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Down in the Dirt, Wonders Beckon

For more than a decade, Jo Handelsman had tantalizing glimpses of an elusive microscopic world she could not enter. When she put samples of soil under the microscope, she saw countless species of organisms she couldn't identify. But efforts to isolate and grow these microbes in the lab failed, and she couldn't learn much about them. Except for one thing: Genetic and statistical analyses revealed that these unknown organisms must make up 99.9% of all the microbes in the soil. One gram of soil--the weight of a little packet of low-calorie sweetener--can contain as many as 10,000 species unknown to science, says Handelsman, a professor of plant pathology at the University of Wisconsin.

Now, for the first time, she and her colleagues, along with several other research groups working independently, are learning to extract the DNA of these mysterious creatures and clone it. They are finding that the microbes differ so profoundly from known bacteria that they could represent entirely new kingdoms of life--as different from other bacteria as animals are from plants. That means that the proteins produced by these creatures could have properties unlike any other such substances known.

Most current antibiotics come from microbes in the soil. They include streptomycin, the first treatment for tuberculosis, and vancomycin, currently the drug of last resort for the toughest infections. By now, however, conventional bacteria have been largely "mined out": Most of their useful properties have already been exploited. Researchers say that studies of the palette of novel biological agents Handelsman and others are discovering could lead to a new wave of medicines, anticancer drugs, insecticides and industrial enzymes, many radically different from those already in use.

The research builds on earlier studies of exotic microbes that live in boiling pools in Yellowstone National Park, at steaming volcanic vents on the sea floor, and in other forbidding locales. These so-called extremophiles--named for their affinity for extreme environments--were crucial in the development of one of molecular biology's most useful tools, a method of extracting and studying DNA called polymerase chain reaction, or PCR.

In a report in mid-November at the annual New Horizons in Science briefing in Tempe, Ariz., Handelsman said she and her colleagues at Wisconsin have already identified several new antibiotics from soil microbes, at least one of which is also proving to be a powerful pesticide. And in California, Edward F. DeLong and his colleagues at the Monterey Bay Aquarium have found a distinctive light-sensitive protein that could have applications in optical computers. They expect these to be only the first of many more such discoveries from a field of research known as metagenomics, or environmental genomics.

DAZZLING VARIETY. The field has led, among other things, to a new view of biological diversity. The dazzling variety of tropical rainforests, it turns out, is dwarfed by the unseen diversity in the microbial world. To take one example, a single gram of sediment on the ocean floor contains 1 billion organisms, says one of the field's pioneers, biologist Norman R. Pace of the University of Colorado. Dig down about one-third of a mile to an even more forbidding environment, and the sediment still contains about 10 million microbes per gram. The microbes in that 500-meter-thick layer of ocean floor make up 10% to 20% of all the biological matter on earth, Pace says. They include uncounted numbers of species unknown to science.

Even human intestines--an environment most people consider pretty familiar--are home to perhaps 10,000 kinds of microbes. "I've been blown away by the diversity there," says Pace, whose work was recognized in October with a MacArthur Foundation Fellowship. Indeed, one of the surprises in the decoding of the human genome was that it contains more than 200 genes that come from bacteria. Microbes not only keep us alive; in some small part, we are made of them.

Pace is looking at how these largely unknown microbes might play a role in Crohn's disease, an inflammation of the small intestine. He has found that the makeup of the mixed "community" of microbes in the intestines changes in people with the disease. A similar thing might happen with tuberculosis, Pace says, leading him to wonder whether some diseases might be caused not by a single dangerous microbe but by a change in the microbial community--an ecological imbalance inside the human body.

Handelsman and Michelle R. Rondon, formerly of the University of Wisconsin and now at Ohio State University, have done most of their work with soil obtained from a University of Wisconsin research station 15 minutes from their lab. They devised a technique for isolating long pieces of DNA from soil, something that other researchers had assured them could not be done. Because soil is full of contaminants that can interfere with the finicky chemicals used to isolate DNA, it was a trial-and-error process--and in the beginning, it was mostly error. Rondon's persistence paid off, however, and the researchers learned to extract strings of DNA from soil long enough to contain 50 to 80 genes. Some of this DNA came from known organisms, of course, but most of it came from the vast profusion of unknown organisms that couldn't be grown in the lab. "This sent shivers down our spines, because it was the first glimpse we had of the uncultured world," Handelsman says.

One of her primary interests is the development of new antibiotics, and her earlier work has already led to several new candidates. One of them, called Zwittermicin A, is effective not only against bacteria but also against gypsy moth caterpillars. When used in combination with Bt toxin, one of the most widely used pesticides for gypsy moths, it greatly enhances Bt's effect.

Handelsman suspected that Zwittermicin A might alter the way Bt is handled in the digestive system of the caterpillars, making it more lethal. To find out, she turned her DNA extraction techniques on the microbes in the gut of the caterpillars--where she was surprised to discover 36 kinds of bacteria, more than two-thirds of which had not been seen before and many of which may be markedly different from known bacteria. The search for an answer had led to a batch of new questions.

WAVELENGTHS. The development of new antibiotics is also the aim of Julian Davies, a microbiologist at Cubist Pharmaceuticals Inc. (CBST) and at the University of British Columbia. He is pursuing a different set of organisms that are also difficult to study: lichens. "Most of them will not grow in the lab," he says. "The way to get at them is to get at their genes." Davies and his colleagues have been able to extract many antibiotic-related genes from lichens. Like Handelsman, he is working with strings of DNA long enough to contain the complete set of genes that may be needed to manufacture an antibiotic--the whole antibiotic pathway, as researchers say. "I think we're a long way from finding the next superdrug from this approach," he says. But lichens "make a lot of interesting biologically active compounds."

DeLong and his colleagues have done similar DNA extraction using seawater samples from Monterey Bay. One of their first discoveries was that organisms near the surface of the sea carry proteins that can use sunlight to make energy. Plants do that through photosynthesis, but this alternate system was unknown. Furthermore, the researchers discovered that microbes at different depths responded to different wavelengths of light--corresponding to the changes in the color of sunlight as it penetrates deeper into the ocean and is partly absorbed. The proteins' light-sensing ability could make them useful in the construction of optical computer memory, DeLong says.

Handelsman, DeLong, and the others are confident their research will lead to new medicines and other useful products. But part of their excitement is the exploration of a new world as mysterious, alien, and beguiling as the surface of Mars--and a lot easier to get to. By Paul Raeburn in Tempe, Ariz.

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