No wonder. As Tom described it to me one day, in his professor of psychiatry mode, the brain is made up of about 20 trillion neurons that are wired to work in harmony, bundled to process different tasks involving different parts of the brain—cognition, emotion, memory. Ordinarily, big emotions like love or fear would flip the switch on some bundles, while reason and memory would use others to keep things steady. With PTSD, he explained, whenever he thought about a hallucination, it was like looking at a memory circuit in his brain. But as the memory flooded back “it was as if all of the 20 billion neurons in my brain were bundled into a single high-voltage wire. When I touched that wire there was nothing else but emotion.” No capacity to rationally differentiate between the past trauma and present moment, no way to keep things steady. Trying to forget the memories only left the tripwire hidden for repeated high-voltage shocks. With help, he was able to process the trauma differently, hold it as memory, but without the high-voltage wire.
Some days, Tom was depressed; other days, elated. Mostly, he seemed grateful to be alive and was filled with a new sense of awe about everything, no matter how mundane. He had to relearn how to do the simplest of tasks, like brushing his teeth and combing his hair. He played cards with Carly and thumbed through Sibley’s Field Guide to Birds of Western North America with Frances like he’d done when the girls had been young. More often than not when I arrived at the hospital, I would find one or both of the girls perched on the side of his bed while they watched old movies. One afternoon, as they left and were out of earshot, he complained—about himself.
“Look at me,” he said darkly. He held out his arms and stared at them in shock. I tried hard to hide my own. Once his kidney function had finally started to improve, the docs had started pumping him full of diuretics—the ones my grandma used to call “water pills”—that prevented the body from absorbing too much salt. As the extra fluids began to be siphoned off, he’d turned from a bloated pufferfish to a deflated balloon.
His forearms, which had been as thick as tree trunks, were now matchsticks. Folds of skin under his chin sagged and wobbled when he moved his head. The skin on his legs drooped like Granny’s pantyhose.
“I’m an old man!” he said angrily. “I was playing cards with the girls, and I dropped some like a two-year-old because my hands won’t close all the way!”
We were all so grateful he was alive, so relieved to even be able to see him conscious and conversant, that his appearance seemed secondary. But it was true: the robust Tom who’d taken steps two at a time up the face of the Red Pyramid had wasted away. There was a medical word for that: cachexia. Extreme weight loss and muscle wasting, commonly associated with malnutrition, debilitating disease… and dying. I remembered the first time I’d ever seen someone who looked this way. It was at Casey House, the AIDS hospice where I’d volunteered during the earliest days of the epidemic. My husband had become a walking skeleton. Or a living one, anyway. Walking would have to wait, but whatever else had wasted away, that bit of stubborn grit remained.
“I didn’t make it this far to give up now,” he said.
No retreat.
I bought him some wrist and ankle weights, and he dutifully exercised with them to regain his muscle strength, while I hummed the title soundtrack from the Stallone movie Rocky.
The day I wheeled him outside for the first time, a month after phage therapy began, it felt like we were going to prom. I brought along his favorite hat—a fedora that my parents had given him—and plopped it on his head, then wrapped a blanket around him. The nurse’s aide, Carmen, helped me place two pillows under his butt, or what was left of it.
“Here we go, honey…” I whispered as I released the brakes on the wheelchair and pushed him out the double doors of the TICU. Carmen pushed the IV pole, as Marilyn, the charge nurse, looked on approvingly.
“Be back in fifteen minutes,” she clucked like a chaperone.
“Or I’ll turn into a pumpkin?” Tom retorted.
The look on Tom’s face as I wheeled him past the palm trees in the lobby and the dapper doorman in the double-breasted uniform, out into the San Diego sun, was priceless. He told me later that when he took his first breath of truly fresh air, every molecule bombarded his senses. Cherry blossoms. Fresh cut grass. Espresso from the coffee wagon. He wept when he heard the familiar sound of a song sparrow calling for its mate: Madge-Madge-Madge, put-on-your-tea-kettle-ettle-ettle. This passionate ornithologist, a man whose ear was more attuned to birdsong than the chatter of his own species, had not heard a bird in nearly five months.
Little by little, though, the life-support accessories began to disappear, a reassuring sign. Tom’s ka was making a comeback. A week later, he took his first baby steps in months, with Amy and the lift team supporting him on either side. A new CT showed that his pancreatic pseudocyst was no longer the size of a football, “but maybe a softball” said Tom Savides, the GI doc. On May 1, the cardiac monitor was unhooked and wheeled out of Bed 11.
“Good riddance!” Tom declared, with a note of finality and a ceremonial salute.
One afternoon in mid-May, six months since Tom had first fallen ill, Chip stood next to Tom’s bed, perusing the lab report on his most recent blood test. He beamed at the opportunity to share good news.
“I am happy to confirm that we officially have the Acinetobacter on the run now,” he said, smiling ear to ear. “In fact, two of the phages, including one that we added a few weeks ago, are synergistic with minocycline.”
Tom looked at Chip in surprise. “Does that mean that the Super Killer phage is actually making the antibiotic work better?”
“Precisely,” said Chip. “It’s a perfect textbook example of synergy. Neither the antibiotic nor the phage were as effective on their own as they needed to be, but together—bingo. Stronger together. That is the definition of synergy.” Limited studies with animals had suggested that the benefits of using phages with antibiotics together was greater than either one by itself, Chip said. Now Tom’s case provided human evidence that antibiotic-phage synergy was not only possible but extremely promising.
Tom’s immune system had rallied, too.
“Looks like Biswajit’s in vitro results panned out in vivo,” Chip explained. “The synergistic effect made the bacteria more vulnerable to other bacteria-fighting agents, whether drugs or your immune system. Or maybe both.”
The scientific literature was still thin on this front, but it was an area of urgent interest now in the fight against superbugs, he said. Researchers were searching through subtleties in drugs’ interactions with drugs and with bacteria—and now phages could be part of that equation.
The possibilities were exciting, as Chip described them. This was just his kind of cutting-edge challenge, working with new data to save one patient, then pushing for new clinical trials for the data to save many more.
“From the phage therapy perspective, the serial samples we drew last week have provided some of the best phage PK data generated to date,” he said, referring to the pharmokinetic activity, how the body absorbs, metabolizes, distributes, and eventually disposes of drugs or, in this case, phage. The data also confirmed the phage’s continued synergy with the antibiotics, boosting the drugs’ effectiveness. And the bold guess regarding dosing—how much and how often to administer the phage infusions—also appeared to have been the right guess to anticipate the complex interactions that would follow the phage infusions.
“There are still quite a few details to sort out,” he said, cautious but not confounded. “But an ongoing presence of bacteria that shows some resistance to the phages means that the phages are still taking on the Acinetobacter.”
Things could have easily turned out differently. Had we given up on phage therapy that roller-coaster Sunday morning when Tom’s blood pressure had dropped suddenly because of the Bacteroides infection, Tom would not have survived, and we’d be just another anecdote in the strange history of phage therapy. The flip side of that would be to stop with a s
imple conclusion about the phage therapy success without learning more about all the contributing factors.
Whatever emerged in the new data from Tom’s case, Chip said, the fact that it had been documented so carefully was a clinical coup worth celebrating.
“Although phage therapy has been around a long time, with Tom’s case, we overcame a lot of the obstacles that have been preventing it from becoming more widely used to treat multi-drug-resistant bacterial infections outside of Georgia, Russia, and Poland.”
“How so?” asked Tom, wide-eyed.
I piped up and told them about my readings of medical historian Bill Summers’s takedown of the politics, prejudice, and skewed view of scientific evidence that had shut the door on phage therapy research in the US more than fifty years ago. Chip added that Carl Merril had expressed frustration at those who had dismissed phage therapy’s potential on the basis of predictable bacterial resistance, choosing to ignore that phage could actually respond to resistance through mutations to counter it—the Darwinian dance. That was something drugs simply could not do.
“The FDA is doing cartwheels,” Chip said. “This is the kind of data they need to start considering a new regulatory model so that phage therapy can hopefully be offered more easily to other patients someday, without having to secure an eIND for every phage cocktail.”
“That’s great!” Tom and I cheered in unison.
“I’m sure that’s going to take some time,” Chip continued, “but based on the success of Tom’s case, the Navy is ramping up their phage program. They see the potential for offering phage therapy on demand, ideally using an ever-expanding phage bank. By partnering with industry, they hope to offer phage therapy to more civilians without some of the hoops we had to go through. And with your permission, Tom, we’ll publish your case report to move the field forward.”
Tom was all in. “Absolutely!”
I snorted in mock derision. “You’re the only scientist I know who generated the most important publication in his career while lying in a coma.”
“Speaking of brainstorms,” Tom said, half musing but excited in the gleeful way he gets over aha moments in research. “Am I an n of one?
An n of one is scientist lingo meaning the only patient in a clinical trial.
“Was I the first person to get phage therapy?”
I shook my head no, and realized—again—that Tom had little to no recollection of all the stuff I’d been sharing with him about this all along. The history, the science, the bold guesses—and the big risks—that were part of his one-man miracle. He’d always teased me about my habit of launching into professorial mode with a full-blown lecture at any opportunity, so I tried to just stick to his question.
“Not exactly. Félix d’Hérelle was the true discoverer of bacteriophages one hundred years ago. He was also the first one to try phage therapy. Starting with himself…”
“My kind of guy!” Tom interrupted, marveling at his new invisible friend Félix.
“Speaking of your kind of guys,” Chip chimed in as he pulled out his cell phone, searched for a moment before he found what he was looking for and passed the phone to Tom and me. There was a grainy black and white triptych—of phages. I’d looked at so many phages online that this seemed like another murky mug shot of the classic variety. With their angular geodesic heads and spindly legs, they really did look like alien spiders, or lunar landers, alongside the pudgy podophage. Or “potty-phage,” as Tom called it, no disrespect intended.
“Meet your new BFFs,” Chip said. “These are Theron’s electron micrographs of your phages. And here’s another one,” he went on, scrolling through his smartphone. “This one’s a scanning electron micrograph courtesy of one of Theron’s colleagues, showing the Navy phages attacking your Iraqibacter.”
Tom was instantly transfixed. Imagine being kidnapped and held hostage for six months, near death the whole time, and then meeting the superheroes who saved your life, heroes invisible to the naked eye. I was pretty wide-eyed myself. They’d saved our family, too.
“Monsters from the Black Lagoon!” Tom marveled, the pantheon of sci-fi mutants never far from his mind.
“Yeah,” I mused, “but at least they’re our monsters.”
We soon saw just how beautiful these micro-monsters were. Forest and Anca, the dynamic duo from SDSU whose lab had stepped in at the eleventh hour to repurify the Texas phage cocktail, stopped by one afternoon bearing a gift. It was a copy of the lavishly illustrated Life in Our Phage World: A Centennial Field Guide to the Earth’s Most Diverse Inhabitants, which Forest had co-written with several collaborators, all experts in various dimensions of phage ecology and history. A series of pen-and-ink phage portraits by illustrator Ben Darby caught our eye. As podophage family resemblance goes, enterobacteria phage T7 was a dead ringer for our Super Killer. Roundish and stout, with compact appendages. Practically cuddly. Looks can be deceiving.
“That puffy beachball is our Super Killer?!” Tom chortled. The cute factor was undeniable.
One of T7’s traits, as described in the Field Guide, is that it “delivers its genome in a slow, highly-controlled fashion, thereby evading a host defense.” Bingo. That had proved to be one of the superpowers of our Super Killer. And its habitat: mammalian intestines and sewage. Delish.
The pantheon of other phages is wildly diverse, and not even a drop in the bucket of the perhaps tens of trillions of types of phages roaming our mammalian guts, oceans, and sewers. Streptococcus phage 2972 is a long, lean, elegant slip of a thing with a delicate tassel for legs, known for being able to evade CRISPR defenses. Bacillus phage Φ29 and bacillus phage PZA look like something out of Game of Thrones, spiked bludgeons, no legs at all, adept at evasive strategies. Pseudomonas phage Φ6, partial to parasitizing plant pathogens, resembles a croquet ball covered with soccer cleats.
Phages have been called the dark matter of the virosphere, reflecting how little we know about them and the estimated two billion pieces of genetic code they carry around. But unlike the sci-fi drama, Forest’s book—and our own experience—brought that teeming world into a brighter light. Forest had published the Field Guide to commemorate the one hundredth anniversary of phage biology, but he dedicated the book “to the second century of phage explorers.” Tom had earned his explorer’s badge the hard way.
Forest and Anca glowed when they saw Tom awake and alert. From the start, when they’d delivered the first round of Texas phage, they had both checked in on him periodically when one or the other would swing by to pick up Tom’s newest isolate samples or drop off another round of purified phage prep.
“The ‘before’ and ‘after’ is pretty dramatic,” Anca told Tom.
In this Darwinian ball, the phages were having the last dance. A victory dance.
28
THE BUDDHA’S GIFT
August 2016
When the day finally came, I kept pinching myself. Were we dreaming? After being hospitalized for nearly nine months, Tom was finally discharged from the hospital on August 12, 2016, and came home. Day 259 from the start of his illness in Luxor. He’d been admitted to Thornton, via Luxor and Frankfurt, on December 12, 2015. It made for an odd anniversary.
We’d already started celebrating the small milestones. A couple weeks earlier, when the last of his drains had been removed, we liked the new direction.
“Nice to have you guys removing drains instead of adding them, for a change,” I said to Tom Savides, when he’d done the deed. After the procedure, my Tom pulled up his hospital gown to show me the holes where the last two drains had been.
“Looks like Dracula missed,” I teased, adjusting the Velcro strap on his wrist weights to keep them from chafing. “But I guess we showed the docs that a Hail Mary pass is possible when the quarterback is blindfolded with less than a minute left in the game.”
“That makes you the quarterback,” Tom quipped.
“And Chip, and—”
“Time to get T-shirts for the team,” Tom said
brightly. Only this one can say WE BEAT IRAQIBACTER!”
We had. The two-part phage therapy, begun on March 15, had continued for eight weeks, concluding on May 12, when it appeared that A. baumannii, while present in some blood workups, was at a level that Tom’s immune system was able to manage. Until then, the second-generation phage cocktail continued to prey on the A. baumannii and synergize with one of his antibiotics to make it more effective. This was the one-two punch Tom’s immune system had needed to catch a break and return to action.
Eight weeks. Eight weeks that had put the brakes on a lethal infection that had raged for nearly four months before, an antibiotic-resistant superbug that moved like a wrecking ball through Tom’s body before it was finally stopped. We would never know for sure exactly what triggered the gallstone pancreatitis or the pseudocyst, or when, and we would never know precisely where Tom picked up the A. baumannii. But from the day Dr. Zeuzem in Frankfurt had identified the football-size pseudocyst and the presence of multi-drug-resistant A. baumannii, the big-gun antibiotics had taken their own untold toll on Tom’s system with negligible effect on the infection. At least fifteen antibiotics, most of them tried in the first six weeks of his illness, had failed to stop Tom’s A. baumannii. And the uncontrolled infection had contributed to the cascade of other complications that pushed Tom so close to dying. We couldn’t help but think now how this personalized phage therapy—had it been available and done earlier—could have helped so much sooner, slowed the extreme deterioration Tom suffered, and made for a shorter and smoother recovery.
The Perfect Predator Page 28
