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1 Introduction n 1674, in the Netherlands, Anton van Lecuwenhoek placed a drop of pond water under a glass that he had ground and saw a community of microorganisms never before seen by humans. He called the creatures animalcules. Two centuries later, a French scientist, Louis Pasteur, identi- fied a set of animalcules that required no oxygen for life. Pasteur soon uncovered the extraordinary role of these microorganisms in the universe. By the ebb and flow of their own respiration, they connect the living and mineral worlds and recycle the nutrients that sustain life on Earth. Pasteur called these organisms anaerobes. Today, 150 years after Pasteur's dis- covery, a lot more is known about the important role of microorganisms on Earth for example, they produce diverse sources of energy, including methane and hydrogen, and they influence biogeochemical cycles. How- ever, given the number of microbial species on Earth and the complexity of microbial ecosystems, many aspects of microorganisms and of the commu- . . , . Sties t" fey torm remain a mystery. Microbiologists have become interested in applying "systems biology" to understand and harness complex biological processes in microbial com- munities. Systems biology has been defined by Ideker et al.i as an approach to study "biological systems by systematically perturbing them (biologi- cally, genetically, or chemically); monitoring the gene, protein, and infor- mational pathway responses; integrating these data; and ultimately, formu- iIdeker, T., T. Galitski, and L. Hood. 2001. A new approach to decoding life: Systems Biology. Annul Rev. Genom. Hum. Genet. 2:343-372. 1

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2 PROMISE AND CHALLENGES IN SYSTEMS MICROBIOLOGY rating mathematical models that describe the structure of the system and its responses to individual perturbations." A systems approach, which at- tempts to use comparative, high-throughput assays, and mathematical or computational models, has been used to generate a picture of system-wide activity that can yield insight into processes operating within a single cell. But the concept of integrating advances in genomics, proteomics, and metabolomics and incorporating them into mathematical models can also be applied to microbial ecosystems, which typically occur in consortia of related and unrelated organisms. Research on microbial communities using a system-based approach could provide a broader perspective on controls on biological processes and how they operate in and among microorganisms. The US Department of Energy (DOE) sponsored a National Research Council workshop on "Progress and Promise of Systems Microbiology" that complements its Genome to Life program (GTL). GTL's key goal is to attain a basic understanding of thousands of microorganisms and their com- munities in their habitat and to apply this knowledge toward clean energy production and bioremediation. This workshop, held on August 19, 2003, in Washington, DC, was intended to be a forum for discussion of the tools, technology, and programs that are needed to advance the study of microor- ganisms through a systems approach. Although some infrastructure for systems microbiology such as high- throughput DNA-sequencing tools and methods is similar to that needed for other genome projects, it also requires additional tools to address issues specific to microbial communities; for example, metagenomics (that is, the analysis of the sum of all genomes in an environment) will facilitate studies of microbial communities. This workshop examined the tools and infra- structure needed to advance systems microbiology. In addition, workshop participants discussed ways to encourage collaboration among scientists of different disciplines because "the combined capabilities and imagination of biological, physical, and computational scientists will be needed to organize creative new venues for discovery," as stated by Frazier et al.2 2Frazier, M.E., G.M. Johnson, D.G. Thomassen, C.E. Oliver, and A. Patrinos. 2003. Real- izing the potential of the genome revolution: The Genomes to Life program. Science 300:290- 293.