New study to explore cellular circuitry

September 07, 2005

As part of a $4.88 million grant from the National Science Foundation (NSF), molecular biologists from the University of Rochester Medical Center will join a team seeking to create the first complete wiring diagram of a living cell. By wiring diagram, researchers mean a detailed model, not only of the cell's genes and their function, but also of the interplay between them. When complete, the diagram has the potential to reveal cellular approaches to treating many diseases, including cancer.

The Frontiers in Integrative Biological Research (FIBR) Program at NSF supports research into central questions in biology by integrating disciplines. Over the next five years, Keck Graduate Institute of Applied Life Sciences, the principal grant recipient, will lead a team of biochemists and computer scientists in an attempt to diagram Saccharomyces cerevisiae, a type of yeast. Although a single-celled fungus, yeast shares many genetic traits with humans, making it a useful model. Researchers hope to build a computer model of gene and protein function, and then test predictions against real world experiments.

For the purposes of the study, each individual gene, and proteins built according to directions stored in that gene, will represent one basic unit of the wiring diagram. The diagram will also be based on the emerging theory that these basic units are modular, or replaceable. Should a single gene/protein module fail, other modules can be re-wired so that existing components replace the faulty circuit. In addition, researchers now believe that modules with related functions are grouped together in networks.

"With most genes redundant and related to other genes and proteins in predictable ways, we can begin to identify the function of unknown cellular players based on their neighbors and associates," said Eric M. Phizicky, Ph.D., professor of Biochemistry and Biophysics at the medical center. "That puts us within reach of a completed diagram and the ability to re-wire cells in the treatment of disease."

Medical Center Tapped for its "Library"

At the outset of the NSF project, researchers know the exact composition of the genes of S. cerevisiae. Gene sequences, however, are just the first step in the wiring of life processes. To complete the diagram, researchers must determine how each gene and their protein products interact with one another.

KGI tapped researchers at the University of Rochester Medical Center for the project because they have developed a unique tool for determining protein function. Based on knowledge of all 6,000 genes present in S. cerevisiae, researchers in the Department of Biochemistry and Biophysics have designed a one-of-a-kind "genomic yeast library" that allows for high-speed, systemic examination of the purpose of each protein in the yeast cell.

Over the last four years, medical center researchers created a library of 6000 clones, or exact copies of the genes of the yeast cell, one clone for each known protein present in the cell. What makes the set of clones useful is that each one manufactures large amounts of a single protein with a "tag" attached. One common application of the library is to separate the tagged proteins from all others in the cell, and then use the collection of tagged proteins to determine which protein is involved in any given biochemical process. Only the tagged protein involved in a given reaction will show up in the results of specially designed tests.

A second potential application of the library relies on its clones' ability to produce large amounts of protein, which can help re-wire cells that have undergone an unhealthy genetic change (mutation) and allow those cells to survive. Learning the identity of the proteins that can re-wire particular mutant cells will also help researchers complete the wiring diagram.

"A completed yeast cell diagram would help us build one for humans," said Elizabeth J. Grayhack, Ph.D., a research associate professor of Biochemistry and Biophysics at the medical center. "We could then, in principle, work around self-destructive genetic mutations in cells on the way to treating many diseases with genetic roots," said Grayhack, a co-developer of the library along with Phizicky, Mark Dumont, Ph.D., associate professor in the department and researchers at Yale led by Michael Snyder, Ph.D.
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University of Rochester Medical Center

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