Links to Other ASM Pages:

• Table of Contents
• ASM News Issues

Officials in the Department of Energy (DOE) intensified planning efforts this spring for their ongoing microbial genome research programs along with a nascent microbial cell initiative, part of a far-reaching post-genomics program. Despite evident enthusiasm, plans for this initiative were still vague late in April, when members of the DOE Biological and Environmental Research Advisory Committee (BERAC) met in Washington, D.C., to help officials shape those plans. DOE officials say that the microbial cell initiative could be considered a pilot project for a much larger undertaking—one that entails developing, in collaboration with other federal science agencies, a broad understanding of how living cells operate.

As part of its fiscal year (FY) 2001 budget request, DOE is asking $22 million for continuing microbial genome work, increased by $8 million over the current level, and $12 million for the proposed microbial cell initiative. Part of the selling point for that initiative is the continued, rapid progress being made on the broadly defined genome front. DOE scientists recently completed draft sequences of human chromosomes 5, 16, and 19 ahead of schedule. On the microbial end of the genomic spectrum, more than 100 microbial genome projects are under way and about 30 have been completed, according to BERAC member Claire Fraser of the Institute for Genomic Research in Rockville, Md. Moreover, researchers collaborating with the staff at a new DOE genomics facility recently sequenced the genome of Enterococcus faecium in one intensive day’s work (see box).

Those 30 or so microorganisms include 16 pathogens, five bacterial nonpathogens, five archaea, one eukaryote, and three chromosomes from the parasite responsible for malaria, Fraser says. Although these efforts involve other federal agencies, particularly the National Institutes of Health (NIH), and private-sector sponsors as well as DOE, there is little doubt that they are rocketing ahead while providing a sweeping new view of microbial genetics. Because of obvious technical difficulties in obtaining adequate supplies of pure DNA, several major types of microorganisms are missing from the current mix, including those that cannot be cultivated in the laboratory and those that grow as part of microbial communities, she points out.

Nonetheless, within the next two or three years, some 120 microbial genomic sequences will be in hand, ready for more sophisticated analysis, according to Fraser. Meanwhile, the sequences that are available offer several surprising insights. For instance, the number of still-undefined and otherwise unexpected gene sequences is far greater than expected, accounting for about half the DNA sequenced so far and suggesting as many as 50,000 novel genes among those several dozen microbial species. Moreover, the pattern of variation in single gene types does not necessarily parallel how the microorganisms in which they are situated appear to have evolved; instead, the pattern seems consistent with frequent, perhaps promiscuous, gene exchange among distantly related microorganisms.

DOE officials say that microorganisms are identified for genomic analysis mainly on the basis of one-day "which bugs" workshops in which microbiologists from the broader research community participate in a consensus-building process. Because of the department’s mission, those choices are biased in favor of particular interests, such as bioremediation, energy production, carbon management, or irradiation mutation damage responsiveness.

This surge in genomics has DOE officials and many of the academic and private sector researchers who work with them looking for ways to put those microbial genome-based insights to use on topics of still-broader biological research impact. Hence, the microbial cell initiative for FY 2001. Although the short-term focus is on the relatively tractable microbial cell, these efforts are recognized as a springboard for an even more ambitious program, which still lacks an agreed-upon title but which centers on plans for comprehensive, post-genomic, multidisciplinary analysis and modeling of the behavior of more complex eukaryotic living cells.

Although bacterial cells are simpler than their eukaryotic counterparts, modeling at the prokaryotic level remains a daunting task. Even a relatively simple bacterial cell contains some 10¹⁰ molecules of about 4,000 types, according to BERAC member Adam Arkin of Lawrence Berkeley National Laboratory. Thus, modeling bacterial cell behavior is not so easy, based on preliminary attempts involving several extensively studied bacterial behaviors, including chemotaxis, fimbriation, sporulation, and lysogeny of lambda phage. A major difficulty is that experiments on the "same" behavior conducted in many different laboratories almost always differ in many subtle ways, further complicating the use of accumulated data to build centralized models, he says.

One critical part of the microbial initiative will entail an extended analysis of the novel open reading frames (ORFs) and the important non-protein-coding regions within genomes, some of which are presumed to be regulatory sequences. How all those regulatory sequences will be identified and analyzed is difficult to predict at this point, but some leading biologists are saying that a systematic rather than a case-by-case approach would be a more efficient strategy to follow—at least insofar as they tackle cis-acting regulatory sequences during this early phase. These efforts also are expected to rely heavily on bioinformatics providing new ways to recognize patterns that may be embedded within raw genomics and post-genomics data sets.

Another critical matter facing DOE officials and members of BERAC is their short-term choice of a bacterial model system or systems on which to focus. Here again, DOE officials appear to recognize more keenly the need to choose a microorganism that satisfies departmental mandates than do members of the advisory committee.

Biologists who work on multicellular eukaryotes and who study complex developmental processes are among those advising DOE on these initiatives and suggesting where to aim for the longer term. For instance, BERAC member Barbara Wold of the California Institute of Technology in Pasadena urges that this venture eventually move toward understanding the 400 or more distinct cell types that are found within

an adult mammal and how they work together while maintaining their distinct identities. Addressing such questions will entail looking at how genes work in ensembles, and how those ensembles are regulated, perhaps through very subtle changes in concentrations of gene end-products, she says. For several reasons, she recommends identifying regulatory elements in several—at least three—evolutionarily distinct animal model systems.

Jeffrey L. Fox