by Joshua Timmons, Biology, 2017
A year ago, the world buzzed after discovery of the first promising new antibiotic in 30 years. The news came at a time of mounting concern about antibiotic-resistant bacteria and was featured in The New York Times, Forbes, NPR, BBC, Foreign Policy and a score of other major news outlets. The new antibiotic is unique for both its dual-mechanism—a double punch against bacteria that makes developing resistance unprecedentedly difficult for them—and the tool that made its discovery possible: the iChip. Despite the device’s Silicon Valley conjuring name, its inventor, Professor Slava Epstein, grew up and began his research in Soviet Russia. His relentless approach to daunting problems and his otherworldly musings have led to the isolation of previously uncultivable microbes with plans to do even more.
When Epstein first arrived in America, he had little more than his family, a smuggled cat, and an “enormous amount of data” from his research in Russia. Unfortunately, he didn’t speak English. “I had a PhD, some publications, but no English. There was no prospect of getting a professorial job anytime soon.” Instead, he devoted himself to painting with NPR for background noise.
“All this time I was scraping paint off walls, I kept my headphones on.” While working the background sounds of a foreign language played through the earbuds as an uninterpretable flow of syllables. But, with time, that began to change. “In eight months I realized that it wasn’t background noise any more… I was listening to the news.”
With time, he restarted his prior research by volunteering in a lab at the University of Massachusetts Boston, eventually moving up to a post-doctoral position while at the same time working as a parking attendant. Within a couple years of arriving, he had learned the language and published some papers. Epstein continued to climb hurdles, first with a Northeastern University soft-money lab funded entirely by difficult-to-come-by NSF grants, then a microbiology faculty position, also at Northeastern. He describes the work as tough but exciting, “I was teaching anywhere and everywhere, all the while doing full-time research—a stimulating challenge.”
Dr. Epstein’s research focused on what he believes to be the single greatest barrier in the way of understanding microbial life. It is known as the great plate count anomaly. “The challenge is this: 150 years of microbiology have brought into culture a minute percent of the global microbial diversity. Somewhere around 1 percent. It’s small.” Despite basic observation by, for example, microscopic cell counting making it clear that there are huge numbers of microbes in the environment, scientists are only able to cultivate a small number of them. Not being able to grow the microbes in a lab setting has significant implications. “The remaining 99 percent is THE largest source of biological and chemical novelty in the world, and it’s unexplored and essentially untouched.”
Where many researchers may have seen a barrier, an obstacle that simply limits their studiable material, Epstein saw a challenge. “It’s an opportunity that you cannot simply dismiss. You know it exists, you want to resolve on it, and for that, you have to become a microbiologist.”
Epstein realized there was a problem with the manner in which people were approaching the problem. He explains his view with an oft-repeated thought experiment in which a microbiologist tries to culture a single colony.
The microbiologist goes out into the environment, collects a single bacterium, and then takes it back to their lab where it grows into a colony on a petri dish. Another microbiologist collects the same bacterium, but stops halfway back to the lab. This second microbiologist turns around and places the bacterium back into the soil, where it too grows into a colony. In both cases a bacterium is manipulated, and in both cases a colony is produced. From this, Epstein surmises that it was not the cultivation that represents a challenge: growing unknown microbes in their natural environment is easy. The actual issue lies elsewhere. “We’re focused on cultivation, attempting to create a perfect growth medium in the lab. Why, when it already exists, in the natural environment of the species we want to grow. What we really should be focusing on is how to separate that microbe’s growth from other microorganisms, which is a totally different task. Once the task is formulated in this way, the resolution of the overall problem becomes simple,” said Epstein.
With a small grant from the NSF, Epstein and his graduate student Tammi Kaeberlein, in collaboration with director of Northeastern’s Antimicrobial Discovery Center, Kim Lewis, built and successfully tested a prototype of a device that enables cultivation of microbes in their natural environment. On its basis, and this time with support from NSF, NIH, and DOE, Slava’s lab introduced an even better tool they dubbed iChip. With 384 individual wells, iChip enabled cultivation of previously unknown species in a high-throughput manner.
While isolating new bacteria is important for microbial ecology, and understanding why some colonies grow and others don’t, iChip’s major utility has been its application in biotechnology. With new biological life comes new and potentially useful chemistry. To seize this unparalleled opportunity, Epstein and Lewis formed a company called NovoBiotic Pharmaceuticals. Although there was no guarantee that the new compounds would be of clinical benefit, several have already proven worth a further look. “The practice provides you with hard data to support the assumption that there is lots of interesting new bioactive compounds that you can discover at a really good frequency,” said Epstein.
One of them, teixobactin, represents a new class of antibiotics against gram-positive pathogens. This discovery generated international attention after its announcement in Nature. In addition to potentially being the first new class of antibiotics in 30 years, the compound is unique for its method of attack on bacteria. By inactivating two separate lipid targets in bacteria, teixobactin kills pathogens simultaneously from two different sides, and this makes the development of resistance a highly unlikely event. Teixobactin and the iChip have been named one of the top 100 discoveries of 2015 by Discover Magazine, one of the top 10 discoveries in 2015 by the United Press International, and one of the top five most important medical developments of 2015 by the BBC. In addition to these accolades, Epstein and Lewis were also named among the top 100 Global Thinkers by Foreign Policy magazine.
NovaBiotic now has two other leads in the pipeline: Novo10 and Lassomycin. The former is a promising anti-cancer agent, whereas the second specifically targets Mycobacterium tuberculosis, the causative agent of TB.
When asked to explain his success, Epstein cites a willingness to follow his own interests irrespective of grant climate and prevailing funding trends. “In science, there have always been things that I want to do. Are they aligned with what would be strategic for grants? No, not necessarily. After all, one way to succeed is not to compete for space in a given niche, but to create a totally new one.” Making connections between his evolving work, he sees only his own interest in the material. “What unites my work from 10 years ago and my work 20 years ago is not the topic, but that they were all things so interesting that I could not but fall for them, one by one.”
Having already expanded the number of researchable bacteria, Epstein wants to take the approach further by removing an additional variable from the equation. Interestingly, it is himself and his fellow microbiologists. To isolate bacteria a researcher needs to collect samples, obtain cells, plate them, etc. At the very least, this requires a person. This is a limitation in Epstein’s mind, “One obvious result of this is that little is possible in the cultivating and studying microbes without a microbiologist.” It follows that microbiology is impossible where a microbiologist cannot go. Again, where many scientists might see a line in the sand they don’t cross, staying in a more tried and true area, Epstein sees an opportunity to explore.
“What I would like to do now is simplify microbiology to the point when microbes can be collected, sorted, grown, and their properties investigated without a microbiologist,” said Epstein. He plans to build on the success of his former approach with the iChip by making an isolation chip with built-in nanosensors, which would record microbial activities as they grow in nature, and transmit the data into the hands of – up until that point not needed – scientist. Epstein believes that colony properties like respiration, various aspects metabolism, and interspecies communication could all be reduced to data points on a chip under the observation of nanosensors.
Like the iChip, Epstein sees immediate application by imagining a test case where researchers are looking for novel, previously uncultivated bacteria capable of degrading cellulose into bioethanol. “Using your iPhone, you open up a valve, and cellulose is released into thousands of iChip compartments, each with its own microbe growing there. If a given microbe, even if one out of thousands can utilize cellulose, nanosensors will detect it and point to the researcher where the valuable culture is, eliminating an enormous amount of needless efforts that would otherwise be required.
Taking the potential of such device, dubbed Gulliver to the extreme, Epstein sees the new chip being used in places where humans have yet to visit. In September, NASA announced the discovery of flowing liquid water on the surface of Mars, an occurrence that seems to oscillate with the planet’s seasons. A more recent discovery by the Curiosity rover was a high silicon concentration, something that would require areas of heat and moisture, both requirements for life. Scientists believe that if microbial life exists on Mars, areas such as these would be the locations to support it. But identifying a potential location is only the first step. “If there is life on Mars, how do we study it?” asks Epstein. He believes that Gulliver will not only be able detect microbial life forms there, but also interrogate them, something that today would truly be impossible without sending a microbiologist to the Red planet.
The goal might seem outlandish, but Epstein has already shown that his approach can work. His ability to see problems differently and invent his own solutions has already proven itself, unlocking microbial diversity that was for over a century seemed unreachable. Time will tell how his willingness to follow his own interests might change the game again.
