Rather than culturing soil bacteria one by one in a search for new medicines, chemists at Cornell will collaborate with molecular biologists at the University of Wisconsin-Madison to produce a kind of whole-earth catalog of all the genes responsible for potentially useful natural products in thousands of different microbial species.
The ambitious effort to access the chemical diversity of soil life by cloning the collective genomes of soil bacteria -- the so-called metagenome of microbes -- and determine the function of various biosynthesis genes is supported by a $960,000 grant from the David and Lucile Packard Foundation's Interdisciplinary Science Award program. The award for the five-year project is made to molecular biologists at the University of Wisconsin, who will collaborate with a Cornell chemistry group led by Jon Clardy, the Horace White Professor in the Department of Chemistry and Chemical Biology.
Ultimately the investigators are searching for the next streptomycin, FK506 or actinomycin D, the antibiotic, immunosuppressant and anticancer agent, respectively, that came from soil-dwelling microorganisms. Those drugs were discovered by culturing microbes in soil samples in a nutrient, such as agar, and growing enough of each variety to collect metabolites, the chemicals that microbes "learned" to make for their own purposes during eons of competitive interactions with other organisms.
But some of the most promising microorganisms -- including many of the estimated 1,000 to 10,000 unidentified species awaiting discovery in any given gram of soil -- cannot be cultured by traditional techniques available to microbiologists. So the Wisconsin-Cornell team hopes to "culture the unculturable" by taking advantage of a trait that soil microbes seem to have in common: All the genes responsible for biosynthesis of natural-product metabolites are clustered together on one contiguous and easily captured piece of DNA in the producing microbe.
Using molecular biology techniques, the investigators plan to move DNA fragments with natural-product genes from each unculturable microbe into bacterial hosts that can be cultured, such as E. coli and Bacillus. They will clone the gene-based pathways for metabolite production with bacterial artificial chromosome (or BAC) vectors and encourage the hosts to make another organism's natural product (through heterologous expression).
The Wisconsin-Cornell collaboration estimates that roughly 1 million clones should be enough to outline the metagenome of the soil. Without recent advances in DNA cloning, nanoscale screening of chemicals for biological activity and genomics information-management techniques, such a project would not be feasible, the investigators say.
In proposing the microbial metagenome project to the Packard Foundation, Wisconsin biologists Jo Handelsman and Robert M. Goodman and Cornell's Clardy said the power of their approach "lies in the fusion of chemistry and biology to dissect one of the most complex problems in modern science -- the biological and chemical diversity of soil, the richest environment on Earth." Foundation advisers apparently agreed, selecting the Wisconsin-Cornell project as one of 11, from a field of more than 100, to be funded in the first year of the Packard Interdisciplinary Science program.
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