I remembered the dream, the nightmare really, that I’d had only a few weeks ago. I’d waded in that putrid, swirling swamp, hunting for phages like an old California prospector panning for gold. I’d woken in a sweat, seeing the cracked bedpan from Luxor as a bad omen. Now the dream was rewriting itself, the image transforming before my eyes in real life, and in ways I could never have imagined. I wasn’t alone. These wonderful people, this volunteer army of strangers, had stepped forward from far corners of a world that had been invisible to me before. They were the gold. And they were working day and night to find the phages that would prove golden, too.
I knew how labs operated, the demands on staff and resources, the precision of the tasks, and extensive planning that goes into their scheduling and the work itself. This had to have been a nightmare for them, too. A project dropped in out of nowhere, on a desperation deadline, disrupting everything and demanding even more. All that, and with a human life at stake. I could relate, but then, this was my husband. Tom was a stranger to them. And this was a huge gamble, with all odds against success. Professionally and personally, it had all the signs of a heartbreaker. And yet they stepped up.
From time to time, someone would share a glimpse of how personal the project had become to them. Each of them had the dedication it takes to work for years on something that you hope will eventually save lives. But it’s not often in research labs that the opportunity presents itself for you to be a first responder in an effort to save someone’s life right now.
After one long stretch of particularly frustrating work to tease out differences between the phages she’d found, Adriana later said, she suddenly hit the jackpot and found what they needed to add the fourth phage to the arsenal against Tom’s A. baumannii. She was ecstatic.
“I named that one Mago,” she said. “Magician in Spanish, my native language.”
Perfect. We needed all the magic we could get.
The same day, Jacob and Adriana in Texas texted me a photo of the package as they waited for the special pickup for a same-day delivery to the UCSD lab. I knew they had just pulled several all-nighters. With phages en route from Maryland and Texas, it was our own California Gold Rush, westward ho.
As the teams worked as fast as they could, the vigil with Tom continued at the hospital. With the photo from Jacob and Adriana fresh in mind, I put a damp cloth on Tom’s forehead to give him relief from yet another low-grade fever. He had not been awake for days.
“Hold on, honey,” I said, leaning close, “the phages are coming!” The vent and pressor settings were now set to high. I squeezed his hand as hard as I dared. He did not squeeze back.
19
JOURNEYING
March 12–15, 2016
I think his spirit is traveling,” said Frances pensively, as she poured herself a cup of tea, a brew she had concocted from black Chinese herbs with unpronounceable names. A pungent smell like burnt licorice filled the kitchen and wafted after her as she carried two steaming mugs toward the couch. She held one out to me. “Here, Steff, have some tea. It’s good for you.”
“Thanks, Fran.” I smiled at her from my favorite spot on the sectional sofa. “I hope it tastes better than it smells,” I said with a wink, and crinkled my nose. Frances had taken a course in herbalism and was planning to enroll in a traditional medicine program. She knew her herbs. I took a small sip, which tasted like treacle. Not bad.
“I think he is, too,” said Carly, who had emerged from the bedroom to plop down beside her sister and me. She released her hair from a long ponytail and gave it a shake.
Carly and Frances had returned a few days ago and we took turns at Tom’s bedside, waiting with bated breath for the phages to arrive. At rounds earlier that morning, the mood had turned from anticipatory to bleak. After reviewing Tom’s chart, Dr. Fernandes looked me in the eye and asked if the three of us could attend a family meeting later that afternoon. We returned home for a few hours, leaving Tom with our friends Chuck and Judy.
We were all coping with Tom’s illness in different ways.
Every morning, Carly would retreat into the guest bedroom, insert earbuds, and listen to a recording of shamanic drums as she kept one question at the center of her mind: How can I help my dad? She described her journeys as traveling to a world bathed in light where she met with one of a council of guides. In her most recent journeys, she said, she would immerse herself in something like a giant centrifuge that spun off her sadness so that she would be ready to help her father without the burden of her own feelings. The drone of the drums would then lead her to a place where her dad was lying in bed. She would help him up, and together they would walk to a bench overlooking the Pacific Ocean, where they would sit and talk.
“Maybe Pops is wrapping up, saying goodbye,” Frances suggested now, refilling my cup. She had just finished meditating, too, and she spoke in a calm voice that hid the fact that she was more upset than she was letting on. I had spent the last few hours pacing the floor, double-checking the online tracking number for the phage delivery to the hospital pharmacy and conferring with Chip. I could not sit still unless I had a kitty on my lap. Thankfully, Paradita had complied and was purring and kneading my velveteen bathrobe; her claws were like tiny scalpels.
Carly and Frances were seated on either side of me on the sectional. We gazed out at the mesmerizing view of the ocean through a floor-to-ceiling window that spanned the back wall of our house. Tom and I had spent hours watching the sun set over the ocean from our backyard. He was always searching for the green flash, a rare but natural phenomenon at sundown that is caused by refracted sunlight. I had almost finished my tea and tilted my mug so I could pluck out a piece of broken leaf that had clung to the bottom.
Within the hour, Chip called me with bad news. Before administering the phage, we would need to reduce the endotoxin concentrations in the phage preparations further, to as low a level as possible. The FDA had guidelines about this for other kinds of pharmaceuticals and vaccines but not for phage preparations.
“They have quite a bit of experience in this area, and I’ve been talking with them about what concentrations they think we should shoot for,” he said.
The phages that were to be used to treat Tom’s infection had been grown in large-scale cultures of his own A. baumannii at both Texas A&M and at the Navy. When these bacteria were destroyed as the population of phages was expanded in the lab, they released one of their key components that the human immune system recognizes when it is invaded by bacteria: endotoxin. Endotoxins are important triggers of the immune response and one of the major drivers of fever and low blood pressure in severe infection. The FDA was concerned that if there were significant residual levels of endotoxin in the phage preparations with which we planned to treat Tom, it could lead to septic shock. I knew from my crash course in phage biology over the last few weeks that the majority of deaths during phage therapy had been attributed to endotoxins that had not been adequately removed in the purification process. However, the phages themselves would also release endotoxin originating from the bacteria they killed within the body. That could cause septic shock, too, so Chip and I both wondered if concerns about the endotoxin that might still remain in the phage preparations warranted a delay in the treatment. In the end, Chip decided we’d better bring the endotoxin levels down further just in case. Better safe than sorry. Or dead.
Texas A&M had already shipped their phage preparations to the UCSD pharmacy, so their ability to conduct purification assays was limited to the individual phages, and not the cocktail. What was worse, their lab and the Navy had used a different technique for the phage purification, and since administering phage systemically in humans was a new approach, it was not clear which—if either—of these approaches would be workable.
What now? These new hurdles would delay the start of treatment by some unknown margin.
No sooner had I hung up the phone, despondent, when Ry called me.
“I heard about Chip’s discussions with th
e FDA about endotoxin levels in the phage preparations,” he said. “This is exactly the kind of problem others have run into when attempting phage therapy. I am not sure we can overcome it in time to save Tom, but we have to try. As luck would have it, I know a team of phage researchers in your own backyard, at San Diego State University.”
Again, I was stunned by the serendipity that led us to individuals with a particular expertise, some of whom, for a variety of reasons, had simply not shown up in our earlier searches. It seemed more than lucky that some of these people were right here in San Diego, engrossed in work that had nothing to do with using phages to treat sick people. Until now.
“Talk about stars in alignment—what are the odds?” Ry said, genuinely amazed.
The miracle of the moment was to be undertaken by Dr. Forest Rohwer and his research team at SDSU—his lab and life partner, Dr. Anca Segall; their postdoctoral fellow, Dr. Jeremy Barr; and Sean Benler, a doctoral student. Forest’s field was the eco-biology of phages, a field he and Jeremy had put on the map. Generally, their research was focused on phages as a model for studying DNA, genetic engineering, CRISPR, and other basic science—not phages for therapeutic use. Forest was known for his success in “scrubbing” phages clean even when the details made it dicey. Anca, a molecular biologist who was also a SDSU professor, headed up her own lab, and the two collaborated frequently on studies of marine phages. As it happened, Jeremy was an expert in the highly specific endotoxin removal method that was needed, and he had just recently concluded a year-long project using the process, so the lab was set up for this specialized work.
“I’ve left them a message to see if they would step in to run an endotoxin purification assay on our phage cocktail,” Ry said. “They’re good people. They’ll need to have a higher-quality endotoxin kit than the one we have here. Cross your fingers that they can help; otherwise you’ll need to find another lab that can do the assay on the fly, or ship the phage preparations back to us so we can re-scrub them.”
Any delay pressed Tom’s luck, and the repurification step only added to our fear that Tom wouldn’t be able to hold on long enough.
“Ry, thanks so much for stepping up to the plate yet again,” I told him, exhaling loudly. “I’ll call your colleagues at SDSU, too. I hope they’ll agree to help, because time is running out.” I looked at my watch. Eleven a.m. Literally the eleventh hour. “We’re headed to the hospital again this afternoon for a meeting with the doctors, and I have a feeling I am not going to like what they have to say.”
I was right about that. I left a voice mail message for Forest. After lunch, Carly, Frances, and I set out to the hospital, where three familiar faces from the medical team met us in a small conference room.
“The purpose of the meeting is to discuss next steps,” said Dr. Mims, who chaired the meeting. He ran a hand over his head, which was balding prematurely. “I’ve cared for Dr. Patterson off and on for the last several weeks, and he isn’t getting any better. In fact, I think everyone here would agree that his trajectory has worsened.”
We know this, I thought. Get to the point. He did.
“No one can say what will happen, of course,” Dr. Mims went on. “But in my experience, a patient with this kind of clinical profile is not going to improve. We need to know if you want to start planning for kidney dialysis or not. If you start dialysis and he recovers, he may need it forever. And even if he recovers, which I don’t think he will, he will need over a year of intense rehabilitation.”
“But he’s not in kidney failure yet, is he?” I prodded. “I thought you didn’t start dialysis until his creatinine was much higher.” A sick feeling crept into my stomach, like the treacle tea had curdled.
“Nephrology rounded on him earlier, and they don’t like the way things are headed,” Dr. Fernandes added gently. “His creatinine is now over 3.5. He will need dialysis very soon.”
I sat back to process this, closing my eyes. Lungs, heart, and now kidneys, all failing. This was my worst nightmare; Tom was on the verge of multi-system organ failure, the phages weren’t ready, and we were basically being asked whether we wanted to pull the plug.
“If he needs dialysis, and we decide not to give it to him, will he die?” Frances asked, pausing to swallow hard. Dr. Mims looked at her and nodded. “Yes. And soon, I think.”
“So,” Carly said, “would it be possible to just take him home to pass so that he doesn’t have to die in the hospital?”
Dr. Fernandes looked at her calmly and replied in a soft, practiced voice. “He would only live for a few minutes if we took him off the ventilator and stopped the pressors, since they are what is keeping his heart pumping,” he replied.
Carly’s chest deflated. “So, there is no way he can talk to us, just one more time?”
“I’m afraid not,” said the third doctor. His face was a blur to me, and I realized it was because I was crying.
Time to step up, I told myself. “We have not given up yet,” I said firmly, with a cool confidence I did not possess. “The phages are almost ready, and while we do not yet have FDA approval to proceed, we expect it will be granted very soon. So, if his kidneys need dialysis, please give it to him.”
The girls nodded their assent.
“Understood,” said Dr. Mims. “We will leave the phage plans to you and Chip. But I must warn you that there is precious little time left to turn your husband’s course around.” And with that, all three doctors stood to leave, their white coats flapping and reflecting the fluorescent light, which suddenly seemed unduly harsh.
Outside the conference room, I checked my cell phone, which had been set to vibrate. There was a voice mail message from a local caller. It was Forest calling from SDSU. He had received the messages from Ry and me and had cleared the decks at his lab to conduct the endotoxin purification assay. I was so overcome with relief that my knees almost buckled and I held on to a hospital rail to catch myself. An orderly in blue scrubs who was passing by paused to see if I was okay. I waved him on with a thin smile. There was still hope.
A few phone calls later, I had briefed Chip on the good news and located the Texas phage cocktail, which had just been delivered to the UCSD investigational pharmacy unit. Not trusting a courier to get there quickly enough, I asked my colleague Natasha to pick up the box and drive it over to Forest’s lab, so they could start prepping a sample for the assay.
“Remember, the phages are packed on ice and need to be kept at four degrees Celsius,” I instructed her, “or they will die.” I almost corrected myself as I said this, because technically viruses aren’t living or dead. They exist in a form of limbo until they come into contact with a bacterial host cell. Like a coma.
A mix of factors added to the complexity of Tom’s situation as Chip and the team worked to treat the underlying pancreatitis and the riptide of complications that yanked him from one crisis to another. Practical challenges loomed large. For one, no one here was trained to do phage therapy. There wasn’t an established protocol or even a rough draft—yet. But Chip was on it, brainstorming for hours on the phone and by email with Carl Merril in Bethesda and Maia Merabishvili in Brussels, who, in turn, consulted others on details from their varied experiences involving dosages, frequency, and other tips on how best to administer the phages. But as Jason, at the CPT, later put it, the specs were “all over the place.”
While the SDSU and Navy labs worked to purify their phage cocktails to the FDA’s specifications, Chip carefully considered all the data, weighing the evidence and the options against the risks and possible outcomes. “Fully colonized,” Tom’s infection had spread throughout his body, but there was no way to tell precisely every place it festered inside him. Should the phages be injected into the catheters in his abdomen, which would be closest to the source of the infection? Or should they be administered intravenously? How should the pharmacy prepare the phages? What concentration should be used, and how much and how often should a dose be given?
Flooding Tom’s s
ystem with the phages intravenously meant that, hopefully, the phages could be carried throughout to reach any hidden bacterial reservoirs. Phages are inert, so there’s no great mobilization that they initiate as they come aboard. But their infinitesimal size allows them to diffuse easily through the human body. However, an IV infusion was also the riskiest move in terms of endotoxin exposure as the phages burst through the bacteria and left the debris free-floating throughout his system, which could drive Tom’s immune system into yet another episode of septic shock.
Getting the dose right is critical to minimize risk to the patient while still maximizing the element of surprise for the bacteria. Shock and awe. Then repeat. But how do you know the dose to administer when the drug is alive? Phages aren’t drugs; they’re viruses, organisms on a seek-and-destroy mission of their own, and they—like their prey—respond in real time to modify their equipment for attacking their preferred host bacteria.
“Phages are the only medicine that multiply, the only medicine that mutates as it works,” Ry said in a light moment, with a touch of reverence. I thought of all the years that scientists like me had spent in pitched battle with deadly viruses precisely because they’re so good at being such killer adversaries. Now I could only pray that these phages could use those skills to outwit A. baumannii.
“The experience with human phage therapy in the US is a mixed bag,” Chip explained at rounds that weekend in the tone he saved for serious understatement. Animal experiments were one thing. And different kinds of phage applications involving patients—topical treatments, for instance—were another.
If he survived the initial treatment, what next? Which phages would be needed for continued treatment, in what quantity, and for how long? How should the cocktails be modified to match the inevitable resistance that A. baumannii would develop, when there was no way to predict the bacteria’s next move? The concentration, volume, and frequency of the doses would affect how long the initial supply would last. The unknowns clearly outnumbered the knowns. And yet, Chip plugged away at the puzzle with his characteristic capacity for complexity and calculated risk. He’d earned his reputation as a maverick to be trusted, a brilliant mind with a strong moral compass. He was willing to take risks that others might not, but always with a patient’s best outcome as the end that justified the means.
The Perfect Predator Page 20
