1The Surge of the Superbugs
It may have been the slightly dirty glass you drank from at the picnic. Or it may have been the water you accidentally gulped down while swimming in the lake. Or maybe you just didn’t wash your hands enough after using the public bathroom. But somehow, somewhere, you managed to swallow about a dozen hairy, rodlike germs named shigella. They slipped down your esophagus and snuggled next to your intestinal wall. Each then drew out a tiny pincer, punctured your cells, and injected them with a chemical cocktail designed to disrupt the protective outer membrane that normally keeps dangerous invaders out. Confused by the chemicals, your cells opened up and let shigella in, where it quickly set to work, chewing up your insides.
Unlike many other bacteria, shigella can’t move or swim on its own, because it lacks propelling filaments. So it overtakes a cell’s transporting equipment normally used to shuttle around nutrients. It hijacks the proteins floating within the cell and assembles them into so-called comet tails, which act like mini-rockets propelling shigella around—and into other cells. After shigella grows and multiplies inside the cells it invades, it kills them, moving onto its next victims. Along the way, shigella spits out a toxin that damages blood vessels, making you bleed inside. You may not feel your cells bleeding and dying during those early moments of shigella-induced dysentery, but your stomach already begins to churn.1
When your next bout of diarrhea turns bloody, you rush to the doctor’s office. The doctor starts you on azithromycin, an antibiotic commonly prescribed for intestinal infections like the garden-variety stomach bug.2 The problem is that the particular shigella you picked up isn’t a garden variety. This shigella is tough. Its ancestors have stood up to a slew of different antibiotics, and while they saw scores of their relatives die, they were the ones that lived. They are very well equipped to combat your antibiotic weaponry.
You take your first dose and the second one, hoping for quick relief. But that’s not what happens. Shigella has already detected the antibiotic molecules, so its genetic defenses are feverishly chugging out a special enzyme that slices azithromycin like a pair of scissors. Three days later, exhausted and worried, you’re back to the doctor. You leave with a prescription for ciprofloxacin or Cipro, a stronger, broad-range antibiotic that should kill everything in its path, including your own, beneficial intestinal microorganisms. It may damage your microbiome, but you have no choice. You leave relieved, sure that the end is in sight.
Two days later, dehydrated, with your fever spiking, your heart racing, and your blood pressure plummeting, you wind up in a hospital, hooked up to an IV. The toxin that damaged your gut blood vessels snuck into your bloodstream, sending you into kidney failure.3 As doctors urgently run tests, they finally discover that the vicious bacterial infection that is poisoning your insides is the broadly drug-resistant XDR shigella.4 Because this bacteria is so new, the Centers for Disease Control and Prevention (CDC) doesn’t yet offer guidelines on how to treat it, but the risk is well known; in February 2023, the CDC hosted a webinar5 to alert doctors of its dangers. The hospital’s infectious disease specialist starts you on colistin, the antibiotic of last resort, which doctors use only when all else fails because of its long list of side effects, from chest pains to numbness. But you’re heading into kidney failure, so it’s a question of life and death. Either you or the bug has to go.
Unfortunately, this shigella has more genetic tricks up its hairy sleeve, or rather inside its DNA. It finds a way to dodge colistin too. As it multiplies inside you, it shifts the structure of its outer cell membrane ever so slightly—just enough to make it impervious to colistin, because the medicine can no longer cling to the germ and destroy it. It’s as if the bug wraps itself into an invisibility cloak. You may feel better while colistin initially kills all the vulnerable shigella, but they’re soon replaced by a population the antibiotic can’t destroy. Your fever spikes again, your kidneys shut down, and your heart follows, sending you into multi-organ failure.
Sadly, you’re far from being an exception. Four people die every hour from an antibiotic-resistant bacterial infection in the United States.6 That’s why some scientists say that we’ve entered the post-antibiotic era.
It didn’t have to be that way. Instead of prescribing an antibiotic, your doctors could have given you a vial of bacteriophage, a special type of virus that preys on bacteria only. With oblong bodies, spidery legs, and sharp, scorpion-like tails, bacteriophages look like miniature rocket ships from outer space. A thousand times smaller than their prey, they pierce bacteria with their tails, sneak in like Trojan horses, and burst the germs open. Bacteriophages, or phages for short, don’t injure any other cells or tissues in our bodies. Instead, these viruses can destroy the harmful bacteria and leave intact the beneficial ones that help us digest food or protect us from infections. They are the healing viruses, unlike Covid or Ebola or countless others that cause deadly diseases. Had you taken the shigella bacteriophage, you likely would have recovered within a few days.
Unfortunately, you can’t yet buy a bottle of bacteriophage in your local pharmacy—not over the counter or by prescription. They are not available as medications yet, at all. But in the era of skyrocketing antibiotic resistance, these phages might be our best weapons against the next bacterial pandemics.
“Phages can be powerful allies in our rapidly escalating superbug fight,” says Alexander “Sandro” Sulakvelidze, a microbiologist and founder of Intralytix, a biotechnology company that makes shigella-killing phages for a newly launched clinical trial. “Phages have been preying on bacteria for millions of years before humans came along. They are very good at it.”7 They are also constantly evolving, just like bacteria themselves. That’s why it’s much harder for bacteria to develop resistance to a phage than to an antibiotic. The bacteria will mutate to evade a phage, but the phages will quickly catch up and evolve to attack the bugs more effectively. Recent one-off experimental phage treatments for antibiotic-resistant infections proved to be near-miraculous cures, sometimes bringing patients back from the brink of death.
Humans desperately need these alternatives. The deaths from antibiotic-resistant infections are climbing dramatically. First commercially produced in the 1940s, antibiotics were called wonder drugs for their ability to cure almost anything. Early on, penicillin, amoxicillin, and their tougher cousin methicillin snuffed out most bacterial infections. Yet the germs soon evolved to dodge our magic bullets. Humans responded by designing stronger and more expensive armor—ciprofloxacin, gentamicin, vancomycin—but then the bugs bolstered their defenses too. A common Staphylococcus aureus, or staph, that once succumbed to wonder drugs can now shrug them off. Today, this stubborn staph strain has its own name: methicillin-resistant Staphylococcus aureus, or MRSA. This dreaded superbug now lurks in hospitals, sickening nearly 120,000 Americans per year and killing about 20,000.8 It currently responds to vancomycin but might learn to repel it. A vancomycin-resistant enterococcus, or VRE, kills about 1 in 10 people it infects.9 Certain strains of Clostridioides difficile sicken almost 224,000 Americans each year, and also dodge vancomycin, killing at least 12,800.10 A study published in The Lancet attributed 1.27 million deaths to antimicrobial resistance in 2019 alone.11
Covid made things worse. It wiped out years of progress in our antibacterial war, says CDC’s 2022 special report COVID-19: U.S. Impact on Antimicrobial Resistance. The coronavirus weakened patients’ immune systems so that they could no longer fight off even garden-variety germs. Doctors had no choice but to prescribe more and more antibiotics. The increased antibiotic use led to a 15 percent spike in various resistant infections in 2020 alone. MRSA and VRE cases grew by 13 and 14 percent, respectively. Two other scourges, Pseudomonas aeruginosa and Enterobacterales, found in hospitals and often resistant to multiple antibiotics, spiked over 30 percent.
The CDC’s report warns that antimicrobial resistance is already a leading cause of death globally,12 but the future looks even grimmer. If we don’t find better alternatives to our quickly diminishing antibiotic arsenal by 2050, the deadly toll of bacterial disease can reach ten million annually,13 according to the United Nations estimate. That far surpasses the number of lives Covid claimed. In addition to new diseases, we might see the return of older plagues once thought vanquished. Covid, for example, has nothing on the truly scary microbial monsters like Yersinia pestis, the bubonic plague that depopulated Europe in the Middle Ages. Its respiratory airborne version, called the pneumonic plague, kills most people who catch it. “Pneumonic plague is rare because humans don’t commonly interact with rodents that carry it, but we know that hot spots exist, both in Asia and in the Unites States,” Sandro explains. “And just like Covid, it takes a few days to make you sick, so you can travel and spread it far and wide.14 An outbreak of Y. pestis will be far more deadly than Covid. And if it develops antibiotic resistance, we’ll be in dire shape.”
The growing antibiotic resistance troubled scientists even during the pandemic. With his utmost attention on the coronavirus, Anthony Fauci, then the director of the National Institute of Allergy and Infectious Diseases (NIAID), still found time to speak about this existential threat. “In recent decades, multidrug-resistant bacteria, particularly those that cause potentially deadly diseases like tuberculosis, have become a serious and growing global public health concern,” Fauci said. Bacteriophages are viable alternatives, and Fauci emphasized that research is “needed to determine if phage therapy might be used in combination with antibiotics—or replace them altogether—in treating evolving antibiotic-resistant bacterial diseases.”15
That’s exactly what Intralytix is doing. The first American biotech company to get an NIAID grant to test phage medicines in humans, Intralytix is now running three clinical trials. The first, launched with the Mount Sinai Hospital before the pandemic and delayed because of it, is using phages against a specific strain of Escherichia coli (E. coli) implicated in Crohn’s disease, a chronic intestinal inflammation with no cure. If phages are effective in wiping out that pathogenic E. coli strain that fuels Crohn’s, they will prove their worth as agents that can fine-tune our microbiome, offering new ways to treat chronic digestive problems. The shigella trial, backed by a $7 million grant from the National Institutes of Health (NIH), just started recruiting patients at the University of Maryland School of Medicine. The third trial, recently approved by the Food and Drug Administration (FDA), will pit phages against VRE, the very superbug that surged during Covid.
It may sound bizarre that viruses can heal, cure, and protect against disease, but phages play a vital role in the human virome—a viral counterpart of our microbiome, which safeguards us from pathogens we encounter constantly. “Phages naturally live in and on us—in our nose, throat, skin, and gut, protecting us from harmful bacteria,” Sandro says. That’s why phages are sometimes called living medicines, even though scientists are still debating whether viruses are too primitive to be considered alive.
As living medicines, however, phages are very different from antibiotics.
Antibiotics are fixed, static molecules that poison bacteria. Typically, they work by breaking bacterial cells or halting their replication. The cells wither or rupture, spilling out their microbial guts and dying. But we have used antibiotics too often. Doctors overprescribe them to patients, dishing them out when they aren’t necessary. We overuse them in agriculture, indiscriminately feeding them to livestock. We over-add them to cleaning products to eliminate germs from our homes. To survive, the bugs mutated their genes and learned to produce their own molecules that destroy our antibiotic ones. Some germs produce enzymes that act like molecular scissors, shredding antibiotic molecules before they have a chance to act. Other germs surround themselves in protective cloaks or eject antibiotics from their cells before they take effect. That’s the unfortunate side effect of evolution. We bred our superbugs ourselves.
We used to think that we could outpace bacterial evolution with our pharmaceutical prowess, but they mutate faster than we can keep up. Pharmaceutical research can’t foretell with certainty what germs will learn or how they will change when faced with a threat, so it’s impossible to stay a step ahead of them. “You can’t outrun Mother Nature,” Sandro tells me.
Phages operate very differently. They do the guesswork for us.
Unlike the static molecules of antibiotics, phages are biological entities that fend for themselves—attacking, multiplying, and mutating like all other creatures on earth. Phages have been feeding on bacteria for eons, so they are better equipped than our pharmaceutical industry to keep up with bacterial evolution. Scientists don’t have to invent a new phage if it loses grip on its prey. They just need to slosh phages and bacteria together in a test tube, let them fight each other, and harvest the winners.
Phages have other advantages too. They are highly specialized in their microbial diet. A particular phage will only kill the specific bacteria it feeds on, leaving others intact. Phages that kill shigella or salmonella will not harm acidophilus or firmicutes—our native gut bacteria, which we need for digestion and nutrient absorption. That’s a big win over antibiotics that carpet-bomb our intestinal tract, wreaking havoc on our microbiome. Unlike taking antibiotics, drinking phages would destroy only the pathogenic bugs while leaving the good ones intact.
Finding phages is also significantly easier than making antibiotics. Phages are abundant in water, soil, and especially in sewage. “They are the most plentiful biological entities in any habitat, but sewage is particularly good for phage-hunting because it’s teeming with various bacteria that becomes phage food,” Sandro says.16 To date, Intralytix has harvested hundreds of species of phages, most of which were fished out from sewage plants with the goal of eventually turning them into medicinal agents. Sandro’s team still makes such phage-hunting trips, because not every phage will devour every bug. Intralytix specializes in identifying the right phages for the right bacteria.
In my quest to learn more about the phage therapy revival, I visited Intralytix several times over the last few years. First conceived in 1998, when Sandro was growing Yersinia cultures at the University of Maryland’s infectious diseases lab as a postdoc who had recently arrived from the crumbling Soviet Union, his company now occupies its own building, surrounded by Maryland woods, and uses high-tech equipment to find the right phages. “Given the near-infinite number of combinations one needs to test, it’s not a task a human can muster in a reasonable amount of time. It would take months, if not years. So we don’t use humans anymore,” Sandro says as we walk into his lab. “We use robots. Let me introduce you to Neptune.”
A biotech robot the size of a living room with a price tag of $2 million, Neptune stages microbial warfare between bacteria and phages inside ninety-six-well plates. Humans set the stage: pipette in the raw sewage; load up the target bacteria; and supply some bouillon to feed the bacteria so they can grow and multiply, becoming phage food. When loaded, Neptune whirs to life, lining up seven ninety-six-well battlefields, in which it doles out precise amounts of bouillon, bugs, and phages with its automated seven-pipette arm. Finally, it whisks the plates into an incubator attached to its back, where phages will mount their attack—but not before Neptune runs the initial health check on the troops to note their starting numbers.
“It has a way of reading how many bacterial cells are floating in the solution right now,” Sandro explains to me as I watch Neptune’s manipulations, mesmerized by its precision and perfection. “It will do these reads every half hour to see whether bacteria are proliferating or decreasing. At first, their population will grow, but then it should drop. That’s how we know we’ve got good phages.”
To isolate phages against specific germs, for instance, to identify the most potent shigella destroyers, Neptune will preload the plates with shigella’s favorite meal—a soup of glucose, amino acids, and iron, which it finds inside our gut. Then Neptune drops the same amount of shigella in every well before adding different shigella phages, or different combinations of them, into the wells. This reveals which phage will extinguish the shigella most efficiently. With that information loaded into Intralytix’s Information Management System, its PhageSelector arm can whip up a remedy recipe for any number of bacterial strains it knows, and its PhagePredictor, an artificial intelligence network, can extrapolate that information for novel strains and phages to attack them.
Even a few years ago, lab technicians would pipette everything by hand, toiling for days. Today, the robot does the same job a thousand times faster—and without making a single mistake. “Imagine testing one hundred different phages on one hundred different shigella strains, and in different concentrations. It would take a person several months to try all these combinations,” Sandro says. And then he adds affectionately, like a proud father of a prodigy kid, “But Neptune does it in twenty-four to seventy-two hours! We spent a year custom-designing it, so it’s one of a kind.”
While plates incubate, Sandro shows me his phage factory and warehouse. In addition to doing clinical trials, Intralytix manufactures and sells five FDA-approved phage preparations for the food industry. The CDC estimates that every year, one in seven Americans falls ill from foodborne bugs—salmonella, listeria, shigella, E. coli, or campylobacter. That tallies up to 48 million cases, with 120,000 hospitalizations and 3,000 deaths.17 The germs slip in via contaminated lettuce, hitchhike on sausages, and sneak into burgers. To decontaminate our food supply, companies use harsh sterilizing chemicals, such as chlorine or peracetic acid. Intralytix offers a more holistic and natural method: phage sprays, which combat some of the most common bacteria—SalmoFresh, ListShield, ShigaShield, EcoShield, and CampyShield. The sprays kill more efficiently and selectively than chemicals. Because phages continue to multiply for as long as there are bacteria to chew on, they only stop when no germs are left—and they only wipe out the pathogenic ones, leaving beneficial microorganisms intact.
To make sprays, Intralytix grows phages inside enormous fermenters—one-thousand-liter or about 264-gallon shiny stainless steel towers installed in a room adjacent to the lab. Inside, phages feed on their favorite bacterial fodder until their numbers grow large enough to harvest, purify, and pour into bottles. They can also be dried and shipped in powder form to be added to water later.
The plates are still incubating, so we head over to Sandro’s office to play with the PhageSelector, which formulates custom-remedy recipes based on years of data collection that preceded Neptune’s arrival. The login screen flashes a green letter I—Intralytix—that looks like a chess figurine and greets me with a spread of pathogenic names, from common listerias to rare acinetobacters. We select bacteria to target—for example, all 1,234 strains of salmonella gathered in Intralytix’s database, many of which may randomly lurk in a chicken factory. The electronic brain immediately spits out a recipe: this nine-phage brew will kill 100 percent of the bacteria. Next, we ask what it would take to extinguish particular shigella strains that, for example, originated from Chile. Turns out we’d need only two phages.
PhageSelector works the same way for medicinal use. “That’s how we designed our EcoActive cocktail for Crohn’s patients in the Mount Sinai study,” Sandro reveals, clicking through the screens. Intralytix collected the specific strains of invasive E. coli found in the patients’ guts. Sandro would feed the strains’ info into the system and have the recipe seconds later. The Intralytix team would mix the phages and ship them off to Mount Sinai.
“As soon as Neptune enters a new phage into our system, I can formulate a cocktail against that bacterial strain, whether from my office, home, or any part of the planet,” he says. “And we have a few hundred well-characterized phages in our freezers. We even have phages for Y. pestis, which we tested in rats—and they worked great. If a request comes for particular bacterial strains, I can design that cocktail on the spot.”18 Meanwhile, PhageSelector’s sister system PhagePredictor can extrapolate information from the already existing knowledge, foreseeing cocktails’ efficacies for cases Neptune hasn’t tried yet.
This next-generation AI method might as well be humankind’s magic armor against bacterial infectious disease of the twenty-first century. It took Sandro twenty-five years to assemble and nearly as long to convince the FDA that phages were medicinally safe. Even though phages have been widely used for decades in Sandro’s homeland, to the American medical establishment, they were as foreign as space aliens. He worked long and hard to change this view. When the FDA finally green-lighted the Intralytix Crohn’s trial in 2018—the first such trial in the agency’s history—it marked a massive mindset shift.
“Was it worth a quarter-century-long effort?” I ask.
Sandro chuckles. “Had I known how hard it would be when I first started, I might not have pursued it,” he quips, assembling the next brew on his screen, this time for vaginal infections. Once grown, this cocktail will be shipped to his collaborators in Georgia for another clinical trial starting in a few weeks. “But I was so shocked that in America people died from infections we treated in Tbilisi with medicines I grew up drinking, that I just couldn’t let go. As a scientist, I had no choice but to keep pushing.”
LIFE WORKS IN MYSTERIOUS WAYS
Raised in Tbilisi, an ancient city dating back to the fifth century, Sandro grew up in an apartment on the same floor as his three cousins, where the kids constantly ran back and forth across the hall, leaving the doors wide open. From that six-story apartment building, Sandro walked to school, ran to meet his mother coming home from work, and rode his bike down to the neighborhood’s Vake Park, buzzing underneath the crown of grapevines that formed a canopy over the road. In the distance stood the snow-peaked Caucasus Mountains.19
Sandro’s childhood shattered at age twelve, when his mother fell ill. Though she complained of sore spots around her spine, she didn’t think much of it. When she finally went to the doctor, it was too late. The tumor had spread to her bones, spine, and tissues. That night, the family gathered and called Sandro to tell him the bad news. He knew the moment he walked into the room, because he turned bright red before anyone spoke. He took it like an adult, fought back tears, and didn’t cry.20 When his mother died, Sandro’s aunt stepped in to take care of him.21
Sandro grew up accustomed to phage medicines. In Tbilisi, they were sold in little vials at every pharmacy, next to aspirin. People drank phage remedies for stomach bugs. They gargled with them to cure sore throats. Made at Tbilisi’s Institute of Bacteriophage, Microbiology, and Virology, an organization so well hidden behind the Iron Curtain that barely anyone in the West had heard of it, the remedies were part of the everyday first aid tool kit. People kept them in medicine cabinets. They packed some when they went on vacation. Founded by a luminary yet tragic early Soviet-era scientist, Giorgi Eliava, and eventually named after him, the institute sat on the banks of the Mtkvari River, from where many of the phages were sourced. The research team cultivated the phages to make medicines against the most notorious scourges—shigella, cholera, staph. They loaded phages into bottles and ampoules and shipped them to pharmacies in Georgia and other parts of the Soviet Union.
Patients battling stubborn skin, throat, ear, and gut infections flocked to the institute from across the country. The Eliava doctors took their swabs and stool samples, identified bacterial culprits, and matched them with phages that preyed on those specific strains. It was personalized medicine at its finest—decades before the term was even coined. Sometimes phages worked fast enough that patients could go home after a few days. Stubborn infections took several weeks or even months. Sometimes patients went home with a supply of ampoules. The most obstinate cases sometimes required extra research and trial and error in assembling a personalized phage mix—formulated specifically to match the bacterial strains the person carried.
Eliava researchers constantly looked for new phages, mixed different phages together, and tried these cocktails on various bacterial strains. Long before Neptune-like robots existed, they did it all by hand, painstakingly pipetting bacteria, its food, and its predators together. They recorded their results in cursive, in big books of lined paper, painstakingly filling out numbers, ratios, sizes, and dates. When they zeroed in on a cocktail that worked well against a particular malady, they added it to their arsenal of living medicines, filing it away in those cursive-filled books.
In the West, antibiotics reigned supreme ever since they were mass-produced after World War II. But the Soviet Union never quite mastered the feat due to the peculiar quirks of the country’s economy and medical system. The Soviets struggled with mass production of antibiotics because that required factories, specialized equipment, and a steady supply of chemical reagents. In the USSR, known for shortages of almost everything, a factory could run out of reagents and sit idle for a month. Phages, on the contrary, were always available—and if not, could be grown.
When Sandro announced that he was going to study biology at Tbilisi State University, his father, Levan, an engineer, was not amused. Georgia’s traditional gender stereotypes deemed biology a woman’s profession. Men were expected to be out in the world braving nature, weathering storms, and defeating the elements. They were supposed to build bridges, erect buildings, and lay train tracks through the frozen Siberian woods. The women, as more delicate and finer creatures, were supposed to pursue gentler disciplines that kept them out of harm’s way. Biology, the majority of which took place inside comfortable lab conditions, was viewed as women’s work—but Sandro was not easily dissuaded.
“I was really interested in microbes and genetics, so I went against my family to pursue it,” he says. “Eventually, my dad accepted the fact that I will be ‘chasing butterflies’ for a living and let me be.” Sandro earned his PhD in microbiology and epidemiology, with a focus on molecular biology—a new discipline at the time. His dissertation advisor was the Eliava Institute’s director, Teimuraz Chanishvili, and his thesis focused on identifying Yersinia enterocolitica by cutting the bug’s DNA into the so-called bacterial fingerprints. A distant cousin of the plague-causing Y. pestis, Y. enterocolitica was far less dangerous, but still caused stomach problems, making it a worthy research subject.22
Sandro’s cutting-edge research career moved fast. In 1990, at age twenty-seven, he was appointed a director of the molecular biology program at the Georgian Anti-plague Center, now called the National Center for Disease Control (NCDC)—the region’s equivalent of the CDC—and tasked with keeping all infectious disease outbreaks under control. “Molecular biology was in its infancy in Georgia, and my job was to establish it as a discipline,” he recalls. “I was the head of the lab, and I had the entire floor in NCDC with several people working for me.” He was eager to pursue every opportunity in Georgia.
During the Soviet era, the Eliava Institute, back then called the Institute of Vaccines and Serums, and the newly established NCDC were prestigious and innovative. There was money for research. Scientists were well paid. Sandro’s personal life was equally exciting. With a mop of curly black hair and disarming smile, he enjoyed a varied life. He became engaged to a young journalist, Nino Kasvadze, had a circle of close friends, and explored daring hobbies. He was a contestant on the Russian version of Jeopardy! and once almost won a car. He learned karate, a banned sport under the Soviet regime, which only made it more enticing. He went scuba diving with his friends from the military. Despite his ambitions, he never planned to leave Tbilisi. “Back then, you were born in the same city, went to school in the same city, got your degree in the same city, worked, got married, and raised a family—all in the same place,” he recalls. “I never expected to do anything else—and why would I? I had a great Soviet career.”23
And then, the Soviet Union fell apart.
After the USSR dissolved in 1991, Georgia declared its independence—and plunged into chaos. Elected in May of 1991, President Zviad Gamsakhurdia was ousted in a military coup the following year and fled the country, while attempting to govern from exile. The fallout wreaked havoc in science.
“You couldn’t get chemicals to do experiments,” Sandro recalls. “You’d spend hours on the phone with Moscow and get nowhere. You’d go to Moscow and beg for the reagents you needed and you still couldn’t get any.” Things grew worse when Tbilisi started having power outages—now scientists couldn’t stage their reactions even if they had the chemicals. There were days with no electricity, weeks with no gas, and months with no hot water. When buildings lost heat in winter, people started chopping up wood, building fires in their apartments to keep warm. Morose and forlorn, scientists came to work to play chess and dominoes, or simply stare out the windows of their vacant laboratories. Sandro felt his best years were being squandered.24 One of his colleagues, Nina Chanishvili—then a phage researcher at the Eliava Institute—landed a yearlong fellowship in Geneva.25 Sandro decided to look abroad too. “I felt that I was wasting my life away,” he says. “I started looking elsewhere.”
He applied for several postdoctoral positions in America, Europe, and Australia. Mailing the envelopes from Tbilisi’s post office felt like sending them into a black hole. In 1993, mail took up to sixty days to cross the ocean, so by the time the envelope landed on someone’s desk, the deadline could have passed. Yet to Sandro’s delight, the American Association for the Advancement of Science granted him funding for a fellowship position. Now he had to find a research institution to take him in. He wrote to three different places and waited.26
The most interesting offer came from well-known infectious disease expert Glenn Morris at the University of Maryland. Morris studied Yersinia and wanted to compare the disease-causing mechanisms of different strains. “I had never worked with anyone from Georgia, so I thought it was worth a try,” Morris says. He wrote Sandro an offer for a nine-month postdoctoral fellowship.
Replying to Morris was an endeavor. Time was tight, so Sandro couldn’t answer by mail. “I had to find a fax machine because my institute didn’t have one,” he remembers. “Good luck finding one in Tbilisi when electricity cuts out.” But the fax was sent, and Morris helped too. He fixed some mistakes on Sandro’s application, filled out some boxes he missed, and pushed the papers through. Sandro’s NCDC director promised to keep his position open until he came back home next year, with more knowledge and expertise. Sandro wanted to bring his fiancée along, but the meager fellowship of $12,000 wouldn’t cover living expenses and airplane tickets for two. The couple decided Sandro would go alone. Nine months would pass quickly—he’d be back home by spring. By then, the political situation would improve, electricity would return, and doing research would be possible again. Or so they hoped.27
In early fall, Sandro packed a suitcase, hugged his dad, aunts, uncles, and cousins, kissed his fiancée, Nino, and his beloved collie, Archibald—and flew to Moscow. “I never thought I would stay in America,” he says. “I grew up in Georgia. My home was there. My father was there. My fiancée was there. My family and friends were there. Immigrating to another country? Leaving all of this behind? No, it just wasn’t possible.”28
On October 2, 1993, Sandro boarded a plane from Moscow’s Sheremetyevo International Airport to New York. In his luggage, he carried enough clothes to get through the northeastern winter and $500 in cash, all his possessions at that time. A bunch of local yersinia samples for his research were already en route to Baltimore, painstakingly sealed, wrapped, and packaged inside metal containers. He lay back in his seat watching the familiar landscape fly by the window as the plane picked up speed and took off. Little did he know that he was leaving Moscow on the day of a massive constitutional crisis that was already unfurling as he became airborne.
Beginning the month before as a political standoff between the Russian Parliament and President Boris Yeltsin, the dispute escalated, with protestors storming government buildings and the military stepping in. The wheels of Sandro’s plane left the tarmac just as Russian tanks rolled onto the Moscow streets. The armed conflict lasted ten days, bringing Russia to the brink of a civil war. While it eventually resolved, the former Soviet empire continued to decline. Sandro had left for good. He just didn’t know it yet.
THE PHAGE PHENOMENON
When Sandro climbed out of the puddle jumper that carried him from New York to Baltimore, the entire Morris family, including three young kids, picked him up, treated him to dinner at Baltimore’s Inner Harbor, and took him to their house. As they conversed, Morris was impressed by his postdoc’s English. “You must’ve taken a lot of classes with good teachers because you speak really well,” he complimented his new fellow.
Sandro shook his head. “I learned English by watching movies,” he said.
The next day, Morris’s wife, Deborah, helped Sandro settle. With no credit card, no bank account, and no financial history, he couldn’t rent an apartment by himself. He couldn’t afford one either—the fellowship paid too little. But he earned enough to rent a room in the house of an elderly woman the Morrises knew, which became Sandro’s first American home.
Over the next few months, Morris taught Sandro the American ways of life. How to get a driver’s license. How to open a bank account. How to write a check. “I didn’t know how to take money out of the ATM,” Sandro recalls. “Punching the keys on the ATM machine and seeing the green bills slide out was science to me—or more like a miracle, really. I didn’t even know how to put gas in the car—not that I had a car when I first got here, but the point is I really couldn’t navigate my American life without Glenn.”29
With bare necessities taken care of, Sandro threw himself into research. Now he had plenty of everything, from equipment to reagents. He worked obsessively, as if trying to compensate for months of forced idleness in his home country. Sandro’s Yersinia bercovieri species were brewing in the petri dishes of the University of Maryland Infectious Diseases Lab. The bugs were healthy, but the mice infected with them were not. In fact, they got very sick, very fast. Some were already dead, their bellies swollen like birthday balloons. This development was surprising and concerning. Y. bercovieri was a close relative to Y. enterocolitica, a mild pathogen that causes intestinal distress, but certainly not death. What made Y. bercovieri so vicious? Sandro and Morris hypothesized it harbored a novel toxin that its cousin lacked.30 That meant that Y. bercovieri was to be taken much more seriously by the medical community than its less toxic brethren. Sandro and Morris began writing a paper about this phenomenon.
Sandro’s discoveries about the peculiar differences between various yersinias’ modus operandi were so intriguing that Morris was able to extend his fellowship for a few extra months. When the next term ran out, he did it again. And again. “He was producing some very interesting results,” Morris recalls. “So we wanted to continue.”31
As a microbiologist, Sandro spent most of his time in the lab. Morris, on the contrary, was a physician who tended to patients at the University of Maryland Medical Center. One of the leading infectious disease experts there, he often treated the desperately ill—those who took immunosuppressants after an organ transplant or received chemotherapy that weakened their immune systems, letting infections take hold. Antibiotics were Morris’s go-to drugs, but they were starting to fail more and more often. The infections that once were cleared with common medications wouldn’t respond even to the more potent ones.
One of Morris’s patients, a young man treated for cancer, had been battling an enterococcus infection. An intestinal bacterium that can live peacefully in the human gut, enterococcus has an uncanny ability to cause infections in immune-compromised patients. In hospital settings, it can become resistant to antibiotics, including vancomycin—the drug used to treat it when all else fails. In the mid-1990s, Morris had seen several VRE cases. The young cancer patient was one of them. Despite everything Morris tried, he couldn’t save the man.
That afternoon, when Morris dropped into the lab to check in with his research crew, he didn’t look like himself. A soft-spoken, kindhearted, confident, and positive person, he was a shadow of his usual self. He seemed strangely aloof. His mind was elsewhere. Sandro asked him what was wrong.
“We lost a patient to VRE,” Morris told him with a heavy heart. “After rounds of chemotherapy that wiped out his cancer, he just couldn’t fight off enterococcus from his own gut.” Like any physician who lost a patient he hoped he could save, Morris felt helpless and useless. “I don’t know how to handle these cases,” Morris lamented to Sandro. “They don’t respond to antibiotics.”32
Without thinking, Sandro asked a question. “Did a bacteriophage fail too?”
Morris blinked and gave him a blank look. “What bacteriophage?” he asked, dumbfounded. “What are you talking about?”
The other people in the room looked equally perplexed.
It was Sandro’s turn to feel perplexed. Clearly, his colleagues would have known about the viral cures for bacterial infections. If his former coworkers still concocted phage cocktails in the war-ravaged, poverty-stricken Tbilisi, successfully treating infections when antibiotics weren’t available, the American doctors would have certainly excelled at that.
“I mean, if you can’t treat something with antibiotics because of the resistance, you can try a phage, because they kill bacteria with a different mechanism,” he went on to elaborate. But Morris was still looking at him with the same what-are-you-talking-about stare. He had no clue what his Georgian fellow meant. “I’d never heard about phage therapy until that conversation,” Morris recalls. He had never treated anyone with a phage, nor had any other American doctor he knew.
Sandro was shocked. “It was one of those moments you never forget,” he says. “It left a deep impression on me. Somebody just died in the most developed country in the world, after a most sophisticated medical procedure, only because his infection couldn’t be treated? Somebody who is a father, a husband, a friend, just died from an infection that could be cured in a developing country like Georgia. It just didn’t make sense.”
But to American physicians of the early 1990s, the concept of using viruses as medicinal agents didn’t make sense. American physicians didn’t think of phages as their allies in antibacterial warfare. Morris had known about bacteriophages in nature, but not about their use as living medicines. “How do you know about this?” he asked Sandro.
“The Eliava Institute in Tbilisi has been using phage therapy for decades,” Sandro replied. “But the very first time phages were used as medicine was in 1917, in France.”
It was Morris’s turn to be surprised. He had never heard any of this before.
Sandro realized he had a really big gap to fill, a historical void of about seventy years that spanned from Tbilisi to Paris to Moscow, across the entire Soviet Union, and now all the way to Maryland. “It’s a long and complicated story,” he said. “But I can tell you everything I know.”
THE LIVING MEDICINE. Copyright © 2024 by Lina Zeldovich.
