Millions of lives worldwide depend on science’s ability to find new antibiotics. The improvisation and persistence of Northeastern University’s Slava S. Epstein may now be one of their best hopes.
For decades, his fellow scientists banged their heads over most bacteria’s refusal to grow in laboratories. Mr. Epstein, a Russian émigré biology professor and a nonstop generator of ideas and energy, simply took another path.
Bacteria usually live in dirt. Mr. Epstein’s innovation was to create a small plastic container, dubbed the iChip, that allows him to grow bacteria in that natural habitat and then bring them into the lab. In doing so, he estimates he multiplied by thousands the chances of finding cures for a range of deadly bacterial diseases. Within the past two years, he has identified two dozen possible new drugs.
The creation of Mr. Epstein’s iChip is “a remarkable story,” leading scientists to antibiotic candidates that never could have been cultivated in a laboratory, said Francis S. Collins, director of the National Institutes of Health.
Making antibiotics is just one use, said Margaret A. Riley, a professor of biology at the University of Massachusetts at Amherst. The iChip looms as a fundamentally new tool for a variety of applications associated with microbiology, Ms. Riley said. “My guess is that you’re going to see a million applications of it,” she said.
That wasn’t immediately obvious to some federal grant-writing agencies when Mr. Epstein first came to them. And it wasn’t the first time that Mr. Epstein, who left Russia in 1988 and joined Northeastern University in 1992, sidestepped bureaucracies that for generations seemed hopelessly ironbound. Back in his hometown of Moscow, Soviet rulers had banned almost all private enterprise. One of the few exceptions concerned artists.
Seeing an opportunity, Mr. Epstein bought a cheap set of plaster molds and began making jewelry in the shape of zodiac symbols. The scheme required convincing city officials that the handicrafts were homemade, not mass-produced. Some timely shedding of tears help sell the ruse. Before long, the Moscow State University graduate turned doctoral candidate in marine biology was “bringing money home in suitcases” and financing his own research trips to the Russian Arctic.
“I was making in a day more than my parents were doing in a year,” he now recalls, 30 years later.
Buried in the Dirt
After escaping from Russia, Mr. Epstein tackled another challenge: the Great Plate Count Anomaly, a dominating roadblock in modern microbiology. The term refers to the fact that an estimated 99 percent of bacterial species do not grow in lab settings, apparently because they need nutrients and chemicals found only in their natural environments.
That’s been a huge problem: Scientists typically find antibiotics by growing and studying many different bacteria in labs and then identifying the protein molecules that each produces and emits to kill or fend off neighboring bacteria.
“They fight with each other—that’s their weapons,” said Kim Lewis, Mr. Epstein’s research partner, also a Russia émigré, and a fellow professor of biology at Northeastern. “And then we borrow those weapons to kill our pathogens.”
Bacteria, however, are good at evolving defenses against the proteins that are repeatedly used to kill them. And with scientists able to grow only about 1 percent of all bacteria in their labs, that antibiotic resistance has long outpaced the discovery of new antibiotics.
Rather than trying to find better techniques to grow bacteria in labs, Mr. Epstein reasoned, it made more sense to work in the environments in which they already grow quite well.
For many types of bacteria found in nature, that meant burying the iChip in a pile of dirt. One early variation of the iChip attaches to a retainer that clips inside a human mouth, to investigate bacterial causes of periodontal disease. More-automated future versions might enable the study of bacteria in the human gut or on distant planets.
Yet Mr. Epstein’s solution was so simple and elegant that, for a time, the National Institutes of Health and the National Science Foundation wouldn’t finance his work, he said. Nor would the U.S. Patent and Trademark Office certify his inventions. Mr. Epstein summarizes a typical response from a grant-review panel: “It’s a good idea, a new idea—but Slava, it cannot be that simple.”
In some respects, it was not. Previous researchers had tried putting microscope slides in dirt to see what might grow on them. But Mr. Epstein tackled the concept with far more determination. His key advances included finding the right type of covering membrane—a polymer with microscopic pores that can keep a target bacterium trapped inside the iChip while allowing the free entry and exit of naturally occurring compounds that are apparently key to stimulating its growth.
Mr. Epstein refined the iChip further by designing a device with almost 400 individual micro-chambers. In most cases, each chamber traps only a single type of bacteria, greatly reducing the time that lab workers spend teasing apart intertwined colonies to investigate their individual properties.
‘The Dark Ages’
Although the iChip is now gaining its greatest attention in microbiology, Mr. Epstein arrived at the idea as a marine biologist, and he initially found success developing it for dentistry. As he realized the range of possibilities, around 1999, it became clear he needed partners. A friend suggested Mr. Lewis, a molecular microbiologist specializing in antibiotics, who was then working at Tufts University. Within a couple of years, Mr. Lewis moved to Northeastern. After another two years, they formed a company, NovoBiotic Pharmaceuticals, to begin systematically picking through all the new drug candidates being generated by the iChip and its predecessor versions.
Federal research-financing agencies also awoke to the possibilities, with the NIH, the NSF, and the Department of Energy eventually providing Mr. Epstein with more than $3-million in support. One early believer was R. Dwayne Lunsford, a microbiology-program director at the NIH. Mr. Lunsford recognized the tool’s value to dental science, given that labs can grow only about a third of the 300 kinds of bacteria found in the mouth. “Being able to get somebody like that, with that brain power, into the medical field was the coup that I saw,” Mr. Lunsford said.
In antibiotic research, however, the resistance problem has reached a crisis. Resistance from overuse—by doctors, farmers, and consumers—is driving the need for new medicines to thwart bacterial diseases at the same time major drug companies are scaling back their research operations. Antibiotics may save millions of lives, but the economics are poor because users buy them for only a few days rather than a lifetime. Pfizer and Merck are among the heavyweight drug producers that have given up, due to the trickle of results from standard lab-cultivation processes.
The 1 percent of bacteria that can be grown in a lab were “over-mined a very long time ago,” Mr. Lewis said. “By the early 60s, people stopped discovering new classes of useful antibiotics, so we had our golden era and then we had the dark ages.”
Even with the iChip, it’s a long slog. NovoBiotic Pharmaceuticals already has identified 25 candidate drugs, including one called Teixobactin, a molecule that has shown effectiveness in initial animal tests against bacteria that can cause pneumonia, tuberculosis, and staph infections. There are encouraging signs that Teixobactin’s particular method of attacking bacteria may make it tougher for the bacteria to develop a resistance. Still, most newly identified bacteria-killers end up proving toxic to human beings, so the ultimate success of any one candidate drug depends on years of testing.
A Scientific Upheaval
Nevertheless, the iChip method may now be the best option out there. Some small biotechnology companies are trying to work around the problem of microbial uncultivability by tweaking the structure of existing antibiotics. That approach has led, however, to just a handful of recent candidate drugs. And yet for decades, that’s been better than nothing: Such modifications account for most of the new antibiotics created in the past 40 years. (The 25 new compounds found by NovoBiotic were among 50,000 microbial strains cultivated by the company, a ratio thousands of times better than the estimated new-discovery rate of about one in 10 million seen in labs using traditional cultivation methods, Mr. Epstein said.)
A more-popular recent approach, at least in university labs, aims to exploit the sweeping advances in reading genetic information. Rather than trying to cultivate actual bacteria, scientists have begun collecting large samples of genetic material from dirt and other natural settings, and then trying to devise antibiotics by studying the molecules created by that DNA.
That approach has been tried for at least 20 years, also with little to show for it. But one of its leading advocates, Julian E. Davies, a professor emeritus of microbiology at the University of British Columbia, said that the track record will soon change with the arrival of super-fast gene-sequencing technologies. Mr. Davies said he regarded Mr. Epstein and Mr. Lewis as “both very ingenious guys,” but insisted the value of their discovery of Teixobactin had been “vastly overestimated.”
Mr. Epstein isn’t pushing back hard on either point. Teixobactin still needs to survive human testing, he acknowledged. And with millions and perhaps billions of bacteria to sort through, he said, it’s clear no single method will find all possible drug candidates. That said, ecologists such as Mr. Epstein are well accustomed to being overlooked, said Maria Sizova, the senior principal scientist in his lab. Microbial ecology was pioneered in the United States in the 1950s, she said, but it’s no longer considered fashionable. That may help explain, she said, why so many lab-based researchers have spent so long looking for antibiotics in the wrong places.
Dr. Collins said he was hard-pressed to explain the refusal of so many researchers to move beyond lab-based solutions when it was clear they were seeing diminishing results. It might be a lesson in “the way that scientific mind-sets occur,” the NIH director said. “Some of that happens during training, like: ‘OK, you can’t work with a bacterium unless you can culture it.’”
Whatever the long-term outcome, the excitement and pace of a major scientific upheaval is now evident in Mr. Epstein’s cluttered office. There rows of his poster-size travel photographs sit scattered across tables, hinting of a life filled with the global pursuit of microbes, one that leaves no time to actually hang up the souvenirs.
Down the hall in his lab, Brittany Berdy, a fourth-year doctoral student, cheerfully described the Great Plate Count Anomaly as the challenge that had led her to choose upstart Northeastern over Cornell University.
“I wanted to change that,” Ms. Berdy said, referring to the generations stymied by the inability to cultivate bacteria. “I looked everywhere, and Slava was the only person who posed the problem with a potential solution.”
Paul Basken covers university research and its intersection with government policy. He can be found on Twitter @pbasken, or reached by email at paul.basken@chronicle.com.