Illustration by Brian Rea
Illustration by Brian Rea

Once a year, when Slava Epstein was growing up in Moscow, his mother took him to the Exhibition of the Achievements of the National Economy, a showcase for the wonders of Soviet life. The expo featured many things—from industrial harvesters to Uzbek wine—but Epstein, who began going in the nineteen-sixties, when he was eight or nine, was interested primarily in one: the Cosmos Pavilion, a building the size of a hangar, with a ceiling shaped like a giant inverted parabola. Space fever was running high in the city. Since 1961, when Yuri Gagarin orbited the globe, unmanned vessels had been launched toward Mars and Venus. Beside the expo’s entrance, the towering Monument to the Conquerors of Space depicted a probe swooping up to the heavens.

The Pavilion displayed futuristic technology—Vostok rockets and Soyuz orbiters—but Epstein was less interested in the glories of advanced thruster design than in the glories of space. He wanted to devote himself to astronomy. When a textbook that he found on the topic began with algebraic formulas, he prodded his older brother to explain them. During high school, he enrolled in classes in physics and math at Moscow State University. His parents disapproved of his desired career: because he is half Jewish, Epstein would face harsh Soviet quotas limiting Jews in the study of physics, a field deemed relevant to national security. He ignored his parents. But after his first lecture the professor invited him for a walk, and affirmed what they had been saying all along. “Don’t do it,” he warned. “You’ll never get in.”

Soviet Russia may have been a fatalist’s paradise, but from a young age Epstein felt that he was hardwired for optimism. He convinced himself that what is truly important in science is the ability to connect ideas, no matter the field, and so he took up biology. Rather than telescopes, he would use microscopes, which he began taking with him on trips to the White Sea, near the Arctic Circle, to study protozoa along the shore—research that could be conducted with minimal state interference. Over time, he grew interested in even smaller, more ancient forms of life: bacteria.

Studying microbes inevitably causes a reordering of one’s perceptions: for more than two billion years, they were the only life on this planet, and they remain in many ways its dominant life form. Estimates of the number of bacteria—5,000,000,000,000,000,000,000,000,000,000—are higher than for all the stars, and Epstein noticed that when he stained his microbes with fluorescent dyes and placed them under a microscope they looked just like constellations in deep space. To a remarkable extent, the microbial cosmos was less explored than the actual cosmos: precisely how the organisms evolve, replicate, fight, and communicate remains unclear. Nearly all of microbiology, Epstein eventually learned, was built on the study of a tiny fraction of microbial life, perhaps less than one per cent, because most bacteria could not be grown in a laboratory culture, the primary means of analyzing them. By the time he matured as a scientist, many researchers had given up trying to cultivate new species, writing off the majority as “dark matter”—a term used in astronomy for an inscrutable substance that may make up most of the universe but cannot be seen.

For years, the microbial dark matter weighed on Epstein: how could such a vast and primordial form of life evade basic analysis? Was it possible to design an instrument that could probe the bacterial universe, as the rockets in the Cosmos Pavilion had probed space? About fifteen years ago, he came to believe that it was more than possible—it was simple. If such a device worked, it could not only help solve a great scientific mystery but also have profound practical importance.

The near-universal presence of bacteria in nature—from the deepest layer of the Earth’s crust to the upper atmosphere—is reflected in their protean applications. They can be used to make industrial foods, to engineer perfumes, to produce fuel or to clean it up. More than half the cells in the human body are microbial, and many of them exist as biological dark matter, too; learning how they function could offer countless insights into human longevity. For decades, microbes had been a source of essential pharmaceuticals: chemotherapies, blood thinners, and drugs crucial to organ transplants. From just the one per cent of bacterial life that scientists had been able to cultivate, researchers had derived virtually every antibiotic used in modern medicine.

At the time that Epstein began to consider how to gain access to the microbial dark matter, the search for new antibiotics had more or less come to a halt, while well-known pathogens, such as staph, tuberculosis, and enterococcus, were increasingly resistant to the available drugs. A small number of researchers warned that the rise of “superbugs” posed a looming public-health crisis of unprecedented proportions—a possible return to a pre-modern medical age, when common infections were deadly and simple surgeries were often too life-threatening to consider. What would access to even one per cent more of the bacterial universe mean? Perhaps millions of lives could be saved.

Earlier this year, I travelled to Boston to visit Epstein at Northeastern University, where he is a professor. I found him outside his office, on the street, smoking. Epstein regards smoking—a near-lifelong habit—as a voluntary vice; his true addictions, he says, are travel and tango. At fifty-seven, he is trim, with a shaggy hair style that conjures both past and future: either the ragged look of a medieval peasant or an android from “Blade Runner.” He has the manner of a nineteenth-century adventurer-scientist—a generalist with a wandering intellect who can begin a conversation talking about the evolutionary oddity of sexual reproduction and end up discussing his trip to the Erta Ale lava lakes, in Ethiopia.

His office used to be a disastrous mess, he said; he had cleaned it recently, but it still housed an eclectic compendium. There was a book on Arabic grammar, a copy of “The Little Prince,” a cuneiform tablet, a boomerang, a pack of Soviet filterless papirosa cigarettes. There were large photos that he had taken and printed: crashing waves off the Scottish coast; Gaudí’s Casa Batlló, luminous and seductive at night. “He organizes his research in the most faraway lands,” a friend later told me. “I don’t know how he manages to do science with all that travel.”

In 2004, Epstein obtained a million-dollar grant from the National Science Foundation to open an observatory in Venezuela, concentrating on microbes in an ocean trench a mile undersea. He told me, “What we discovered was a new class of ciliates”—a form of protozoa. “Not a new species. Not a new genus. A new class—the first in half a century. Well, it didn’t make headlines on CNN, but in the world of protistology that is as stunning as it gets.” Still, what seemed to excite him more was an expedition he had made into the Venezuelan rain forest to live with the Yanomami, the largest isolated tribe in South America.

In Epstein’s office, we were surrounded by Yanomami artifacts, which hung on the walls alongside African spears, arrows, and satchels. He is a connoisseur of primitive technology—simple yet highly effective tools. He was wearing a bracelet made from metallic beads, which, he explained, he had got while living among the Himba people, in Namibia. “I noticed many of them wearing something made out of these beads,” he said. “I asked, Where do you get them? Oh, they say, there are people we know who make iron out of rocks. What? So I started digging, and here is what I learned: there’s a tribe—no road, no nothing, reachable by at least three days on horses. I will go one day. These guys found a way to make iron from iron ore, probably before the Europeans came.” He looked at his bracelet, given to him by a Himba elder. “This is made by the same technology that your ancestors, my ancestors, everyone’s, were once using. It was made ten years ago, or twenty years ago, but it is like a time machine.”

Microbiology is, in its way, a form of time travel—a field of study that can elucidate the earliest traces of human evolution. If you wind back the clock of life to its beginning, you arrive at a moment, roughly four billion years ago, when the planet was newly formed, and the Age of Microbes was dawning. By human standards, Earth was a forbidding place: the seawater more than a hundred degrees Fahrenheit, the atmosphere a toxic blend devoid of oxygen. Single-celled bacteria didn’t mind. They grew in massive colonies, undersea and in deep soil, breathing in lethal gases and reshaping the planet. That our atmosphere is twenty-one per cent oxygen is a bacterial artifact: the emergence, three and a half billion years ago, of cyanobacteria—a blue-green slime capable of photosynthesis—triggered the Great Oxygenation Event, creating an atmosphere resembling our own, and modulating Earth’s temperature, making it more widely habitable. The Age of Microbes has persisted to the present day without interruption. Not only do bacteria outnumber humans but they outweigh us, too, by a factor of a hundred million. Civilization is only a tweak to their landscape. “If Homo sapiens disappears, cities will be gone and fields will become rain forest again, but life as such will not change,” Epstein told me. “If microbes disappear, then everything is gone—no New York, no rain forest.”

For millennia, humans were blind to microbial life. Bacteria were discovered in the seventeenth century, but the golden age of microbiology did not begin for another two hundred years. Because bacteria are so small—some are one ten-thousandth the size of a red blood cell—they could not be studied individually, so it was necessary to cultivate lots of them. And the colonies had to be kept pure: mixed populations would inevitably generate mixed results.

The petri dish, invented in 1887, provided an elegant solution, allowing scientists to parse the complexity of nature by examining one colony at a time. But, as scientists began to domesticate microorganisms in the laboratory, they noticed that not all bacteria responded to their efforts in the same way. Some grew as easily as weeds; others were extremely stubborn. A tremendous number did not grow at all. As early as 1911, one researcher estimated, by counting bacteria on a microscope plate, that the cells that wouldn’t form colonies outnumbered those that did by a hundred and fifty to one. In an attempt to get better results, researchers revised the growth medium in which bacteria are cultivated, compiling thick recipe books. To the typical medium—a nutrient-rich gelatin called agar, derived from seaweed—they tried adding blood, chicken bouillon, urine. They added oxygen, took it away. They altered temperature. Still, the microbial weeds continued to dominate. In 1985, this baffling phenomenon was given a name, the Great Plate Count Anomaly. But, perhaps because the one per cent of the microbial world that could be cultivated was so immense, few microbiologists gave it serious thought.

Epstein did not learn about the anomaly until after he migrated to Massachusetts, in 1989, but the idea resonated immediately. In his own way, he had been living in a vast petri dish—the Soviet experiment—where he had found it impossible to thrive. As a child, he secretly listened to Voice of America at his parents’ dacha; later, in college, he grew close to dissident students, who exposed him to samizdat. Epstein imagined his future taking one of two paths: either a life of political nonconformity, in the manner of Sakharov, or exile. After graduating, he could not secure work in the academy; a professor privately explained that the K.G.B. disapproved of his social milieu. Through a friend, Epstein found a job ten time zones away, in Kamchatka, where he manned a lone microbial-research station on the Bering Sea. He hiked. He avoided bears. And, dreaming of exile, he memorized seven thousand English words from an old dictionary, with no sense of how they fit together. When the Soviet authorities permitted a wave of Jewish emigration, he and his wife, Lena Kashevsky, fled with their two children. Epstein turned over his raw data to a contact at the Dutch Embassy, who smuggled it out via diplomatic pouch.

The family landed in a walkup in Cambridge, where Epstein bartered for rent by helping to fix up the building. His wife, who had also studied biology, found a job in a Harvard laboratory. For Epstein, with his limited English, reëntering academia was impossible at first, and he half-considered becoming a contractor. While fixing driveways, he listened to NPR, the language flowing by in an undifferentiated stream. Over time, the words revealed themselves, until one day he realized that he was listening to the news.

As Epstein gained his footing, he sought out unsalaried academic postings, hoping that he could find grants to re-start his scientific work. For a time, he left his family to live in a university lab in Milwaukee. Gradually, he found his way to Northeastern, and he learned about the problem of uncultivatable bacteria. “It’s not necessarily thought of as big by many people,” he told me. “But imagine that you are taking a course in microbiology. You’re preparing yourself for the final exam, and you are using a textbook. You open it and see that ninety-nine per cent of the words are blacked out. All that you can read is a random one per cent. What are the chances you will pass? That’s where we are in microbiology, so how much bigger can it be?”

Epstein questioned the prevailing assumption that the Great Plate Count Anomaly was tied to growth media—to simply finding the right nutrients. Too often, he thought, humans assumed that microbial ecology was merely a Lilliputian version of the world that they could see. “A remarkable thing about microbes—and it is only remarkable from our anthropocentric point of view—is the coöperation among them,” he told me. “We in the macroscopic world need organic material as food, and oxygen to oxidize it, to get energy. You, a cow, a giraffe—we’re all the same. We may not be in each other’s way if one eats fish and the other grass, but little coöperation is possible, considering our metabolic needs.” Bacterial metabolism, on the other hand, is staggeringly diverse: some microbes eat ammonium, some eat hydrogen; some breathe sulfates, some breathe iron. Often, microbes are interdependent: what is waste for one is essential for another. “At some point, it becomes almost philosophical,” he said. “Perhaps the coöperation that evolved for four billion years in the microbial world has not evolved in the macroscopic world because it is younger. Maybe in two billion years we will find it to the same degree.”

Epstein had gone to Milwaukee at the invitation of a friend at the University of Wisconsin, Ken Nealson, who was researching bacteria that live symbiotically with lantern-eye fish in the Red Sea. The bacteria develop colonies in a special cavity beneath the fish’s eye, but only after generating a dense cluster of ten million cells will they glow, helping their host lure prey. Nealson was curious: were the microbes somehow taking a census of themselves? It turned out that they were, using chemical signals. When the bacteria were let loose in seawater, the census failed, and they refused to glow.

For Epstein, such research underscored that context in microbiology was everything: the lantern-eye bacteria were highly sensitive to where they were and who was with them. Clearly, more than nutrition was defining their behavior. Once you acknowledged that microbial ecology was so delicately interconnected, the assumption that one bacterium could thrive alone in a dish began to seem odd. Researchers were trying to force microbes to grow under conditions dictated by the rules of the macroscopic world, when, perhaps, the key was to submit to the small.

“My thoughts were all over the place,” Epstein told me. “But what I realized was that, while I and other people were wondering how to get access to this ‘dark matter,’ all of us were thinking in the wrong way. Here is what I mean. Suppose I take a bacterium from soil, and I put it in a petri dish, and it forms a colony. We would call it cultivation, of course. Now, suppose I take the same bacterium, but halfway to the lab I change my mind and return it to the environment. What would that bacterium do? It would form a colony. Would we call that cultivation? Well, it is, no matter how you look at it.” Even if most researchers dismissed the idea—because, unlike pure colonies in a lab, bacteria in nature become hopelessly intermingled—such a colony would still be growing. “So what is the lesson here?” Epstein said. “Oh, the lesson is really important. The problem is not cultivation. It is how to separate one growth from another growth.”

Considered in this way, the problem was far simpler. If it could be solved, then perhaps microbiologists—like anthropologists travelling to rain forests to observe isolated tribes—could study bacteria where they were already thriving. Epstein became obsessed with the idea. One day, he was relaying it to Michael Sherman, a biochemist from Russia who teaches at Boston University. Sherman said that he knew another researcher who was thinking along the same lines: a microbiologist from Moscow State who had moved to Tufts. Offering to make an introduction, he said, “You should meet.”

The two men, it turned out, had met already—in a way that could make sense only during the Cold War. The other scientist was known in Moscow as Alexei Nikolaevich Glagolev. His real name was Kim Lewis; he was born in New York in 1953.

“It started out as my itemized deductions, but it’s turned into a novel.”

Epstein had occasionally run into Lewis in the Soviet academy, but how Lewis had ended up behind the Iron Curtain was a story that he learned only later. Lewis’s parents had divorced when he was two, and his mother, in a fit of idealism, had decided to involve herself in the Communist project. She moved to Russia, and remarried in Moscow, where Lewis gained a new family, new citizenship, a new identity. “Nobody knew that I was American, apart from the K.G.B.,” he told me.

At Moscow State, Lewis studied under a professor who had carved out a small zone of academic freedom. “I was doing very well, science-wise,” Lewis said. “I had two papers in Nature.” Like any good Soviet citizen, he understood how to navigate the privations of Communism—when thieves stole the front seats of his car, he replaced them with folding chairs. But, on a deeper level, he found assimilation impossible. “One evening, I visited Kim at his apartment,” Sherman recalled. “There were several pounds of peanuts on the counter, which he was mixing with butter, in a blender, into a gooey mess. I asked, ‘What is this?’ And he said it was peanut butter. To me, it was inedible. But Kim told me that love for it comes from mother’s milk—that every American child has a peanut-butter sandwich for lunch—and he had to maintain his Americanism in this foreign land.”

In 1984, at the age of thirty-one, Lewis began trying to leave. He applied several times for an exit visa, but in each instance the Soviet Union rejected his application. Eventually, he held a press conference with four other Americans stranded in Russia, hoping that publicity would advance his cause. “I just can’t take it here any longer,” he declared. “We consider ourselves hostages, and we ask the American government not to forget its hostages in Moscow.” Lewis lost his job, as did his wife. “We became refuseniks,” he told me. “It took us three years—and, ultimately, help from President Reagan—to get out.”

When Lewis finally returned to the United States, his predicament differed from Epstein’s. He spoke English fluently, and he had already built an accomplished career. Echoing his personal experience, his research began to explore questions of adaptation—how organisms survive hostile environments. He helped discover how some bacteria used microscopic pumps to purge themselves of antibiotics, and he unravelled a paradox involving biofilms: groupings of microbes that are often deadly and impervious to medication, even though in isolation they are easily eradicated.

“I am generally attracted to old, unsolved problems,” he told me. By the time Lewis met Epstein, he was pondering the Great Plate Count Anomaly, too. “By simply counting cells—what was done a hundred years ago—one did not truly know the diversity of organisms that was missing,” he told me. But advances in DNA analysis made it possible to determine just how varied bacteria were: one microbe could be as different from another as a hippopotamus was from a daisy.

Like Epstein, Lewis believed that, if the anomaly could be reframed as a problem of bacterial isolation, then it could be circumvented. The hard part had been reformulating the question—but that was a habit that he had developed from Soviet life. “We had limited resources, and had to think long and hard about a problem,” he told me. “We couldn’t do just random descriptions of complex systems—taking them apart, putting them together again.”

Epstein, too, had grown accustomed to ingenuity born out of limitation. In Moscow, unable to find a job, he had obtained a license to sell “fine art,” and, applying a lenient definition of the term, cast zodiac pendants out of gypsum for sale at weekend markets. The pendants were crude—“nothing beautiful about them”—but they were novel, in a place that craved novelty. He corralled friends into the venture, hired police as security, and, “at the end of a day, we would go to an apartment and sort suitcases of money.”

Epstein liked to work with his hands, and he was unafraid of trial and error. While collaborating with Lewis on a device to sequester microbial colonies in nature, he became the chief tinkerer. At first, the two scientists tried a Slide-A-Lyzer—a small permeable box used in laboratories to separate proteins from other chemicals. They thought they could place bacteria inside, then embed them in soil. As Epstein put it, “The cells will never leave, other organisms will not crawl in, but chemical diffusion would provide everything that is naturally available in the field.” With no funding, though, they could not afford enough Slide-A-Lyzers to run experiments, so Lewis called the manufacturer and explained that they were hoping to turn the device into the successor to the petri dish. The manufacturer donated hundreds of them, and even threw in a little development money.

Epstein tested the device in marine sediment at a research station in the Massachusetts Bay—experiments that, he recalled, involved trudging in mud with rubber boots, cutting his hands on mussel beds, and enduring “late fall rains that, with wind, feel brittle on your skin.” Quickly, it became clear that the chamber would not work: microbes pushing up against the exterior ate right through. “That membrane happens to be a really good food,” he told me. “So we incubate, we remove, and we have only a frame.”

“You know, if we didn’t walk this way we might get close enough to eat someone.”

Returning to Northeastern, Epstein hunted for new material, rummaging through laboratory drawers, and scanning scientific catalogues. He settled on a membrane made from polycarbonate. “Microorganisms are not interested in it,” he said. “You can visualize it as a plastic bag, like from the supermarket, with tiny holes.” Unlike the Slide-A-Lyzer, it did not come in a premade structure, so the two men tried to design a framework made from plastic and screws. “Nothing was really working,” Epstein told me. “We were not engineers. One day, I was at Kim’s office. It was late, and we kept going over different scenarios, and Kim says, ‘Slava, enough is enough.’ He goes to his door, locks it, and says, ‘You and I are not leaving until we have a solution.’ This happened on a day that I had a date with my wife, who does not tolerate one minute of lateness.” With the clock ticking—Epstein had forty minutes—an idea emerged, one so simple that to render it as a blueprint would require not much more than drawing a circle: simply glue the membrane to each side of a metal washer about the thickness of a quarter. Bacteria in agar could easily be sandwiched between the layers.

Within a few weeks, the system was cultivating novel colonies in the Massachusetts Bay; astonishingly, some bacteria even thrived when relocated to a petri dish. “All the hopes that we were holding up at that point became reality,” Epstein told me. Without a team of grad students dedicated to the project, Epstein and Lewis channelled their excitement into lab work. Epstein took photos, and sent a few to Michael Sherman, who had trained as a microbiologist with Lewis. “Slava asked me, ‘What do you think these are?’ ” Sherman recalled. “I thought they were some kind of Martian structure, nothing similar to anything I’d seen in nature. I said, ‘I don’t know. Is it from a sci-fi movie?’ And he said, ‘No, these are colonies. These are really beautiful, new forms of life.’ ”

When Epstein first considered the microbial dark matter, he paid little heed to its practical uses. “I was a fairly snobbish academician who looked down on biotechnology,” he told me. “My interest in the Great Plate Count Anomaly was ninety-nine per cent academic; it was a big intellectual challenge.” But during his collaboration with Lewis he began to meet people in the pharmaceutical industry who had been searching for bacteria that produced novel antibiotics. The problems that they encountered struck Epstein as surprisingly complex, and his snobbery dissipated.

The word “antibiotic”—a Latinate term meaning “life-negating”—suggests a misleading confidence about how these chemicals work in nature. “We actually don’t know,” Epstein told me. The conventional theory is that they are weapons, deployed in a primeval struggle among microorganisms. Long before humans began making use of them, evolutionary pressure caused some bacteria to mutate and develop resistance to attacks from others. Those defenses in turn promoted the evolution of new forms of weaponry.

Epstein is skeptical of this theory. For one thing, no one has ever measured concentrations of antibiotics in nature which are lethal to bacteria. He is open to the notion that these chemicals might be for signalling, and that they seem like weapons because of how we use them. As an illustration, imagine if curious Martians sampled the air around pedestrians in New York City and determined that some people were coated in aromatic compounds. And suppose they isolated those compounds and, as an experiment, dumped tons of them, at a hundred million times the concentration, into Madison Square Garden on a packed night. They might conclude from the resulting mass casualties that cologne is a tool of violence. In Epstein’s view, human researchers may hold a similar bias toward microbial life. “The default hypothesis should be that this or that molecule is used in coöperation rather than in fighting, because that is what dominates among microbes in the first place,” he told me. He mentioned a recent experiment, in which researchers found that a chemical used by a microbe called P. aeruginosa to conduct a census of its colony could also be used, in significantly higher doses, as an antibiotic.

Kim Lewis believes in the weapons theory, and most people who work on antibiotic resistance do, too. There may be no observational evidence for it, but there are important clues in DNA. Not long ago, researchers discovered genetic mutations in bacteria that were frozen in the Yukon thirty thousand years ago. The adaptations appeared to indicate antibiotic resistance, raising the question: Why would evolution select for those defenses unless there was something to defend against?

If antibiotics are indeed weapons, then humans are latecomers to an aeons-old arms race, whose rules remain opaque to us. “It is absurd to believe that we could ever claim victory in a war against organisms that outnumber us by a factor of 1022, that outweigh us by a factor of 108, that have existed for a thousand times longer than our species, and that can undergo as many as five hundred thousand generations during one of our generations,” several scientists argued in a recent paper. The arsenals in question took bacteria billions of years to develop. “In contrast, antibiotics were not discovered by humans until the first half of the twentieth century.”

Even for the pioneers of antibiotic research, the forbidding odds were apparent. As Sir Alexander Fleming, who discovered penicillin, in 1928, noted, “There is the danger that the ignorant man may easily underdose himself and by exposing his microbes to nonlethal quantities of the drug make them resistant.” During the Second World War, penicillin was used widely, and it did not take long for resistant bacteria to spread. But many new drugs were being discovered, particularly from easily cultivatable species of actinobacteria. In 1943, there was streptomycin, the first cure for tuberculosis, and on the heels of that came chloramphenicol, chlortetracycline, neomycin, erythromycin. The rush of discovery gave the impression that nature contained an infinitely deep trove of new medicines. In 1962, a Nobel-winning immunologist went so far as to declare “the virtual elimination of the infectious diseases as a significant factor in social life.” Antibiotics became omnipresent. In industrial farming, they were used to hasten animal growth and to shield plants from pests; in medicine they were often overprescribed or incorrectly prescribed. Microbes, meanwhile, kept evolving. Bacteria do not pass genetic information just to their progeny; they also pass it to neighbors, across species—even to potential victims. In a sense, this shared catalogue of genes evolves as if vast heterogeneous masses of microbial life were one superorganism.

“He’s allergic to peanuts, sensitive to wheat, lactose-intolerant, and just plain weirded out by fruit.”

In the nineteen-eighties, the war started to seem much less winnable. Few new antibiotics could be found among cultivatable microbes, and the tools of modern genetics proved unable to pry many new drugs from uncultivatable ones. As costs rose and results diminished, most of the largest pharmaceutical companies shuttered their antibiotic-discovery programs. The fear now is that the aging war chest will be rendered totally ineffective. Already there are strains of tuberculosis and gonorrhea, among other pathogens, that are resistant to virtually every drug in the medical arsenal. By conservative estimates, there are now seven hundred thousand fatalities from antibiotic-resistant bacteria in the world each year.

In desperation, hospitals have begun to revive old antibiotics that were discarded because they were too toxic. One such drug, colistin, was set aside for decades because its side effects included kidney damage and neurotoxicity. Today, it is a last line of defense against the hardiest of pathogens—though probably not for long. In 2012, the World Health Organization recommended that it be administered under strict regulation, but farmers around the world continued to use the drug liberally, particularly in China, where it was given to livestock by the ton. In 2013, researchers in China discovered colistin-resistant E. coli in the intestine of a pig, and a few weeks ago a similar strain was found in a patient in Pennsylvania—prompting the head of the Centers for Disease Control to declare that “the end of the road isn’t very far away for antibiotics.”

The consequences of a “post-antibiotic world” are difficult to quantify, but a study commissioned by the British government predicts that, if trends continue, annual fatalities from drug-resistant microbes could exceed ten million by 2050, eclipsing those from cancer. Many key advancements in modern medicine could be reversed. As one researcher noted recently, “A lot of major surgery would be seriously threatened. I used to show students pictures of people being treated for tuberculosis in London. It was just a row of beds outside a hospital—you lived or you died.”

On a clear Boston morning, Epstein picked me up at my hotel in his Mini Cooper and drove me to NovoBiotic Pharmaceuticals, in Cambridge. He and Lewis founded the company in 2003, after their success with the washer. By the time the two émigrés became entrepreneurs, Lewis had moved from Tufts to Northeastern, where he established the Antimicrobial Discovery Center. Epstein, meanwhile, tinkered with the technology. The washer was productive but inefficient. Among other things, its interior was enormous relative to microbial life, making it hard to sort out colonies growing inside. “Imagine looking for a coffee cup inside a skyscraper,” he told me.

With the help of his father-in-law, who works at Argonne National Laboratory, Epstein designed an upgrade: a plastic chip with three hundred and eighty-four holes in it, each hole a tiny isolation chamber for one bacterium. He called it the iChip. The design was far more sophisticated, the production far more expensive, yet the results were mixed. The iChip made it possible to grow colonies in the soil from only a single cell. But, after a few uses, scratches compromised the integrity of the chambers, so Epstein built a more primitive version, using the perforated base of a pipette stand, which was cheap enough to throw away when it became worn.

In the Mini Cooper, we headed down a leafy suburban road, to an office park. NovoBiotic is housed in a building about as distinctive as a cardboard box. Fifteen people work there. Although it is a for-profit enterprise, most of its budget comes from the National Institutes of Health. Rules at Northeastern prevent Epstein and Lewis from spending more than a day a week at the company, and the office they share there looks it. We made camp between two desks supporting a mess of journals, until Amy Spoering, the director of biological research, arrived to show me around. Spoering—quick to smile and precise in manner—had been a grad student in Lewis’s lab but abandoned her postdoc to join NovoBiotic. “I just knew I needed to do this,” she told me. “It’s like the Wild West of microbiology.”

To avoid the legal complications of sampling from public lands, NovoBiotic uses social media to solicit friends, and friends of friends, to send in dirt from their yards. (Because a gram of soil can contain fifty thousand species of bacteria, this methodological informality is not especially limiting.) Researchers isolate bacteria from the dirt, place them in growth media, and incubate them in bins filled with their native soil. Originally, they focussed on uncultured species of actinobacteria, which had been a plentiful source of antibiotics. But, even as they discovered new life, they kept running into the old arsenal.

Now the company focusses on the strange stuff. Spoering showed me notes she had made in 2011, on soil that had been dug up in rural Maine. The dirt contained conventional-looking colonies: “yellowish, centered, rumpled on surface with a light dusting of spores.” But there were also exotic life forms; one colony grew in bulbous structures that, over time, became concave. “The bulbousness was definitely something that piqued my curiosity, and also the way that it was sticky,” she said. “This is going to sound crazy, but, if you’ve touched ten thousand isolates with a toothpick, at some point you get a sense of how sticky things can be. This one looked like it should have broken apart really easily. When you touched it, it actually stuck to itself and held together.”

A DNA analysis confirmed the organism’s novelty: the genetic difference between the bacterium and its closest known relative was three per cent—comparable to the variation between humans and mice. The microbes, it turned out, were a species of proteobacteria, named for Proteus, the shape-shifting Greek god. Even though there are more species of proteobacteria than of any other form of bacteria, very few antibiotic drugs had been derived from them. But the sample from Maine was secreting a deadly compound. When researchers placed the microbes on plastic coated with staphylococcus, clear circles formed around them: a zone in which no staph could survive.

“I can’t believe I didn’t think of this before.”

Subsequent experiments revealed that the secretion was lethal to many pathogens—including strep pneumonia, anthrax, and tuberculosis. But excitement at NovoBiotic did not grow until it was clear that the active compound had a unique mass, suggesting that it was an antibiotic no one had discovered before. While chemists rushed to figure out what the molecule was, Spoering and her colleagues tried to figure out how it killed. The standard test is a kind of microbial murder mystery: an antibiotic is used again and again, until bacteria in the victim colonies mutate, developing resistance. The mutant DNA is then studied, and the changes that allow survival reveal how the victims were slaughtered.

As the researchers began the test, they faced an unexpected problem: they could not breed mutants. All they could find beneath the microscope was the debris of bacteria that came into contact with the mysterious chemical and exploded. Nothing survived. Had the compound been acting like detergent—indiscriminately killing living tissue—this might have explained the microscopic carnage, but in tests with mammalian cells it was nontoxic. The chemical targeted only microbial life. “It was actually very vexing,” Spoering told me. “We knew we had something odd.” As the team ruled out possible explanations, frustration gave way to the elated suspicion that the improbable was true: the drug they had discovered was resistant to resistance itself. “At that point, I realized what we had in our hands,” Lewis said. He directed his university lab to start working on the new microbe, which he named Eleftheria terrae, combining the Greek word for freedom with the Latin for earth.

By exploring just a fraction of the microbial dark matter, a small team had discovered a potentially revolutionary drug—quickly accomplishing what large pharmaceutical companies had been unable to do for years. After the compound’s structure was identified, it was given a code, Novo-25, and later a name, teixobactin. NovoBiotic brought in other laboratories, which helped work out how the compound kills: it interferes with lipids that sustain the cell wall of certain bacteria. In tests with animals, the drug demonstrated efficacy, but NovoBiotic was unable to secure grants to develop it into a marketable drug. Although pharmaceutical companies typically guard their early research, the scientists at NovoBiotic decided to announce their progress with a paper in Nature, hoping to generate interest and investment. “We would never have published if we had been able to get funding to move forward,” Spoering told me.

In Nature, the research was presented under a triumphant headline: “A New Antibiotic Kills Pathogens Without Detectable Resistance.” The discovery and the iChip technology were heralded, but there was also skepticism about the implication that microbes could never adapt to the new drug. Some unconvinced scientists sent the company detailed ideas on how to cultivate mutants. (They were all tried, and they failed, Spoering told me.) Others initiated tests of their own. But Lewis told me that he remains confident that no one is going to produce a strain of tuberculosis, or a similar pathogen, that is resistant to teixobactin. “The fact that the producing bacteria are proteobacteria is key,” he said. Eleftheria terrae has a tough, second outer membrane, protecting itself from the compound it produces. “That’s its own mechanism of resistance, and the target organisms—staph, enterococcus, TB—don’t have it.” It would be unrealistic, he argued, to expect the targeted bacteria to develop such a profound adaptation by natural selection, or by borrowing the DNA for such a defense from other microbes. “You can borrow one or two proteins, but to borrow an entire membrane genetically? The equivalent would be if you or I developed wings.”

Gerry Wright, an antibiotics researcher at McMaster University, told me that the history of microbial evolution demanded humility. Perhaps, he speculated, pathogens will evolve to secrete enzymes that degrade teixobactin before it even reaches them. “I have no knowledge of how difficult it would be, but evolution is impossible to beat,” he said. And yet he did not want to undervalue the discovery. In his view, whether teixobactin works forever—or even at all—is almost irrelevant: “As long as that discovery is not just an incredible stroke of luck, then we can spend the next several years as a community trying to find new compounds, and who knows what we will find.”

On the day that I visited NovoBiotic, Spoering was focussing on another candidate drug: Novo-28, drawn from soil from Nevada. Under a microscope, she showed me its unusual morphology—like raindrops frozen on a pane of glass. “Isn’t it beautiful?” she said. “If you let it grow for another week, it will have a hint of pink color. If you let it sit on a plate for a month, it will go mauve.” In the fermentation room, machines swirling racks of beakers in steady gyrations had just made forty litres of Novo-28, for experiments. Near a life-size cutout of David Hasselhoff on a surfboard, a technician was using a glass still to separate Novo-28 from fermented bacterial broth. The chemical appeared to focus, laserlike, on multi-drug-resistant tuberculosis, while leaving beneficial bacteria in the human body unscathed. Because of TB’s extreme resistance, patients must now take a cocktail of harsh, broad-spectrum drugs for months. Novo-28 promised a quicker, less taxing cure.

“Oh, that—that’s the hard drive from my first marriage.”

“We are still very early on,” Spoering cautioned. Even teixobactin will need years of additional investment and testing—the same steep climb as for any new drug. “I am clearly a crazy optimist—working here at all,” Spoering said. “Huge pharmaceutical companies have gotten out of this business. They’re not stupid. It is really hard—not only to find new compounds but then getting them to clinical trials. Then you have to recruit patients with antibiotic-resistant infections who are not too sick from something else, so you can prove the compound works. But it’s not even that you have to prove it works—you have to prove it works better than everything else on the market. Then, once you get to market—people are used to paying not very much for antibiotics. Pharmaceutical companies say, ‘Why would we spend all this money to develop something that can cure somebody in ten days, when we can spend this money for a disease or condition where people have to take a drug for the rest of their lives?’ But the reason I am here is that the science is incredible—the promise is amazing.”

We found Epstein back in his office, hunched at his laptop—a scraped-up Macbook that he calls Roo, after the tiny kangaroo in “Winnie-the-Pooh.” Like Spoering, he was preoccupied by the forbidding costs of drug development, and by the limits of a tiny company like NovoBiotic. As an example, he mentioned pathogens like E. coli, which also have second membranes, making them impervious to teixobactin. Such microbes are among the most resistant, and the deadliest. To find new antibiotics for them, he said, NovoBiotic’s annual research budget would have to increase from three million dollars to thirty million: “Otherwise, the odds are not there.”

Still, Epstein did not share the apocalyptic sense about antibiotic resistance. “I’m sure we will find a way to deal with the problem,” he told me. This wasn’t just his native optimism, he said: “Optimism implies belief in a happy outcome. I do not believe—I know it’s possible.” Other researchers had already begun discovering new compounds with the iChip idea, among them academics from Ningbo University, near Shanghai. “The provincial government is investing tens of millions of dollars in biotechnology,” Epstein told me. “They are building an institute at the university—fifty, sixty million dollars. Grants are available for asking.”

Epstein will begin collaborating closely with the Ningbo team later this year. Certainly, joining with the Chinese, masters of scaling up, is a way to expand. Whether he will stay focussed is another matter. Amid the maelstrom of invitations, inquiries, and grant proposals, he was still wrestling with a theory to explain the Great Plate Count Anomaly. He had trips lined up—Washington, New York, Moscow, Argentina (where he planned to forgo sleep, so he could tango four hours a day). A multinational corporation was seeking his input on skin care. And he had even returned his attention to space.

That last one he explained over lunch at a Japanese restaurant. Epstein does not eat in the middle of the day (a habit borrowed from the Yanomami), but out of decorum he ordered sashimi as he spoke of the possibility of life on other planets. Microbes could well be as prevalent across the cosmos as they are here—a universal biological constant—and it upset him that the astrobiological search for them was not more sophisticated. “The way we’ve looked for life in these places, or are planning to look, is pathetic,” he said. “We’re looking for chemical signatures”—organic molecules that living matter on Earth tends to produce. “So we are going to look for those on Mars? Come on! Who tells you that organisms have to have that? Is that the best we can do?” He lowered his voice. “Well, maybe, if we can’t send a microbiologist there. So I was thinking: Is it possible to cultivate organisms without a microbiologist?” Then he nudged some papers beside my plate. “That is Gulliver,” he said, proudly.

They were diagrams for his latest invention, an iChip upgrade, with as many as a hundred thousand chambers, that could trap microbes and analyze them. “You put nano-sensors inside, and they gather information. Do they respire? Do they ferment? Do they communicate? All of that is transmitted to your iPhone. You are just on a yacht in Hawaii.” As he rattled off details, he brightened, until he ended where he’d started, as if concluding a proof. “Now, tell me—at which point is a microbiologist needed?” he exclaimed. Already, gazing through his telescope at night, he envisions the device exploring the solar system. He was leaning in and grinning. “Can you do it on Mars? How do you like it?” ♦