"The majority of the human genome consists of genes with no known function," Charles Cho told BioWorld Today.

A paper published in the Oct. 3, 2006, issue of the Proceedings of the National Academy of Sciences shines a light onto some of that darkness, by screening the entire genome for genes that regulate each stage of the cell cycle.

Cho called the genome-wide screen "discovery science," meaning that it is not driven by a hypothesis about which genes might be important for a given stage of the cell cycle.

"It's when you do an unbiased approach that you find the unexpected," he said. One unexpected finding to come out of the paper was that a cell's mission to divide apparently can be influenced by the environment at every stage of the cell cycle.

The mammalian cell cycle starts in growth phase 1 (G1), and "the popular thinking has been that once you commit, you just keep going," through DNA duplication (S phase), G2 and mitosis (M phase), Cho said. "People really haven't thought much about whether or not the environment can still regulate what happens to the cell cycle" once the initial decision that it's time to split has been made.

The scientists used a library of small interfering RNAs to knock down almost 25,000 genes - more than 95 percent of the protein-coding genes in the human genome - in cell culture. They found about 5 percent of those siRNAs stopped the cells in their tracks at one point of the cell cycle or another. The genes had effects on the cells that could be sorted into eight categories, depending on which cell cycle stage they affected, as well as their effects on the anatomy of the nucleus.

One of the main attractions of the study, Cho said, was that "it suggests functions for genes that people don't know much about." To gain insight into such currently unemployed genes, the scientists sorted them into groups, by comparing them to a database of protein-protein interactions.

Co-author Sudhir Sahasrabudhe, founder and chief scientific officer of Salt Lake City-based Prolexys Pharmaceuticals Inc., told BioWorld Today that "the interest on our part was to showcase the technology, to make people understand how protein-protein interactions can be used in drug discovery."

He noted that Prolexys has a preclinical drug discovery program aimed at beta-catenin, with targets identified through the same interaction database that was used for the PNAS paper. But for the paper itself, he said that "some of the findings we are following up on, but we have not filed any [patents]."

Cho, his colleagues at the Scripps Research Institute, in La Jolla, Calif., and researchers from Prolexys and the Novartis Institutes for BioMedical Research in Cambridge, Mass., and Basel, Switzerland, found - among other discoveries - more than 120 genes for receptors and their modulators, metabolism-related genes and translation-related genes that Cho said "seem essential for G2/M progression."

Among those genes were 15 that are part of the tumor necrosis factor (TNF)-NFkB pathway. TNF and NFkB are being targeted in the clinic for inflammatory diseases, and already are well-known players in the initiation of the cell cycle during the G1 phase.

The data suggested that TNF and NFkB might be able to add involvement in the later stages of the cell cycle to their resumes. Cho, who is a senior scientist at the Genomics Institute of the Novartis Research Foundation in La Jolla, stressed that the PNAS paper is exploratory, with the main goal of identifying genes that might be worth characterizing further. "The models we have built, we have not actually tested," he said.

The research may turn out to be useful for cancer research. In principle, Cho said, "if you inhibit some of these genes, you could halt cell-cycle progression, and that could ultimately be a target for cancer treatment."

Sahasrabudhe of Prolexys agreed, but also pointed out that such practical applications are a good bit in the future for the genes identified in the paper: "Clearly, this is enabling information," he said, "as opposed to specific information we could use to launch a drug discovery program."