The ambitious goal of the Alpha Project is to define every chemical reaction in one of the hundreds of biochemical pathways in yeast, mapping the complex signaling pathway like a flowchart so scientists can predict the yeast's reaction to a particular input, such as stimulation by a hormone.

If successful, this would be the first predictive model of any complex organism, essentially reducing it to the level of a machine or computer.

The five-year project will be headed by the Molecular Sciences Institute, a private research laboratory in Berkeley, in collaboration with UC Berkeley, the California Institute of Technology, the Massachusetts Institute of Technology, and Pacific Northwest National Laboratory. The grant from the National Human Genome Research Institute of NIH was announced July 31 by the genome research institute's director, Francis S. Collins, MD, PhD.

A second, equivalent grant went to a collaboration led by Stanford University to examine the genomic basis of vertebrate diversity, using two common laboratory fish as models. Both projects were named Centers of Excellence in Genomic Science, unique centers where scientists from many disciplines explore the genome.

The Alpha Project will attempt to model how yeast respond to external signals, specifically sex pheromones. The pathway involves relaying the signal through the cell membrane and to various sites around the cell, eventually generating a specific behavior - in this case, mating between two different yeast cell types, or sexes. In most, if not all, the hundreds of chemical steps along the way, a protein is somehow modified - added to, snipped or snagged by another protein.

"We will start looking for patterns in the proteins produced by yeast when they're in a particular state, such as stationary phase or proliferation, and then see if we can track the proteins before and after they're modified, or phosphorylated," said UC Berkeley collaborator Julie Leary, adjunct professor of chemistry and director of UC Berkeley's Mass Spectrometry Research Laboratories in the College of Chemistry. "It's a broad sweep attempt: first a top-down approach looking at pattern recognition and then a bottom-up approach doing mass spectroscopy and total structural elucidation of important proteins that we identify along the way."

Mass spectrometry is a sensitive way of measuring the mass of a molecule. With the help of a state-of-the-art Fourier transform ion cyclotron resonance (FTICR) mass spectrometer available in her laboratory, Leary hopes to be able to distinguish between proteins before and after they have been modified, for example, by the addition of a sugar molecule or a single phosphate group. Both types of modifications are used by the cell to trigger reactions or transmit signals.

Leary expects to work closely with Richard Smith at Battelle Northwest Laboratories, with Leary developing methods to detect phosphorylated proteins and Battelle using their equipment to do rapid analyses of many proteins. Leary's share of the award will be about $800,000 over five years.

The head of the project is Roger Brent, PhD, scientific director and president of the Molecular Sciences Institute, who expects that the insights gained from modeling yeast, Saccharomyces cerevisiae, will help target future treatments for disease.

"The Human Genome Project has shown us what proteins are encoded by the genome, but we still don't know very much about how individual proteins within cells interact with each other to cause diseases or other complex outcomes. Our work aims to understand this choreography so that we can predict the results of cellular changes, and ultimately, how certain changes contribute to disease," Brent said.

Quantifying how cells sense and respond to various stimuli and creating a model that will accurately predict these responses are the first important steps to understanding diseases and eventually to tailoring precise treatments to each individual.

The project gets its name from alpha factor, a yeast mating pheromone that triggers a signaling pathway that arrests yeast cell growth and prepares cells for mating. The Alpha Project team chose to model this signaling pathway because of its similarity to regulatory pathways in higher organisms. It also involves a manageable number of genes, about 25.