LATimes

Understanding the Early Bird

Researchers at the University of Utah have found a mutant gene that causes people's internal clocks to run fast. The team is looking for other genes that cause the trait and for ways to treat it.

By ROSIE MESTEL, Times Medical Writer

At 3 in the morning, when most of us are dead to the world, Roger Davis is opening his eyes. By 4:30, he's sweating at the gym or walking briskly with his dog. More than once, a patrol car has pulled up beside him to find out why he is prowling around in the dark.

Davis, 61, has never known what makes him live like this: up about 3, in bed by 7:30 or 8 ever since he can remember. It's the same for three of his siblings and one of his daughters.

"You always thought you were weird, out of step, out of sync with what everyone else thought was normal," he said.

Now at last Davis knows why he's different. His inner biological "clock"--a timekeeper in the brain that tells the body when to do things like wake, sleep, eat or go to the bathroom--doesn't work the way most others do. The cause is a mutant gene that runs in his family.

We all know early risers, but extreme cases like Davis' are somewhat new to medical science. A decade ago, there were only two documented examples--and those were individuals, not whole families.

Then, in 1999, scientists at the University of Utah in Salt Lake City described Davis' family and two others like it in the journal Nature Medicine. Today, "familial advanced sleep phase syndrome" is accepted as a rare but real genetic trait.

This year, the same research team reported in the journal Science that they had pinpointed the gene causing the trait in one of those three families. Present in many animals, the gene plays a pivotal role in the ticking of their biological clocks.

Now the Utah team is trying to better understand how a small difference in that gene causes people's clocks to run fast, waking them up in the wee hours of the morning. The team is looking for other genes that can also cause the trait--in Davis' family, for instance. And it's trying to figure out whether people with the condition can be treated so they can live lives more in tune with the rest of society. "They're struggling," said Dr. Louis Ptacek, a neurogeneticist at the University of Utah and a co-author of the research. "Some of them would go to sleep as early as 2 or 3 in the afternoon if they allowed themselves."

Nearly every species that has been studied--from mold to plant to worm to human--has a biological clock controlled by a battery of genes. It stands to reason that we've developed such timekeepers. After all, conditions on Earth change rhythmically as the sun rises and sets, and creatures that can keep track of time and pick opportune moments for foraging, sleeping and waking have a distinct survival edge.

But biological clocks aren't perfect. If they weren't regularly resynchronized, they would drift out of phase with the 24-hour day, and creatures would start waking and sleeping at odd times. That doesn't happen, because each day such clocks are reset, using sunlight.

Abnormal biological clocks are new to human medicine, but they're not new to science. Thirty years ago, Caltech student Ron Konopka discovered mutant fruit flies that are active or inactive with unusually long or short biological rhythms--or without rhythms at all. Konopka's work was considered downright quirky at the time. But it became the foundation for a research field that has exploded in recent years.

Today, scientists know of many genes in flies, mice and humans that act together to make us march in smart, 24-hour time with the world. The genes have names like "period," "clock" and "cycle."

These genes, in turn, direct the production of proteins that are the cogs and springs of the clock and are created, altered and destroyed in rhythmic waves.

Slight changes in these proteins, scientists think, cause the normal variation we see in human rhythms. They are responsible for people who love the morning and flake out at parties, and people who snooze late and happily dance till dawn.

But big differences lead to extreme cases like Davis'. As a teen, he would fake illness rather than let his peers know that he liked to go to bed earlier than many 5-year-olds. Today, he's a lover of fine dining who struggles to find good restaurants that open before 6. Thrice-married, he endured lonely mornings while his night owl wives felt cut off from a normal evening social life.

"It was a serious problem for them--other than the fact that I'd always be up to make their breakfast for them," he said. Davis has lived all his life with it. But scientists discovered the disorder--known as FASPS--only in 1992, after similar difficulties led a 69-year-old woman to visit Dr. Christopher Jones, assistant professor of neurology at the University of Utah. Jones, Ptacek and co-workers went on to show that a variety of rhythms were abnormal in the woman and other affected people. Daily cycles of sleeping, waking, body temperature and blood levels of a hormone called melatonin were off kilter.

In February, the scientists showed that a small genetic change is the cause of the problem in the woman's family. The change affects a gene called Per2, the human version of the gene that was altered in Konopka's 1971 fruit flies.

"It's very exciting," said Joseph Takahashi, a neuroscientist at Northwestern University in Evanston, Ill. "It fits right in with the whole clock gene story."

Now the Utah researchers are trying to pinpoint genes that are speeding up clocks in Davis' family and other people who have since contacted the university.

Davis himself has helped Jones and Ptacek recruit more study volunteers--by dragging them to his all-night gym.

"I almost drove off the road getting there, I was so sleepy," Jones said. But it was worth it. Three of Davis' gym pals appear to have the syndrome, too.

The scientists also want to see whether there's a way to shift those people's clocks with carefully timed pulses of light so they can live more normal lives.

Or perhaps the answer is timed doses of the hormone melatonin, which can also reset clocks. Blind people sometimes have out-of-step rhythms because their clocks aren't adjusted each day with light. Last year, scientists at the Oregon Health Sciences University in Portland showed that melatonin can keep such people in step with the world.

But not all people with the syndrome want to be in step.

"About half of them will say, 'This is great, it's quiet, it's beautiful in the morning. . . . the sunrise, the chirping birds. . . .' " Jones said. "Others say, 'This is horrible, it's cold and dark and lonely.' "

Davis said he wouldn't get his clock recalibrated. The dawn, he said, has a mystical quality. And, after 61 years, he's used to being up at that time.

"I don't think I could change," he said. "I'm way too set in my ways."

Mestel can be reached at rosie. mestel@latimes.com

-- Anonymous, April 27, 2001