It may sound like a diet plan or a new-age religion, but to microbiologists, metagenomics is something far more important: a new way of looking at the world.
The microbial world, that is. That teeming universe of microscopic organisms swirling around us and inside us, affecting almost everything we do. Since Van Leeuwenhoek, the study of this world has depended on isolating single species and growing them in pure culture. There are major drawbacks to this approach, however. First, the vast majority of microbes-99 percent, by many estimates-cannot be grown in the laboratory. Second, microbes outside the lab live and interact in complex, delicate communities which can't truly be understood by their isolated components. By harnessing the power of genomic analysis, metagenomics offers a first-ever look inside these living systems.
While genomics is the study of an individual organism's DNA code, metagenomics transcends the individual genome. Taking advantage of dramatic advances in DNA-sequencing technology, this new approach allows the study of entire communities of microbes simultaneously, bypassing the need for isolation and culture.
"What you do," says Ming Tien, Penn State professor of biochemistry, "is you go into the environment you want to study and extract all the DNA that's there." The resulting sample is an alphabet soup, the genetic information of every organism present. But today's sequencing technology, Tien says, is powerful enough to sort out the mess.
"Basically, you sequence in small fragments and you assemble the genomes based on overlapping sequences," he explains. "It's impossible to put together an entire genome, but what you end up with are representative sequences, which give you a pretty good idea of the genes-and the organisms-that are there."
The "environments" ripe for metagenomic analysis range from desert hot springs to deep-ocean vents, from crime scenes to human gastrointestinal tracts. The potential gains for applications in medicine, alternative energy, agriculture, and many other fields, as well as for fundamental biology, are enormous.
At Penn State, metagenomics has played a key role in two recent high-profile discoveries. Working with colleagues in Europe and the U.S., genomicists Stephan Schuster and Webb Miller used the approach to obtain the first genomic sequence from a prehistoric woolly mammoth, an important breakthrough in the sequencing of ancient DNA. And biochemist Don Bryant, with colleague David Ward at Montana State, used it to uncover a brand-new phototrophic bacterium in the hot springs of Yellowstone National Park.
Tien is part of another Penn State team using metagenomics for what he calls "bioprospecting." With entomologist Kelli Hoover, molecular geneticist John Carlson, plant pathologist Maria del Mar Jimenez-Gasco and graduate student Scott Geib, he has isolated DNA from the intestinal tract of the Asian longhorned beetle, an invasive pest that is particularly adept at digesting maple trees and other hardwoods. By sequencing all the genes they find in the insect's gut, the team hopes to discover a new enzyme that might be useful for breaking down lignin, a crucial step in the making of ethanol from woody plants for biofuels.
Until recently, Tien notes, such a blanket approach would have been unthinkable, but "sequencing technology has advanced to the degree where it's possible now to get fairly good coverage of all the DNA you isolate.
"A story I like to tell is that when I came here in 1985 I was working on sequencing the gene encoding the first lignin-degrading enzyme. I sequenced a total of 3,000 base pairs and it took me three months," he adds. "Now at the Huck Institutes, they can sequence four million base pairs in four hours. It's probably even faster than that now.
"The point is the sequencing is allowing us to study systems which we couldn't really study before. Before metagenomics, all these organisms were invisible to us."