- The Washington Times - Tuesday, January 7, 2003

WEST LAFAYETTE, Ind., Jan. 7 (UPI) — The biological clock that keeps time for almost every activity within living creatures turns out to be a single protein, Purdue University researchers have reported.

The finding likely will surprise many scientists, said lead researcher, James Morr, Dow Distinguished Professor of Medicinal Chemistry, who has spent 40 years searching for the source of the biological clock, also known as the "circadian rhythm." Previous theories, he said, have been that the clock results from a complicated network of biochemical interactions.

"Probably 99 percent of the scientific community had given up on ever finding a single protein," Morr told United Press International. The research, by Morr, his wife Dorothy and colleagues, is reported in a recent issue of the journal Biochemistry, published by the American Chemical Society.

The protein, dubbed CNOX, "pulsates" in two opposite 12-minute cycles. "Our model is that of a Janus-head protein with two opposing faces," Morr said, referring to the ancient Roman god of beginnings. "One 'face' handles cell largement. Then the protein 'flips over,' allowing the second face to carry out other activities while cell enlargement rests."

The precise, twin cycles of the protein drive the circadian rhythm and "the day length an organism marches to is exactly 60 times this NOX-clock," he explained.

Morr said he first became interested in the biological clock in 1962 when he was a student. "Back then the question was the subject of perennial and lively scientific debate," he said, because air travelers began experiencing the clock-related phenomenon of jet lag. Later one, it was discovered that astronauts suffered bone loss and muscle weakening due partly to space travel's effects on their internal clocks.

Then, in 1971, researchers at the California Institute of Technology showed the common fruit fly has several genes — the first was dubbed "clock" gene — that appear to govern its daily rhythms. Now it appears those genes must be reacting to the protein CNOX, which keeps time much like the tuning fork in a modern watch, Morr said.

"I'm sure those genes probably have something to do with carrying information from our protein to other parts of the cell," he said.

Morr said he first suspected the existence of a time-keeping protein back in the 1960s, when well-known experiments revealed if cells were given "heavy water" — a variation of normal water used to cool nuclear reactors — they adopted daily cycles of 27 hours. He said he thought the only possible explanation was the clock had a chemical basis.

It has taken all this time to find the protein, isolate it, and show that it has the features of a biological clock, he said. "We had an inkling where it was in the mid-'80s, we had a very good idea in the mid-'90s, and now it's the mid-'00s," he said.

One hallmark of the biological clock, Morr said, is it is not affected by heat — whether it is hot or cold, the 24-hour cycle prevails. Most proteins are destroyed by changes in heat, but the protein CNOX continues to work regardless of temperature, he said.

"It keeps time in all temperatures and in every kind of condition that we've thrown at it," he said.

Morr said the emerging science of chronobiology — administering drugs at different times of the day to increase their effectiveness or minimize side-effects — could benefit from a better understanding of the biological clock.

Molecular geneticist Michael Rosbash of Brandeis University in Waltham, Mass., an expert in the study of biological clocks, said the finding is "curious and provocative," but added it will take more research to see how it fits into what currently is known.

"They get some striking effects from this protein on circadian patterns," he told UPI.

(Reported by Michael Smith, UPI Science News, in Toronto)


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