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A radically simple idea may open the door to a new world of antibiotics
STAT, December 3, 2015

BOSTON — Slava Epstein works in aggressively low-tech quarters at Northeastern University. You might expect otherwise, given the extraordinary work that he and his colleagues are doing, discovering new kinds of antibiotics that are fundamentally different than the ones doctors prescribe today.

And yet, when I paid Epstein a visit recently, we sat down amid a veritable landfill of scientific reprints, old Starbucks cups, and empty bottles of Vitamin Water.

“I apologize for the awful, awful mess,” he said in a light Russian accent.

Reaching into the jetsam on his desk, Epstein fished out a metal washer the size of a beer coaster. The hole at the center was sealed with two disk-shaped membranes. He showed it off for a little while, and then he retrieved three black boxes. They had perforations on their sides and were each about the size and shape of a stick of chewing gum. Finally, Epstein unearthed a cast-off box originally used for storing pipette tips. One side was open, and the other was lined with a membrane sheet.

These are the tools that Epstein and his colleagues have used to make scientific headlines. And they’re cheap. The hacked pipette tip box costs less than $10 to make. “You could build this in your garage,” he said, turning the box over in his hand.

Behind these cheap items there’s a powerful idea. Bacteria make antibiotics naturally, which means that if you can grow new bacteria in a lab, the microbes can offer up new drugs. Unfortunately, for the past century, microbiologists have failed to unlock the secret to cultivating the vast majority of bacterial species.

Now Epstein and his colleagues have found a way to make many of them thrive.

“Everyone thought the solution would be high-tech,” said Epstein. But the one that he and his colleagues have found is remarkably straightforward. They raise bacteria by giving them a comfortable place to grow — a disk or a box will do. A company they founded, called NovoBiotic, is now testing the antibiotics made by the bacteria in the hopes of putting them into clinical trials.

“Don’t you just love simple, little, elegant things?” said Gerry Wright when I asked him about Epstein’s work. “You look in my lab, and there are all sorts of machines that go ping,” said Wright, the director of the Michael G. DeGroote Institute for Infectious Disease Research at McMaster University in Hamilton, Ontario. “And here these guys went back and said, ‘Maybe we’re overthinking this.’ You don’t need to have a million dollars worth of equipment. You can go to Home Depot and maybe change the world.”

Epstein’s success may have something to do with the fact that he’s an outsider in the world of drug discovery. Born in the Soviet Union, he earned his PhD in the 1980s at Moscow State University in marine biology. His scientific papers had to be vetted by the KGB, and he was barred from ocean expeditions because the authorities worried that Epstein — a Jew with dissident friends — might jump ship in a foreign port.

In hindsight, Epstein, now 56, thinks it was just as well to be grounded. “In Russia, nothing ever worked,” he said. “If you make yourself dependent on a drunk captain of a falling-apart vessel, you get yourself into trouble.”

Instead, Epstein studied the organisms dwelling in tidal flats. “All you need is two feet to walk to the beach,” he said.

Epstein started out studying invertebrate animals, but soon his attention shifted to microscopic organisms, such as protozoans and the bacteria they hunted. “I was getting interested in progressively smaller and smaller organisms because they appeared to be more important to me,” Epstein said. “The rest just seemed to be a consequence of what the smaller bugs were doing.”

In 1989, history stepped in and led Epstein to put his scientific career on hold. The Soviet regime collapsed, and Jews began to leave the country. Epstein chose to go to Boston. “It was of course very stupid,” he said.

It was stupid because Epstein spoke no English at the time, had no prospect of a job in marine biology in Boston, and had a wife and children to support. To survive, he painted fences and fixed roofs. “Not that I knew how to do it,” Epstein said, “but if someone’s paying you five dollars an hour, they’ll overlook some deficiencies.”

Gradually, Epstein got his bearings. He learned English by listening to the news. He volunteered in a microbiology lab at the University of Massachusetts at Boston, while moonlighting as a parking lot attendant.

Through a friend, Epstein had smuggled his unpublished research notes in Dutch diplomatic pouches when he left Russia, and now the scientists in the lab helped him write up his work for publication. His studies on the ecology of tidal flats earned him a half-time position as a postdoctoral researcher at the university. After a stint in Wisconsin, he landed a job at Northeastern in 1992. He’s been there ever since.

At first, Epstein continued the work he had started in Russia, teasing apart the invisible ecosystems lurking below unwitting beachgoers. He became increasingly curious about bacteria, the smallest residents of the beach. And Epstein grew deeply perplexed by a fundamental challenge facing microbiologists at the time: Almost every species of bacteria was beyond their scientific reach because they couldn’t be grown in the lab.

The problem of plating

Microbiologists have a name for this failure: the Great Plate Count Anomaly.

It’s a problem that had plagued microbiologists pretty much since Julius Petri invented the dish that bears his name in the 1870s. To study bacteria, researchers would place microbes on a dish — a process known as plating — and wait for them to grow. A few species, such as E. coli, would. But most species (99 percent by some estimates) would simply lie on a Petri dish in stubborn dormancy. Microbiologists knew that the species they could count on a plate were a tiny fraction of the diversity of microbes. And there seemed to be nothing they could do to make the Great Plate Count Anomaly go away.

“By the end of the 1990s, I became obsessed,” said Epstein. “There was something really big in front of me that people didn’t understand.”

A friend told Epstein that there was someone who shared his obsession — a microbiologist named Kim Lewis who worked nearby at Tufts University. While Epstein had been trained in ecology, Lewis’s expertise was in molecular biology. But the puzzle of bacteria that couldn’t be cultivated mesmerized Lewis just as much, and it turned out Epstein and Lewis had independently reached a lot of the same conclusions about how to solve it. “He had parallel ideas, and we ended up brainstorming this together,” said Lewis, who moved to Northeastern in 2001.

Epstein and Lewis suspected that bacteria didn’t grow in labs because the conditions there, while comfortable for humans, were toxic for the microbes. So they decided to try to bring the bacteria’s natural environment into the lab to see if they would feel more comfortable. In their first experiments in the early 2000s, Epstein and his students went to Massachusetts beaches and cut out wide slabs of sand. They brought the slabs back to Northeastern and placed them in aquariums.

The scientists hoped that the bacteria, nestled in their sandy environment, would be happy enough to continue growing. But even if they did, the scientists needed a way to isolate different species to study them.

“Cultivation is not a problem,” said Epstein. “The problem is containment, how to separate them from other microbes.”

Epstein and his colleagues set out to build containers that could get this job done.

After a few failed designs, they finally found that metal washers with the membrane walls worked well. The researchers stocked the washers by scooping up the bacteria-laden sand and mixing it with bacteria-free water. Then they took a little of that water and diluted it even further. After many rounds, they ended up with exquisitely low concentrations of bacteria. When they poured this water into the washer chambers, each one received, on average, a single cell.

The researchers then sealed these isolated bacteria inside their washers and then put them back in the sand. Oxygen and nutrient-laden water could pass though the membranes into the space inside, and waste produced by the bacteria could pass out. But the microbes could not escape through the tiny pores in the membranes, nor could others sneak in.

To their delight, the researchers found that the bacteria in some of the containers grew quickly. The colonies became so abundant that the researchers could study them and describe a number of species new to science.

Epstein and his colleagues followed up on this success by designing new homes for other microbes. In one project, they set out to replicate and grow the microbes that live in our mouths. The human mouth is home to several hundred species of bacteria, a complex ecosystem that is vital to our health, from our gums to our hearts.

The scientists recruited a group of undergraduate volunteers and fashioned retainers that fit snugly on their palates. Into each retainer, they carved out a small space where they could put a tiny box. The bacteria inside the box could get all the nutrients they needed to thrive. A day or two later, when Epstein and his colleagues retrieved the retainers, they found growing colonies of mouth bacteria in the boxes — including a number of new species.

These successes were gratifying, but Epstein and Lewis could see a big shortcoming in their technique: It was too artisanal. They wanted to mass-produce containers that could each nurture many different bacteria colonies at once.

Working with materials scientists, Epstein developed small plastic boxes, which he calls isolation chips, or ichips, for short. A single ichip contains 192 wells, each a millimeter deep. Each well is isolated from all the others, allowing Epstein to cultivate 192 different colonies in a single ichip.

Brand-new antibiotics

Epstein is using ichips to understand the ecology of bacteria in the natural world. Most recently, some of his colleagues have buried ichips in Greenland tundra to study Arctic microbes. But ever since Epstein and Lewis started trying to grow bacteria, they’ve also had a very practical hope for their technology: to find new antibiotics.

Growing bacteria to discover antibiotics has a long, venerable history. In the 1930s, Selman Waksman of Rutgers University and his colleagues decided to search for antibiotics in spore-making soil bacteria, known as actinomycetes. They would take pinches of soil from the Rutgers campus and dry them out. Only the tough actinomycete spores survived. When Waksman and his colleagues then gave the spores water and nutrients, they opened up and the bacteria started to grow.

In just a few years, the scientists isolated dozens of antibiotics from these actinomycetes, including some, such as streptomycin and neomycin, that are mainstays today. Waksman won the Nobel Prize in 1952 for those discoveries.

Ever since Waksman, scientists have continued to search for new antibiotics in actinomycetes and paid much less attention to other bacteria. Wright likens the search to the old story of the drunk searching for his keys at night under a lamppost. When asked if he dropped them there, he says, “No, but the light’s better here.”

Wright says the search for antibiotics from actinomycetes has only yielded minor variations on Waksman’s initial discoveries. “We’ve really just mined the hell out of them,” he said, “but we tend to find the same old antibiotics all over again.”

Epstein and Lewis set out to find new antibiotics by growing new bacteria in their ichips. Working with NovoBiotic researchers, they extracted bacteria from soil and put them into ichips, which they then pressed back into dirt for a month to let the colonies in each well grow.

Once the colonies had matured, the scientists tested them for antibiotics. They added disease-causing bacteria to each well in their ichips to see if any of the colonies made compounds that killed off the intruders. A few did. Examining the colonies more closely, the researchers discovered 25 different antibiotics, all of which appear to be new to science.

Lewis led the analysis of two of these new drugs, which he and his colleagues have dubbed lassomycin and teixobactin. “They’re terrifically interesting,” said Lewis. Each one kills bacteria using an attack never seen before in an antibiotic. Lassomycin drains the fuel from bacteria, while teixobactin interferes with the growth of their cell walls.

NovoBiotic has found that teixobactin can cure infections in mice, and it’s now fine-tuning the molecule to get it ready for tests in humans. Epstein hopes a large pharmaceutical company will be able to take on the expensive clinical trials that will determine if teixobactin can win Food and Drug Administration approval.

The fact that a few scientists and a small biotech company found so many promising compounds in so little time makes Lewis optimistic about finding even more. “That tells us that the source that we’re tapping has tremendous potential,” he said.

In the meantime, Epstein has been looking for even better homes for microbes. The black plastic ichips don’t work for very long because they accumulate tiny scratches through which bacteria can sneak in and out. So they’ve turned, instead, to empty pipette tip boxes to do the same job. When other scientists email Epstein to ask where they can buy ichips, he sends them instructions for making their own.

The antibiotic business is so unpredictable that it’s hard to predict whether teixobactin will someday replace streptomycin and other antibiotics faltering as bacteria become resistant. But the fate of a single drug is less important than the discovery of a new way to find them.

“Until someone like Slava showed that you can find new chemistry, it wasn’t something people wanted to take a risk on,” said Wright. “All of a sudden, we’ve got another lamp post we can look for our keys underneath.”

Copyright 2015 Carl Zimmer
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