Working to unravel the secrets of sleep, gene by gene.
By Sumathi Reddy for the Wall Street Journal
In a lab at the University of California, San Francisco, a husband-and-wife team is working to unravel the secrets of sleep, gene by gene.
Louis Ptáček is studying why some people are genetically wired to be morning larks—an estimated 3% of the population who go to bed unusually early and rise early—while others are night owls.
His wife, Ying-Hui Fu, is researching another phenomenon: why some people require unusually short amounts of sleep, a group that is estimated to be less than 1% of the population. These hardy few, called short-sleepers, can biologically get by with less than six hours of sleep a night and feel fully refreshed.
Dr. Ptáček hopes soon to begin testing for drugs that could alter the body’s circadian rhythms—the internal clocks that influence virtually all our biological workings, from sleeping and eating to cardiovascular function. Such a drug might be useful to treat jet lag, for instance, or to enhance the curative powers of cancer treatments.
And Dr. Fu’s goal is to someday develop a drug therapy that can reduce how much sleep we need. “The natural, short-sleeper—these people are very optimistic, very energetic, they are go-getters,” said Dr. Fu, “If we can identify the pathways that can regulate our sleep duration then maybe someday we can come up with something better than caffeine.”
Drs. Fu and Ptáček, both in their 50s, are neurology professors at UCSF and share a lab there. Dr. Fu was trained in molecular biology and human genetics and worked in the biochemical industry before turning to academia. Dr. Ptáček is a neurologist who became interested in human genetics and molecular neuroscience. The couple met at an American Society of Human Genetics conference.
Their interest in circadian rhythm came about by chance in 1996 when the two were professors at the University of Utah. A 69-year-old woman came to the sleep clinic complaining that she had to go to sleep very early at night and woke up very early. The woman and her family are still subjects of the research, as are about 100 other families who fall into the lark group of sleepers.
In the process of studying early risers, Drs. Fu and Ptáček stumbled into the phenomenon of the short-sleeper, which spurred a separate research project.
The researchers enlist subjects for the studies nationwide. The participants submit a questionnaire and send in a blood sample or sometimes a saliva swab.
Lab technicians extract DNA from the samples and sequence the participants’ entire genome to look for genetic mutations. It is time-consuming, needle-in-a-haystack kind of work. The researchers also conduct animal studies to test their work.
“These families are an important way to learn about the genetics of sleep and of clock function in humans. Understanding that is going to help understand the implications of sleep deprivation on our health,” said Dr. Ptáček.
Our internal circadian clocks are located in every cell in our body. They are controlled by a part of the brain called the suprachiasmatic nucleus, which ensures that every cell is in sync with the others.
All our biological functions oscillate daily with our circadian rhythm.
Studies have shown that disrupting the body’s clocks, by working night shifts, for instance, can increase risk for developing chronic diseases such as cancer, obesity and metabolic syndrome.
Light helps our roughly 24-hour internal clocks reset themselves every day, as do our genes. Researchers are trying to identify the specific genes, as well as learn more about how the clock ticking in our brain coordinates the daily oscillation of all our physiological processes.
Dr. Fu is studying the genetics of a database that currently includes more than 50 families of short-sleepers. Many in the group seem to share characteristics in addition to sleep patterns, the research team has observed. They are generally optimistic and appear to have a high pain threshold, Dr. Fu says. One participant doesn’t need Novocaine for dental work. Another said she had little pain during childbirth even without a painkiller.
There are many genes involved in regulating sleep. So far Dr. Fu has discovered one mutation common to short sleepers in the gene Dec2, and is zeroing in on two more mutations in other genes.
She says the next step is to determine what pathways each of the three genes they’ve identified are involved in and if they intersect. She says any effort to begin developing a drug that mimics short-sleepers’ behavior is at least 10 years in the future.
So-called morning larks, the focus of Dr. Ptáček’s research, generally sleep on average seven to eight hours, like a normal adult. But larks’ chronotype, or preferred sleep pattern, is earlier than others. (Those who prefer a later-than-normal sleep time are often called owls. Most people fall somewhere between the two types.)
Dr. Ptáček focuses on the most extreme larks—those that tend to fall asleep at 8:30 p.m. and wake up before 5:30 a.m. His research team has found multiple gene mutations in their group of larks, including in the gene Per2, which plays a central role in regulating circadian rhythms.
The group has already identified a possible therapeutic target—a protein that regulates the Per2 gene—and is currently preparing a lab screening to test the effect of various drugs.
Dr. Ptáček says a drug that manipulates people’s circadian rhythms could be used to help jet-lagged travelers and night-shift workers stay more alert. He says a more important use would be to enhance the effects of existing treatments for diseases, such as chemotherapy for cancer.
Because of people’s circadian rhythms, there is usually an optimal time of day when chemotherapy will be more effective. But scheduling cancer treatment usually doesn’t take this into consideration. With a circadian-rhythm drug, cancer patients would be able to adjust their body clock when they get chemotherapy so their body gets the optimal benefit from it, Dr. Ptáček says.
“Being able to shift the clock, I think, will have profound implications for many different things, from night-shift work to driving at night to conducting chemotherapy,” he said.