Seeking Cures in Kentucky Coal Mines

A boy squats at the entrance of an abandoned coal mine at Barthell Coal Mining Camp, Kentucky. Extreme environments like the depths of coal mining caves could cause organisms to develop high levels of cytotoxicity and antimicrobial compounds. Pat Canova/Alamy

The Matrix Energy Mine No. 1 in eastern Kentucky stretches 7 miles to its deepest point. Tiny cars creak along tracks laid on the ground in the bowels of the operation, opened in 2004, and miners here collect 4,500 tons of coal each day. But Jon Thorson, a professor of pharmaceutical sciences at the University of Kentucky and director at the Center for Pharmaceutical Research and Innovation, isn't all that interested in fossilized carbon. He believes the true value to be found in the mine lies in the soil and rocks. Thorson is digging for blockbuster drugs.

Natural medicine is often associated with ancient civilizations or bogus alternative treatments endorsed by celebrities. However, unique compounds in plants, soil and the sea have played a major role in modern treatments for conditions ranging from bacterial infections and malaria to high cholesterol and cancer. According to one study, as much as 50 percent of drug compounds on the market have their origins or are structurally based upon some type of natural product.

And there's so much more still to be uncovered. According to some research, only about 1 percent of bacterial and 5 percent of fungal species are known, which means it's plausible that there's something natural for everything that ails us.

Thorson says Kentucky's Appalachian region is a good place to start looking. With more than 6,300 species, the area is the largest biodiverse "hot spot" in the U.S. Globally, it's rivaled only by China in terms of its forest diversity. "You could spend the rest of your life [here] just looking for organisms," he says. Scientists like Thorson who go out into the natural world with hopes of identifying the next great cure usually head to locations where they might find "extremophiles"—organisms that thrive in extreme environments uninhabitable for most living things, because of, say, high pressure or high temperature. These harsh environments—like the bottom of the Matrix mine—are also often devoid of natural light and have a limited amount of nutrients to support life. As a result, the extremophiles (or "exotic microorganisms," as Thorson calls them) that live there need to develop certain traits to ensure survival. And by figuring out the naturally produced chemicals that give the extremophiles their extreme traits, we can sometimes harness those characteristics and put them to use for human good.

All living creatures produce primary metabolites, such as vitamins, simple sugars and amino acids, which are created in part through the chemical transformations that are constantly going on in an organism's cells. These primary metabolites are the things required for the normal growth, development and reproduction of any living thing. Thorson is interested in secondary metabolites—the unique compounds that give an organism the ability to do all the other things it might do, from looking a certain way to secreting toxins to fight off enemies. In the case of extremophiles, though, it's like these microorganisms are superheroes and secondary metabolites are their special powers.

Valuable extremophiles are being discovered all over the world. In 1995, researchers sampled fungus growing in a deep, abandoned, open-pit copper mine in Butte, Montana. The group identified valuable compounds from the fungus living in this toxic waste dump filled with highly acidic and metal-heavy sludge, and they published some 20 papers about their findings. Some of these molecules they found inhibited specific pathways of cancer, including leukemia and melanoma cancer cells and non–small cell lung cancer. Others were found to hit targets involved in inflammation or to kill certain bacteria such as Methicillin-resistant Staphylococcus aureus. And in China, at the Kunming Institute of Botany, Chinese Academy of Sciences, researchers have isolated some novel molecules from organisms in tin mine waste streams, including naphthospironone A, which has antimicrobial properties.

If not for secondary metabolites identified in soil microbes, we'd be without several reliable anti-cancer drugs, including bleomycin and doxorubicin, antibiotics such as erythromycin and antifungal treatments such as amphotericin B. Secondary metabolites can also come from plants (cocaine, isolated from the coca plant), animals (tetrodotoxin, an antimicrobial found in pufferfish and some salamanders) and mold (like penicillin). Last year, two researchers were awarded the Nobel Prize for isolating a compound from soil samples collected at a golf course in Japan that would later be developed into the drug avermectin, which is now used to treat parasitic worms. Derivatives of the drug have also helped reduce incidences of elephantiasis and river blindness.

Bacteria grow in Thorson’s University of Kentucky lab. His team collects samples from unusual environments, seeking naturally produced compounds that could then be used to develop drugs. Charles Bertram/Lexington Herald-Leader

Thorson, who started testing samples in Kentucky in 2012, has identified about 200 molecules that could potentially be useful for drug development. For example, one of the first sets of molecules discovered in his lab helps ensure that the protein 4EBP1 continues to repress cell growth in cases when cancers deactivate that functionality. The lab has also identified potential candidates for antibiotic development, and it appears one class of isolated enzymes might be able to make daptomycin—an antibiotic already on the market as Cubicin and used to treat S. aureus and other infections—four to eight times more potent.

Thorson says the University of Kentucky looked at him askance when he asked for approval of a budget that included a rock pulverizer and sledgehammer. But on the flip side, geologists working at the university, like Richard Bowersox, have been thrilled to join the project. "This is a fishing expedition," says Bowersox, adding that the project has allowed him to think about his work in a new and exciting way. In an expedition last year, the geologists were drilling down for their own purposes of surveying a mine, and they collected samples for Thorson every 100 feet below the surface. The geologists have provided Thorson's lab with specimens from as deep as 4,835 feet below ground.

In general, Thorson's team has found the deeper one goes into a coal mine, the more interesting the molecules. This may be because the farther down you go the higher the saline content, since some of the areas explored through deep drilling were ocean beds a long time ago. Thorson has tested samples in his lab that had saline levels 10 times higher than the ocean. The coal fire sites have also provided some promising molecules due to their extreme temperatures that can rise to as high as 500 degrees. That heat appears to produce more exotic microorganisms; for example, the team isolated molecules from a bacteria found in a coal fire site that may provide neuroprotective benefits useful for treating the long-term effects of alcohol damage.

Scientists have been discovering curative secondary metabolites for centuries, as far back as 2600 B.C. in Mesopotamia. But it's only recently that the field has exploded. In fact, in the 1990s, drug companies wanted out of natural product development partly because its returns were slow and relied too much on serendipity. The tools used in labs to sift through these compounds also were not advanced enough. "Part of the reason why the pharmaceutical industry got out of the natural product [development] is they kept rediscovering the same molecules over and over," says Richard Baltz, chief scientific officer at CognoGen Biotechnology. "All the things that were easy to find were already found."

Today, though, advances such as cheaper genome sequencing are prompting more interest in natural product development from big pharma. Labs like Thorson's can use DNA sequencing to sift through thousands of molecules for the ones that are most interesting. That's essential, because a single gram of soil can contain up to a million microbes, and each microbe produces hundreds to thousands of secondary metabolites. Thanks to improving technology, Baltz says that the pharmaceutical industry is headed for the golden age of natural product development. "This is going to revitalize the whole pharma industry particularly for antibacterial, antifungal [and] cancer immunotherapies," he says.

A paper published Wednesday in ACS Central Science reported details of one discovery made through genome sequencing—a previously unknown amino acid-based natural product the researchers named tambromycin. They found the compound could slow the growth of two types of leukemia cells without killing healthy cells.

Pharma may be on the rise, but Kentucky's coal market is flailing and doesn't look primed for recovery. Miners in the state struggle to hold onto their jobs; in 2013 alone, employment at coal mines fell by nearly 16 percent, and more and more states and countries are actively weaning themselves off fossil fuel energy. On January 15, U.S. Interior Secretary Sally Jewell announced the government would stop approving new coal mining leases on public land, and it will consider additional measures to slow down coal extraction in the country. But Thorson's work is at the very least bringing a sense of optimism to those in the mining industry. "It is my hope that a share of any future revenue deriving from our discoveries would ultimately go back to the site owner and/or local community," he says. Paul Horn, president and chief operating officer at Booth Energy, which runs the Matrix mine, wonders if natural drug discovery might be a reason to keep on drilling long-term—but for now he's happy to let any researcher simply collect some dirt. "It's pretty neat because a lot people think coal is bad or dirty," he says. "Who wouldn't want to help cure something?"