Microbial biology to yield biomedical harvest

Two major microbiology projects funded by the US Department of Energy — Genomes to Life and the Microbial Cell Project — may result in the development of virtual cells that enable researchers from a number of different fields to explore cellular behaviour under different conditions.Microbes, more than any other organism, have the potential to facilitate the development of novel applied biotechnology and advances in basic science, the US Department of Energy (DoE) has long been interested in microbes. In 1994 it established the microbial genome project to sequence microbes.Now the DoE is funding two research projects aimed at exploring what the wealth of microbe sequence data that exists (the complete sequence of upwards of 50 microbes is known) can offer biologists looking to understand basic cellular processes as well as those specifically interested in understanding microbial cellular structures and functions.The purpose of the work is to meet the DoE's remit of environmental clean-up and energy production, but, even though most microbes are harmless, the knowledge gained will be of value to the biomedical community interested in pathogenic microorganisms. "There is plenty of evidence," said Dan Drell, a biologist and programme manager for the microbial cell project, "that it takes just a slight tweak to make a harmless microbe pathogenic. Take anthrax, the differences between it [Bacillus anthracis] and harmless relatives are small."Microbes are fascinating because of their adaptability and varied nature. Faced by a novel ecological niche, any self-respecting bacterial microbe knows what to do — evolve. It may take a billenia or two, but the bacterial response to environments ranging from the inside of Antarctic rocks to the waters around deep-sea hydrothermal vents is consistent: let natural selection fine-tune the biology, and then thrive.Those surroundings may be toxic to humans and have extremes of temperature, pressure, salinity or darkness, but, in the course of adapting to their environment, microbes have developed the potential to perform tasks useful for human beings.For instance, the harmless aquatic bacterium, Caulobacter crescentus, can, "convert mercury, copper, cadmium, cobalt and other heavy metals into chemical forms that are less soluble and less toxic to people," explained Alfred Spormann, Associate Professor of Civil and Environmental Engineering at Stanford University, making the microbe a potential agent for environmental clean-up.Yet for all their biodiversity, microbes are unicellular organisms with manageably-sized genomes (in the order of a few thousand genes compared to the tens of thousands in the human genome). This makes them promising experimental candidates for scientists interested in exploring the relationship between a genome and the basic biological workings of a cell.It is this twin allure of novel biotechnology to meet its remit of environmental clean-up and energy production as well as the potential for basic biology that persuaded the DoE to build on its Microbial Genome Project with two initiatives: Genomes to Life (GTL) and the Microbial Cell Project (MCP).The newest of the two is the Genome-to-Life Initiative. It is a development of the MCP, and it received its first funds — of just under $20 million for fiscal year 2002 — in November 2001.Genomes to Life has a 10-year plan, developed in response to a request by Martha Krebs — former director of the DoE's Office of Science — in 1999 for the DoE to determine what the next stage of its contribution to the human genome project should be.The initiative intends to use DNA sequences from microbes and higher organisms, including humans, to explore some of the common essential processes of living systems. It will focus initially on microbes, reported Drell, because of their comparative simplicity and the amount of available sequence data.GTL will solicit research proposals looking at protein-protein interactions, protein complexes, protein concentrations and locations at different stages of the cell cycle, gene-regulation networks and the functional diversity in microbes. "Biologists now need to make a 180 degree shift in their thinking [from genome sequencing] to become reconstructionists," argued Drell, who, besides his role in MCP, is a member of the GTL team.Just over half of the funds allocated for GTL in 2002 will be awarded to new research, the remainder will fund the second year of the existing Microbial Cell Project.MCP, which received $15 million in fiscal year 2001, made 11 awards to multidisciplinary teams this summer. Research got underway in the autumn and will last three years. The programme is now being subsumed under the GTL initiative.The ultimate aim of the MCP is to build sufficient knowledge of the detailed functioning of microbial cells to enable scientists to 'manufacture' microbes to undertake tasks that fall within the DoE's remit. The genome-to-life initiative is also driven by DoE's goals, but will eventually look beyond microbes alone in search of new technological solutions to environmental clean-up and energy production.MCP is taking what DoE officials call a 'whole genome' approach, exploring the relationship between the whole genome and a single specific organism. For example, researchers led by Michael Daly from the Uniformed Services University of the Health Sciences want to explore all the mechanisms that lead to the bacteria, Deinococcus radiodurans, being highly resistant to acute and chronic radiation exposure. Another team, led by Harley McAdams at Stanford, will work with the model microbe, C. crescentus to explore its regulatory pathways during cell reproduction.Yet the MCP does not want to stop with an understanding of individual cell pathways. Its aims, and those of the genome-to-life project, are far more ambitious. The development of new mathematical and computational tools to model cellular processes is an important element of both projects. At some distant date, such models might lead to virtual cells with the potential to provide researchers from all areas with in silico tools for exploring cellular behaviour under different conditions. "We were not born yesterday," said Drell, "so we know the Mount Everest scale of thoroughly understanding and modelling even one cellular pathway," he said. But, he argued, the DoE has the necessary computing power, so a step on the road to building a virtual microbial cell 'in silico' is worth taking. "And," he added, "you've got to start somewhere."Bacterial microbes, the most ancient life form on Earth, seem as good a place to start as any.

Microbial biology to yield biomedical harvest

New initiatives launched by the US Department of Energy aim to extract practical benefits from the vast amount of microbial genomic data available.

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