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For TIGR and Venter, the Goal Now Is to Sequence Entire Ecosystems at a Time

NEW YORK, July 22 - Creature by creature, the natural world is steadily yielding its secrets to the genome sequencers. Life forms move through decoding machines like beasts through a high-tech ark: first bacteria, then people and poodles, now rice, mice, and cattle.


But the sequencers are getting restless. Eager to push the envelope, microbiologists at The Institute for Genomic Research and at Craig Venter's new Institute for Biological Energy Alternatives have an ambitious new goal: to decode the microbial world an ecosystem at a time.


Researchers hope that this genomic approach could provide, for the first time, an accurate picture of the entire range of microbial species in one environment, and also provide a new view into the complex dynamics among organisms, and between organisms and their surroundings.


This idea is now being tested at TIGR, where Karen Nelson and Steven Gill are probing the flora of the human gut by sequencing the entire population of bacteria at once.


"You can think of [this population] not as 200 bacteria, but as one organism," said Gill. "We want to know: What genes are in that 'organism' and which contribute to disease and healthy states?" 


The technique removes one enormous stumbling block in microbial research: the need to culture bacteria. Only a tiny fraction of these tiny creatures have ever been coaxed to survive in the lab, and they are often not the most common or significant organisms in their ecosystem.


"Given that we only know about 1 percent of what's out there, sequencing and assembly seems to be the best way to get to it," said Nelson.


Venter has championed this approach as an obvious next step for whole genome-shotgun sequencing. Success assembling the human and mouse genomes "showed us that we could work at scales far beyond what anybody had anticipated," he said.


Researchers at IBEA hope to use large-scale sequencing to gain new insight into energy production by examining how microorganisms capture carbon dioxide and produce hydrogen, Venter explained. Their first project, in conjunction with TIGR's Nelson, is to examine the microbes in the Sargasso Sea.


"It's been obvious for some time that we could use whole genome shotgun to deal with whole environments," Venter added.


In fact, said Venter, it was an accidentally contaminated sample of Streptococcus in a TIGR lab that first indicated that sequencers could tackle higher organisms: the algorithm accurately assembled two genomes instead of folding the two into one.


Using Celera's assembler, IBEA researchers have successfully tackled a test brew of 100 organisms.


It remains to be seen whether these powerful sequencers and algorithms can tackle the enormously complicated task of decoding and reassembling a real cocktail of hundreds of genomes.


Nelson and Gill will first make a small insert BAC library to generally characterize the phylogenetic diversity found in five samples of healthy human gut.


Next, they'll put these samples--which may contain as many as 500 species of microbes--through random whole genome-shotgun sequencing. Using TIGR's assembly software to crunch the data, the pair will piece together parts of the few hundred most-dominant species and hope also to assemble low-coverage whole genomes from the 10 or so that are most common.


The team got a grant of roughly $500,000 grant from DARPA earlier this summer to launch the project.


They have already put the TIGR assembly program through its paces with a test sample that included 38 different genomes. It performed well, taking about four hours to tease apart and reassemble the organisms, they said.


Nelson and Gill admit the task is daunting. The idea has been widely discussed in microbiology since a Monterey Bay Aquarium Research Institute oceanographer proved earlier this spring that a BAC-by-BAC approach can be used to identify new marine bacteria. Few institutes, however, can muster the computing power and software muscle to take it on.


"The whole idea is pretty risky," said Gild. "I've heard it called stupid. But I think it's important for us to do."


If it works, though, the technique will for the first time paint a comprehensive portrait of the families of bacteria, archaea, and fungi that thrive within our bellies.


"Basically, it's just a natural evolution of the thinking," says Gill, who studies staphylococcal organisms "The human genome is finished. If you think of the human body and its interactions, there are more bacterial cells in the body than somatic cells. That bacterial population has an impact on human health and disease."


And the technique could provide a valuable new launching point for understanding bacterial ecosystems. "Most microbial physiology starts with seeing if you can get something to grow on agar," said Venter. "But starting with the genetic code is not a bad place to begin."

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