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Aiming to help create a safer cigarette and possibly develop drugs, Orion Genomics LLC said its subcontract agreement had been extended with North Carolina State University under the Tobacco Genome Initiative, a $17.6 million project funded by Philip Morris USA.

The extension more than doubles the payments that St. Louis-based Orion stands to gain, bringing the total to more than $4 million, with $1.4 million garnered so far, said CEO Nathan Lakey.

"One of the primary aims is to make harm-reduced cigarettes, but obviously the gift [from Philip Morris] is more broad than that," he told BioWorld Today.

Under the extended agreement, the initiative will apply Orion's GeneThresher methylation-filtering technology to the development of an overall map of the tobacco genome that will identify up to 90 percent of tobacco's genes. The goal of the project, which began in December 2002, is to make the map and sequence as many genes as possible by 2007.

"Tobacco's a great model for how one could make therapeutic proteins in a plant," Lakey said, noting that it's closely related to tomatoes and potatoes, although that's not the specific goal of the initiative.

GeneThresher removes methylated "junk" from plant genomic DNA libraries, leaving only the small, unmethylated portion of the genome that contains genes, thus allowing Orion to catalog the complete gene sets of plant genomes for partners.

"In plant genomes, you have 90 percent of the genome that is repetitive DNA, and only 10 percent might be where the genes reside," Lakey said, but there are applications of Orion's technology in humans as well.

"The human genome is 6 feet long, 200,000 times longer than the width of an average cell, so the cell has a challenge to store all this DNA in the nucleus," he said. "The DNA is folded into dense and loose packaging states. The cell has to make a decision, and the DNA it needs to express is packaged in the loose state, and the other DNA in the dense state. When it's packaged densely, the cell cannot transcribe it. If DNA is methylated, it has been packaged densely, so the genes within that region are silenced. If it's unmethylated, then they're not silenced."

Orion also has MethylScope technology, which uses microarray analysis to assess the degree to which genes are methylated. The approach relies on methods similar to GeneThresher technology to split genomic DNA into two fractions - methylated and unmethylated. Each fraction is labeled with a different color of fluorescent dye and then hybridized to a microarray.

If an array feature corresponding to a single gene in the genome glows red, then that gene was methylated in the tissue from which the DNA was prepared. If an array feature glows green, then that gene was unmethylated. Observing the red-green ratio for each feature on an array lets researchers figure out the extent of methylation.

The company, which started in 1998 and became profitable in 2002, has two business units - one in genomics services and one in molecular diagnostics. Profits from the former have been used to grow the latter, "and we now have a very attractive molecular diagnostics business for cancer," Lakey said, adding that the two are "quite related" in other ways.

Research has discovered that tumor-suppressor genes often are methylated.

"Initially, we thought they'd have a mutation or be deleted," he said. "Aberrantly methylated tumor suppressors have been found in every type of cancer." What's more, DNA from tumors can be found in the blood of cancer patients.

"It's actually quite frequent that a cancer patient has free tumor DNA in their veins," Lakey said.

What this all might mean is molecular diagnostic tests performed by way of an assay on a blood sample, thus opening the door for early detection. Orion has talks under way with potential diagnostics partners, Lakey said.

Orion recently was in the news when the company and ViaLactia Biosciences Ltd., of Auckland, New Zealand, said it would provide sequence data to characterize the gene sequence of ryegrass to Cold Spring Harbor Laboratory researchers in New York. The data stem from a 2001 research alliance. Cold Spring Harbor researchers will use the data to annotate publicly available plant sequences with the aim of improving forage and cereal crops for greater nutritional value and higher yield.

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