September 12, 2008

Cancer Drug Search Aided

By Don Sapatkin

PHILADELPHIA - Emmanuel Skordalakes scrutinized the genetic makeup of pigs and cows and rats and hundreds of other creatures before the red flour beetle, an eighth-of-an-inch-long pest found in Southern kitchens, delivered the breakthrough scientists had sought for more than a decade.

The result - a key protein molecule modeled in 3-D - could speed the search for drugs against most human cancers. It might even help in the quest for the fountain of youth.

"A molecule you can barely see has so much power," said Mr. Skordalakes, a structural biologist at Philadelphia's Wistar Institute and lead author of a paper published online in the journal Nature. Mr. Skordalakes' lab deciphered a key part of beetle telomerase, an enzyme that can enhance or hinder a cell's ability to multiply limitlessly. The catalyst plays an active role in at least 85 percent of all cancers.

Like a shoelace, a strand of DNA frays at the ends if exposed. Shoelaces are shielded by plastic caps. DNA is protected by sections at each end called telomeres. But every time the DNA double helix makes a copy of itself in cell division, the telomeres get shorter.

In this role, telomeres actually operate more like the bottom of a shoe - able to lose a lifetime's worth of layers before the essentials inside become imperiled.

That's fine for most cells most of the time. But in cases that call for rapid cell replication - a developing embryo, for example, or a cancerous tumor - the telomerase machine kicks into gear, manufacturing new tracts of telomere to replace those that are fast disappearing.

Telomerase was discovered in the mid-1980s. Scientists have been testing all sorts of molecules in hopes of finding some that could inactivate the enzyme and point toward new drugs. Not knowing the complex protein's exact structure - the dimensions of the hole for which they needed to locate a peg - made finding a fit daunting.

Mr. Skordalakes, 40, arrived two years ago at the independent research center on the University of Pennsylvania campus determined to do it. He pored over genome databases, looking for telomerase sequences that suggested less floppy, more manageable proteins.

After about a year, the red flour beetle came up. T. castaneum protein is "compact," he said; its sequence is slightly shorter than humans'. By last November, he had created a synthetic beetle gene that was directing E. coli bacteria to produce the copious amounts of protein necessary for making crystals. A few months later, he nailed it.

Mr. Skordalakes said he and the researchers in his lab - Andrew J. Gillis and Anthony P. Schuller - would now turn their attention to the other key part of the enzyme, the RNA. And supplied with the beetle structure, they will pursue human telomerase.

Originally published by Don Sapatkin The Philadelphia Inquirer.

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