had that talk back in the Frankfurt ICU, where I told you that if you want to live, you have to fight?” I began, and my voice faltered, catching in my throat. I swallowed and tried again. “Honey, I know you have been fighting so hard, and you’re very tired. The doctors here are doing all they can, but they tell me they can’t do anything else.”
I knew that he knew this. In the still pause, I watched as a single tear welled up in the corner of his eye and spilled across his eyelashes. He blinked, but his eyes stayed closed as another tear trailed down his ch
eek. I let go of his hand, and wiped his face with a cloth. Later, I realized that I’d clenched my other fist when I saw that my nails had a dug four red half-crescent moons into the palm of my hand.
“I want to grow old with you, Tom. But I don’t want you to live just because I want you to. That would be too selfish. This is your life, not mine.” I took a deep breath. “And the thing is, it’s okay if you don’t want to fight anymore.”
No clear response, if I was being objective, which admittedly was getting harder. He couldn’t see me, but I was pretty sure he heard how my voice wobbled. I held his hand again gently.
“But if you want to fight, I’m going to fight, too. We’re in this together. I will leave no stone unturned. In fact, I’ve been reading some articles on experimental treatment for multi-drug-resistant infections, and I have an idea…”
I told him about the phages, how they’d evolved over millennia to become the perfect predator of their hosts—bacteria. Of course, if he were awake, he’d be chomping at the bit, asking a million questions. But I had to cover all the bases, an effort at informed consent, in case he could hear me. So, I laid it out. Longshot as treatments go. Sound science as far as it went—but untested on humans infected with a fully antibiotic-resistant Acinetobacter baumannii strain that had totally colonized the body. Experimental, which meant it could take time to get permission to use on him. And no guarantees that it would work or, even if it did, that he’d recover from the damage already done.
“I’m not sure how to do it yet, but maybe we can get you some experimental phage therapy.”
I squeezed his hand gently. “If you want to try it, can you squeeze my hand?”
He seemed to stiffen but… nothing. And then—he squeezed back, hard. No retreat.
That night, when I went to bed, even looking at the worst-case scenario with clarity, I didn’t cry myself to sleep. I dreamed of wading waist-deep in a swamp, hunting for phages as if panning for gold. The water was murky and putrid, swirling with images of alien-looking phages, their heads the shape of microscopic geodesic domes and rocket ship tails trailing long filamentous fibers. When I looked down, I saw that I wasn’t holding a miner’s pan, but the cracked bedpan from the clinic in Luxor. I woke in a panic and rubbed my face with sweaty palms. With relief, I realized it was just a dream. But for the first time waking up to the real-life nightmare of Tom’s illness, I felt more exhilarated, less hopeless. I leapt out of bed so fast I startled Newt and the kittens, who had curled around my knees while I slept.
Now all I needed was to find some phages. How hard could that be?
Tom: Interlude V
The curtain goes up on a play. I am in the audience, watching the actors passively. The room is a dull white, which makes it feel even colder and more sterile under the stark artificial light. Two sides of the room are almost all glass; on one side, people peer through a curtain of sphagnum moss into my room, the terrarium. There is a bed in the middle surrounded by a peat bog; the water, barely visible, is black, brackish. Each time someone steps into the room, a wafting smell of decay fills the air; it is the inevitable smell of death. An incandescent bulb on the ceiling flickers and buzzes next to me, like a blowfly waiting for carrion.
Beside the bed, a TV monitor flashes numbers and squiggles, and an alarm rings out. I cannot feel my body, which I know should frighten me, but I no longer care. I am floating above the bed, and I glimpse the top of an IV pole, which has five bags hanging on it, one half full of dark red blood.
Steff is in the play, too. She was nodding off in the corner offstage, but now she jumps up at the sound of the alarm and enters stage left. Rushing over to the bed, she pushes the call button with her gloved finger. Two actors suddenly appear stage right, a man and a woman with long, flowing robes. In seconds, they each pull yellow gowns over their heads and snap on gloves. They too, approach the bed.
Just then, I am struck by the sight of a snake lying in the middle of my bed, all curled up, immobile. Why I didn’t see it before, I don’t know. This confuses me. With a growing sense of dread, I know that I am allowed to stay alive as long as the snake is alive. But the snake is barely alive now. Its eyes are like slits. A web of green veins is visible on the surface of its eyelids, as if spun by a spider. The color of its skin is mostly jaundiced, its belly mottled with gray, black, and red bruises where it has been poked and prodded relentlessly. Its scaly skin is so thin, it is translucent. Through it, I can see that the only spark of life left is an ember in its tail; its glow ebbs and flows faintly, with the beating of its heart. Steff kisses its lips tenderly; they are bluish and covered with caked blood and spittle.
The snake licks its lips, and they are my lips. I am the snake. And I am dying.
The snake is being swallowed by a demon, which emerges like a volcanic island from the quagmire of the netherworld. The demon has a head like a lion and the jaws of a crocodile, the eater of souls. The demon unhinges its jaws, and I retch at its smell: vomit. I feel its teeth tear at my skin, which sloughs off in long papery ribbons and falls into the bog, where it will be absorbed by humification into gelatinous peat. As its asynchronous ratcheting devours me, accordion-like, my lungs gulp for air. I swallow black bile. A wave of gastric acid washes over my exposed heart, which is pale gray and barely pulsing. Is this the demon that has eaten Ra, the Egyptian sun god, when he disappeared into the underworld? If so, I will never see the sun again. I feel an overwhelming sense of despair; I have never felt more alone.
The man and woman circle the snake on the bed; the man inserts a bronchoscope. Its silvery segments slither into the snake’s throat, and within seconds it sucks out a glistening plug of mucus. Oxygen restored, the cobwebs clear briefly from my eyes, and I am back in my body.
A group of three doctors walks toward my terrarium, their white coats flapping. I point at them vigorously. Steff laughs; she knows I am urging her to join rounds, where they will discuss my case like the specimen that I am.
As the brown curtain in front of my eyes closes, I think of phages.
Yeah, bring those little fuckers on.
15
THE PERFECT PREDATOR
February 21, 2016
What did it even mean to go on a phage hunt? Encouraged by Chip’s support for attempting phage therapy, it had all seemed so possible yesterday, and even this morning. But after draining two cups of coffee, I still hadn’t shaken the frantic phage hunt from my dream. I had already pored through a stockpile of research papers on PubMed and learned that there were an estimated 1031 phages on the planet—ten million trillion trillion—in existence at any given time, and no one really knew how many existed that preferentially attacked each species of bacteria. It could be dozens, hundreds, thousands. How would I ever figure out which ones might kill Tom’s bacteria, and then find them in time? Identifying which phages might be effective against Tom’s Acinetobacter made finding a needle in a haystack sound easier. I was suddenly overcome with the impossibility of the task I had taken on for myself. Biting off more than you can chew, my mother would say. She had always been my sharpest critic. I tried to shrug off my doubt. Tom was counting on me. So were the girls. I imagined what he would say if he could talk. “The enemy of my enemy is my friend,” if he was feeling philosophical. “Hey, another killer bug to add to my collection,” if his sense of humor was intact. He’d always been a risk-taker. So, there was no turning back now. Where to turn to was the question.
Who in the world is doing this work? Where do I even start? It’d been a long time since I’d felt like I was starting at square one like this.
Since phage therapy was outside the accepted repertoire of Western medicine, it was going to take outside-the-box thinking to figure out if and how it could be used now. What’s more, that process sometimes takes decades or longer in the methodical world of science and medicine, and there just wasn’t time for that. This had to be on a fast track, or Tom would die waiting.
As an infectious disease epidemiologist, I routine
ly track threads of data and discoveries across time, space, and populations to find fresh insights. Now, as I read about the discovery of phages and the first attempts at phage therapy one hundred years ago, it was beyond ironic that Chip had mused that phage therapy was an idea ahead of its time. Thanks to the internet and our online university library access, I was reaching back in history to published articles that detailed the basic science that scientists had stumbled upon in the days when Model Ts ruled the road. The authors of these studies—my new mentors—had died long before my PhD adviser had.
Articles about phages ranged from clinical and basic science to studies of the evolutionary path they are believed to have traveled since emerging with the first terrestrial animals some 450 million years ago.
Most scholars now credited the “discovery” of bacteriophages to Félix d’Hérelle, a scientist who observed “filterable agents” that killed bacteria in 1917. But clarifying how this antiseptic agent killed bacteria would turn out to be a bigger challenge. In 1915, an English bacteriologist named Frederick Twort was working to develop a smallpox vaccine, but his lab cultures were often contaminated with Staph bacteria. Upon further examination, he observed small, glossy spots in the thin film of Staph in the Petri dishes where the bacteria didn’t grow—just as we’d seen in my virology lab class in 1986. Twort showed that whatever had killed the Staph could pass through a super-fine porcelain Pasteur filter and infect new bacterial cultures. Pasteur filters, so named for the acclaimed father of microbiology Louis Pasteur, kept larger microbes like bacteria from passing through. So, whatever this agent was must be smaller than bacteria. Twort was unsure just what this was. But his findings—the discovery of a “bacteriolytic agent” that killed bacteria—were published in the top medical journal The Lancet.
The Perfect Predator Page 15