More than 50 complete microbial genome sequences have been deciphered since the publication of the first in 1995. These sequences offer scientists an unprecedented opportunity to study cellular life in its simplest form and to begin understanding how nature orchestrates the activities of living systems.

This opportunity is at the root of DOE's new Microbial Cell Project (MCP), begun in 2001 by the Office of Science's offices of Biological and Environmental Research (OBER) and Basic Energy Sciences (OBES), allied with the Office of Advanced Scientific Computing Research (OASCR). OBER and OBES contributed $12 million and OASCR $3 million through its Advanced Modeling and Simulation of Biological Systems Program. The challenges are great. Although the complete list of life's working parts for sequenced genomes is now online, many perform unknown functions. Additionally, little is understood about how and when the parts function together in living cells and respond to environmental changes. Gaining an understanding of the complexities of systems-level functioning also requires new ways of thinking and collaborations with scientists from such other disciplines as engineering; chemistry; physics; and the computer, imaging, and even management sciences.

Why Microbes?
Microbes have evolved for 3.7 billion years and have colonized almost every environment on earth. In the process, they have developed an astonishingly diverse collection of capabilities that can be used to help DOE meet its challenges in toxic-waste cleanup, energy production, global climate change, and biotechnology.

Additionally, their internal organization and complex regulatory systems allow microbial cells to adapt to a myriad of environments. They work as miniature chemistry laboratories, making unique products and carrying out functions specific to their environmental conditions.

Understanding the complex functioning of a single microbial cell ultimately will enable science to go far beyond just exploiting the beneficial capabilities of microbes to meet DOE's missions. Much of the knowledge gained will apply to cells in all living organisms. The MCP thus represents a first step in moving from cataloguing molecular parts to constructing an integrative view of life at the level of a whole organism microbe, plant, or animal.

Goals
The MCP has four main goals:

* Determine how microbial proteins combine into molecular machines that fulfill many of life's important intracellular processes.
* Characterize the internal cell environment and its effects on the proteins and protein machines that perform functions relevant to DOE missions.
* Characterize the intracellular distribution, quantities, and fluxes of the proteins and protein machines inside a microbial cell.
* Use high-end computing to model gene-to-gene, gene-to-protein, and protein-to-protein interactions and the cell's internal biochemistry.

In addition to working with academic, nonprofit, and industrial partners, DOE will take advantage of the scientific capabilities of its national laboratories. These capabilities include high-throughput genomic DNA sequencing, microbial biochemistry and array development and analyses; physiology; very high resolution imaging; and structural biology. National user facilities such as synchrotrons will play important roles, as will high-performance computing.

The MCP's ultimate aim is to learn enough about cellular functions so they can be manipulated knowledgeably to enhance beneficial and suppress unintended effects. MCP planners are well aware that it is premature to explore manipulations or interventions. Given the complexity of metabolic networks in even the simplest cell, such actions would be analogous to throwing the proverbial monkey wrench into a complex machine; the outcomes most likely would not be useful and informative. When greater knowledge is gained about the parts, their interactions, the functional pathways to which they belong, their partners in biochemistry, and their temporal and spatial distribution within the cell, these interventions if and when they merit exploratory research can be more precise and predictable.

The MCP is as bold and major an undertaking as DOE's Human Genome Initiative was in 1987. Much of the MCP's research appeal stems from the simple fact that this is where the science is leading. Like fortunate children with their first Lego set who have seen the pictured item and know it can be built, we have opened the box and found the pieces. The instructions are missing, however, so we must complete the construction through experimentation. Fortunately, we can build on decades of intense biological research to make the job easier.