A Scientific Marriage

Dynamic due brings life-saving,
forest-preserving research projects to UM

Andrea and Don Stierle have a knack for discovery. Their chemistry labs may be modest, but their inquiries are bold, from curing cancer to preventing mountain pine beetles from boring into trees.

“We have been very lucky for such a small lab to have a lot of eureka moments — a fungus that produces Taxol (an anti-cancer drug), a bacteria that produces a compound that targets the AIDS virus and, of course, the microbes in the Berkeley Pit,” Andrea says.

The Stierles joined the research faculty of UM’s College of Health Professions and Biomedical Sciences in 2009, after three decades at Montana Tech in Butte.

As natural-products organic chemists, they look for source organisms in the natural (or unnatural) world that could potentially heal, treat or solve human health or environmental problems.
The married duo gained national fame after finding a host of cancer-fighting organisms (microbes) derived from the toxic mining brew of Butte’s Berkeley Pit. In 2007, that story hit The New York Times and Wired Magazine. You can even watch them in an archived 2006 episode of “The Daily Show with Jon Stewart.”

To survive extreme toxicity, the tiny life-forms produce unique compounds either through mutation, natural selection or switching on dormant genes. Some have shown medical promise in early stage testing, such as attacking ovarian cancer cells or treating lung cancer.

The Stierles alternate time between two labs a mere 100 feet apart but a world apart in look and feel. Open the door to the Small Business Incubator Research lab and breathe in the pungent scent of tree resin. Stacked vertically on shelves are ponderosa pine logs. Each one is part of an ongoing experiment. Many are encased in screened boxes to keep emerging bark beetles from flying off.

There you’ll often find researcher Cliff Bradley, an innovative entrepreneur who has found a fungus that kills bark beetles without harming parasitic wasps and other natural predators. Bradley is the co-owner of Montana Microbial Products, dedicated to finding sustainable solutions to agricultural challenges.

Bradley and the Stierles received a Montana Small Business Innovaton Research grant in fall 2011 to find out if compounds isolated from a Berkeley Pit fungus and from a yew tree fungus could keep the beetles from boring into the trees long enough for Bradley’s spray to kill them. The compounds may prevent beetles from boring into trees altogether. The main objective is to develop an effective, nontoxic spray for individual trees that people value in picnic areas, parks and campgrounds.

In contrast to the pine-scented SBIR room, the Stierle lab features stacks of round plastic petri dishes harboring colorful microbes that demand regular feeding of sugar and yeast. Some are more than 30 years old, reflecting the longevity of their research.

Andrea picks up one of her favorite dishes, which contains a black, coiled yeast blob with one of the stranger origins. The microbe comes from the polluted Berkeley Pit, where the Stierles have isolated more than 50 such organisms and 80 chemical compounds found nowhere else. This one holds special significance. The yeast may have originated in goose poop traced to a 1995 tragedy, when 342 snow geese landed in the pit and died in the poisonous waters.

It turns out the yeast may be beneficial to the cleanup of the Berkeley Pit. The yeast is able to absorb metal salts — such as copper, iron, cadmium and chromium — from its watery surroundings, suggesting its dual potential for bioremediation and secondary ore recovery.

As outlandishly unrelated as the Stierle and bark beetle labs appear, they are closely aligned in methodology. In both settings, the investigations rely on source organisms that produce a suite of compounds called secondary metabolites.

“If we’re diving in the Caribbean and pull up a sponge, we can isolate compounds from that sponge and we can tailor our search toward antiviral agents,” Andrea says, referring to their early career finding of a bacterium that targets the AIDS virus. “Or we can go scuba diving in the Berkeley Pit, pull up microbes, grow them in the lab and search for anti-cancer agents. Or we can work with Cliff Bradley and find compounds that might protect ponderosas from bark beetles.”

“If we extracted you,” adds Don with a bit of an impish grin, “we’d find most of the compounds in you are also in plants, in bacteria and in fungi. These are the primary metabolites we use to make cells, to provide energy and more. We all have a similar metabolism. When we isolate compounds from a microorganism, we are looking for compounds that aren’t produced by you or me.”

The Stierles test the new compounds from secondary metabolites to check for activity of relevance, such as blocking bark beetles from boring into trees. That’s where all those stacks of petri dishes come into play.

While it might seem like a packrat tendency to collect and maintain hundreds of microbes from past research, the Stierles view each one as holding a potential cure or treatment when the time is right.

The new bark beetle research is a classic example of an older investigation being relevant now. One compound the Stierles are testing to prevent beetles from boring dates back to the mid-1990s and a magnificent “eureka moment” — finding a sustainable source for the anti-cancer drug Taxol.

Taxol was originally reported in 1971 as an anti-leukemic and anti-tumor agent derived from the bark of the Pacific yew tree. Over the next 20 years, the need for more Taxol to treat women dealing with breast and ovarian cancers required the harvesting of more yew trees. Unfortunately, yews were in short supply, since many forests that harbored the precious trees had already been clear-cut.

The Stierles saw a problem in need of a solution and began the laborious process of isolating microorganisms from the bark and needles of yew trees in search of a Taxol producer that could be grown in a lab setting. They isolated more than 300 organisms and examined each one for evidence of Taxol production.

Eureka! One previously undescribed fungus growing in a Pacific yew tree near Glacier National Park produced Taxol in culture. The fungus was named after Andrea (Taxomyces andreanae). They published their results in the journal Science and earned 11 U.S. and international patents for the discovery and methods to grow Taxol in laboratories.

The Stierles continued to follow other research into the yew-associated microbes, including a published paper showing one class of compounds that prevented beetles from feeding on Dutch elm trees.

“We always thought it would be fascinating to see if these compounds could actually be used in the fight against bark beetles,” Andrea says. “One of the lovely things about moving our lab from Butte to (UM) is that we are like kids in a candy store. There are people working on bark beetles, on inflammatory disease and on the mechanisms of cancer — and they are willing to collaborate.”

That’s what led them to team up with their longtime colleague Bradley on an SBIR grant. He was intrigued by the idea of a double-whammy treatment on bark beetles of a microbial compound and his beetle-killing spores from the Beauveria fungus. While Bradley’s product is already approved by the U.S. Department of Agriculture for other applications, such as grasshoppers, he wanted to try out a strain specific to bark beetles.

The testing under way uses compounds isolated from the Pacific yew-derived Penicillium, as well as a Penicillium from the Berkeley Pit. The first phase will be completed this summer. If their results show promise, the Stierles and Bradley will apply for a second-phase grant to pursue an intensive field-test study, the next step toward a commercial product.

Meanwhile, the Stierles are delving into another tantalizing project, made possible by UM’s technology, resources and connections.

“We went from the Berkeley Pit to the gut,” says Don, who takes a certain boyish delight in their slimy subjects of study.

The Stierles are examining bacteria living in a healthy person’s abdomen for secondary metabolites that may play a role in stopping inflammation or even cancer. As usual, they’re finding promising early results.

The secret behind the Stierles’ track record of success might lie in their complementary scientific backgrounds and personalities. Andrea’s strength is in biology and chemistry. Don’s forte is pure organic chemistry. Put two bright minds together, and the synapses tend to fire in pioneering directions.

“I’m like a nautilus circling around,” says Andrea of her research style. “Don is very focused. I read papers and look for connections, and Don takes the deep dive. If we were both like me, we’d be going in 10,000 directions instead of only seven or eight.”

Their greatest challenge today is a shrinking pool of federal funding for research. In a competitive field, small labs must have many eureka moments to win grants. Meanwhile, the Stierles continue to ask the big questions, conduct meaningful research, feed microbes and revel in their personal and professional partnership.

“It’s hard work. It’s a lot of hours, but we love what we are doing,” Andrea says.

“We’re very lucky we get to work together and play together,” Don says. “There are not many couples that can do that. We’re very different and complement each other well. That’s the reason small science works for us.”

— By Deborah Richie

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