Wistar lab cracks a cancer mystery

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 Skordalakes, a structural biologist at Philadelphia's Wistar Institute and lead author of a paper published online yesterday in the journal Nature.

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.

"Knowing the atomic structure of one of these little molecular machines is a breakthrough that enables and facilitates future research," said Thomas R. Cech, who shared the 1989 Nobel Prize in chemistry for discovering catalytic properties of RNA. As basic science, he said, "this is a technical tour de force."

The science is so basic that the hurdles ahead are too numerous to name. But so are the potential payoffs.

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 around the world 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.

Researchers who tried to figure out that exact structure were just as frustrated, if not more so.

"People have been beating their heads against walls for quite a while," said Elizabeth H. Blackburn, a professor of biology and physiology at the University of California, San Francisco, and one of the discoverers of telomerase.

To decipher the structure, many scientists have turned to X-ray crystallography, a technique that analyzes the patterns of X-rays beamed at crystals of a molecule. The problem was that telomerase is a protein, and this notoriously persnickety protein refused to crystallize.

After failing, as Skordalakes did, with telomerase from humans and selected other organisms, many researchers gave up, said Cech, the Nobel laureate, whose own lab at the University of Colorado at Boulder had tried to tackle the protein.

"It's huge and it's floppy and it's unstable," Cech said. "These folks from the Wistar Institute deserve enormous credit for persevering and finding an organism, the red flour beetle, that most of us hadn't thought of."

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 - strings such as t-g-a-a-a-t-g-c-a-c - 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.

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.

He thinks the new finding alone will "allow us to zoom in on hot spots" for future drug development.

Blackburn is more cautious. "The subtle details matter. This is a beetle. It's not a human," she said. And there would be many more steps before any medicine reached the market.

The long-term goal is to develop a targeted drug. This relatively new class of drugs works by interfering with specific molecules that are involved with the growth and spread of cancers. They are intended to be more precise than most chemotherapies, which aim to kill an entire cancer cell and are often toxic to healthy tissue as well.

A drug that targets telomerase would be particularly powerful because the enzyme is linked to so many types of cancer. Even so, it probably would need to be used along with conventional chemotherapy, said Richard J. Hodes, the director of the National Institute on Aging.

"Inhibiting telomerase may not kill cells immediately. It may just put them on a trajectory to end their replication capacity," said Hodes, who also studies the enzyme in his National Cancer Institute lab.

But "there will be interest in this at multiple levels," he said.

At Wistar, a colleague of Skordalakes' is intrigued by the role telomerase might play in aging. If an inactivated enzyme could limit the cell proliferation that is an unwanted hallmark of cancer, said Harold Riethman, then perhaps an activated enzyme could somehow enliven cells that degrade as we grow old.

Riethman, who was not involved with Skordalakes' study, was also impressed by the three-dimensional structure of the enzyme he found.

It resembles a doughnut.

"The DNA is like a thread. It fits right into the hole in the doughnut," said Riethman - a perfect mechanism for a biological machine whose raison d'etre is to make an identical copy of a piece of that thread and add it to the tip.

"It's elegant," he said. "You see a structure, and suddenly it becomes crystal clear how nature came up with this."