Sans organism, scientists harvest a trove of DNA

On an overcast spring day, Doreen Gillespie prepares for the hunt.

Gathering a soil auger, a spoon and some tinfoil from a van, Gillespie strides over to an 8-foot-by-8-foot plot, her hunting ground, and prepares to gather a sample of soil that teems with unknown life. If she’s lucky, the dirt she so carefully collects will, in fact, be pay dirt — soil that will yield a trove of genetic information new to science and that may result in a new antibiotic or other lifesaving medicine.

“The overall goal is to use unknown resources in the soil,” explains Gillespie, a post-doctoral fellow at the UW–Madison. “The resources we are looking at are microorganisms.”

Framed more narrowly, the resource Gillespie is tapping into is the microbes’ DNA, genetic instructions for microbe-made chemicals – antibiotics, insecticides, anticancer drugs, antiparasitic agents, and others – that now can only be imagined.

These biochemical secrets are locked away in microorganisms – there may be thousands of different species of bacteria in a single plug of soil – and the majority, perhaps as much as 99 percent, scientists are unable to tame in the lab and, therefore, are largely unknown to science.

“If there are all these different kinds of bacteria, there must be all kinds of chemicals that they’re making,” says Jo Handelsman, a professor of plant pathology and a leader of a project aimed at creating vast libraries of new genetic information from the soil. Indeed, soil microbes, scientists know, live in close relationships with other organisms in the same niche, and they almost certainly depend on the chemicals they make for everything from defense to communication.

“We actually don’t know much about soil microbes and the lives they live,” says Handelsman.

The simple fact that most soil microbes cannot be cultured and studied in the laboratory has prompted Handelsman and colleagues Robert Goodman, also a professor of plant pathology, and Jon Clardy, a Cornell University professor of chemistry, to embark on a novel quest to harvest the hidden potential of soil microbes and the chemicals they make.

The promise of this genetic mother lode is great. The relatively few soil microbes that can be grown in the lab have already yielded a host of helpful products, from critical antibiotics and anticancer drugs to antifungal compounds and herbicides.

Moreover, the techniques being developed by the Wisconsin-Cornell team could potentially be extended to the other domains – insect gut, the deep ocean, fresh water lakes, hot springs – where microbes abound.

“More drugs come from soil organisms than from any other habitat on Earth,” says Handelsman. “Soil will be the richest environment but, technically, it is also the hardest. If we can do this with soil, we think we can do it with material from any environment.”

Last month, Handelsman, Goodman and Clardy published a paper in the journal Applied and Environmental Microbiology that describes the construction of the first libraries of genetic information gathered from pools of soil microbes. The team has also uncovered the first hint of a new antibiotic.

The libraries are created by taking sieved soil samples and exposing them to a freeze-thaw cycle that cracks open the bacteria and allows access to the microorganism’s DNA, which is retrieved by precipitation of a solution. After further preparation, the DNA is cloned into a plasmid, a genetic vector that can insert itself into an E. coli bacterium, the microbiologist’s lab rat. Once there, the new-found DNA can be probed and tested for hints of chemical properties that could be useful in the clinic, on the farm or in industry.

“Since there are so many different environments in the soil, the likelihood of finding different organisms and different chemistries is high,” Goodman says. “The world is full of microorganisms that have learned, chemically, how to get along, how to communicate with, how to influence other animals. It might turn out that they’re making chemical molecules that turn out to be useful to people.”

Still, true success will probably only come from a combination of hard work and luck. Not only are there many, many organisms in the soil, but the amount of DNA collected is vast, and much of that is apparently useless. And a chemical activity, an antibiotic activity, for instance, requires many genes meaning that the piece of DNA responsible must be relatively large.

The mother lode, according to Gillespie and her colleagues, are chemicals that would have some pharmaceutical property such as a growth regulator, a chemical that might inhibit the growth of cancerous tumors, or an antibiotic to augment the world’s shrinking supply of drugs to combat infection. But the risk, they argue, is balanced by a potential payoff of harvesting many new and useful chemicals from, literally, beneath our feet.

“It is relatively high risk,” Gillespie says. “But I don’t think there’s any doubt something will come of it. It’s just a matter of when and what.”