A 46-year-old woman with a history of sleep disorder spent two weeks in a chamber with no clocks, no windows, television or internet – effectively nothing to let her know how much time had passed. The potentially crazy-making ordeal (subjects had regular check-ins with a psychologist throughout) helped scientists pinpoint the so-called night owl gene, a mutation in a gene called CRY1 that helps govern circadian rhythm, the 24-hour sleep/wake cycle present in all life on Earth.
The experiment, published in April, built on the work of Jeffrey C. Hall, Michael Rosbash and Michael W. Young, the three scientists who this year won the Nobel Prize in Physiology or Medicine for work they began more than 30 years ago. They isolated the master gene that controls circadian rhythm in fruit flies, which they called “period,” and has since been found in all mammals.
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A mutation in CRY1 makes our internal clock run slower, contributing to delayed sleep phase disorder, according to the research. Whereas people with typical sleep tend to fall asleep around midnight and wake around seven or eight in the morning, people with DSPD typically fall asleep three to four hours later and wake up around 11 a.m. to noon. This has ramifications beyond sleep.
The Nobel Prize, and continuing research, highlight how far sleep research has come: For many decades it had been neglected by the medical community, even though sleep, especially lack of it, can contribute to disease and cost society billions of dollars, a recent New Yorker magazine piece noted. Forty-seven million U.S. adults do not get a restorative sleep at night; workplace injuries and decreased productivity resulting from sleep deprivation are estimated to cost the United States billions annually; and tired drivers cause 20 percent of all car crashes, more than 1 million crashes a year.
“There definitely are correlations between this late sleep pattern and a variety of secondary diseases, not all of which we understand,” said Alina Patke, a research associate at Rockefeller University and the lead author on the night owl study conducted at Young’s lab. “People who have this preferred late chronotype, this night owl behavior,” tend to score higher on measures of depression and are also more likely to suffer from other serious conditions, including heart disease, diabetes and obesity.
Patke’s research established the genetic condition, but screen time in bed and other visual stimulants “can definitely make it worse,” she said.
CRY1 is not affected by light exposure in humans – night owls will be night owls – but late-night screens can exacerbate the condition. “Somebody might have a natural disposition to be up late that can be aggravated if that person sits in front of a bright computer screen till two am,” Patke said. “That would be bad for anybody, but especially someone who has DSPD.”
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Outside of good sleep hygiene, including turning off screens before bed, there aren’t many treatment options for DSPD, although scientists are beginning to explore novel treatments targeting the biological clock for sleep disorders, and related health conditions.
For those interested in whether they have a dominant night owl gene, short of going to a private lab there is no way to test for it currently. Patke said that her lab does not do that sort of testing (they have had inquiries) and it would in fact be illegal to do so without the necessary licensure for commercial testing.
Commercial mail-in DNA testing service 23andMe doesn’t currently screen for this particular genetic variation, so it won’t show up in their results. But Patke also stresses that even without a CRY1 mutation it is possible to have a sleep disorder, including DSPD.
Patke is herself a night owl and tested her own DNA for the presence of the mutated gene – she doesn’t have it. She fits the bill, however, and thinks she may yet have a sleep disorder that one day will be linked to specific genes.
“ We are looking for other genetic features” in DPSD, she said. “CRY1 is definitely one, but there will be others. … If you understand the mechanism, you can maybe start interfering with it to direct it in the direction we want. We want to keep screening people to see what makes people tick,” Patke said.
Scientists are looking for genetic signatures in other sleep disorders, such as insomnia and narcolepsy, which all together affect an estimated 50 million to 70 million Americans. Sleep apnea – in which a person’s airway closes during sleep – is as prevalent in the United States as mental illness, affecting millions of people.
About 9 million, or 1 in every 25 Americans, take prescription sleep medication, spending $41 billion on sleep aids in 2015. The industry is supposed to reach $52 billion by 2020. Typical sleep meds, including Ambien and Lunesta, work by targeting neurotransmitters, the chemical signalers in the brain, either by enhancing the effects of calming neurotransmitters or diminishing the effects of those involved in arousal.
Although they are effective for many people, others, especially people with more intractable disorders such as insomnia and DSPD, don’t respond as well or at all to prescription sleep medications, which also tend to have a high propensity for addiction. Only a couple of companies – pharmaceutical giant Merck and a small biotechnology start-up called Reset Therapeutics – are currently exploring potential therapeutic compounds that target the genes controlling the biological clock.
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Rather than producing sleep medications, however, both companies are primarily focused on developing medications for the serious, secondary diseases associated with disordered sleep. “The same mechanism that drives circadian rhythm those rhythms exists in pretty much every cell in your body,” explained Ross Bersot, president and CEO of Reset Therapeutics, based in San Francisco, which has developed drug compounds aimed at treating diabetes, non alcoholic fatty liver disease, hepatitis and other metabolic disorders by targeting CRY1 and other genes that control the sleep/wake cycle.
“CRY1 has roles outside the circadian clock,” Patke said.
When we go to sleep and when we wake up has a cascading effect on the rest of the body’s clocks, altering hormone levels throughout the day and impacting when the liver starts secreting certain enzymes, which affects the timing of when we get hungry, as well as glucose tolerance, insulin sensitivity and other factors that can contribute to the development of disease.
“There are clocks in every organ and every tissue in your body, but they aren’t in the same phase. In a body synchronized the way it should be, it could be New York time in brain, Paris time in liver and Beijing time in lungs,” Patke said.
Reset Therapeutics is now halfway through stage one of clinical testing to determine drug safety in humans. In earlier animal studies, molecular compounds designed to delay protein degradation were found to reduce insulin resistance in mice, as well as restore regular body temperature, which goes out of whack in diabetes.
Reset’s strategy is based on research by Joseph S. Takahashi, head of the neuroscience department at University of Texas Southwestern Medical Center, and another pioneer in the field of circadian genetics who serves on Reset’s Advisory Board.
Even if all goes well (which it often doesn’t in clinical trials), however, the company is still years away from FDA approval and bringing a drug to market. Reset Therapeutics is also developing an is Apart from an insomnia medication targeting biological clock genes other than CRY1, which is in an earlier phase of testing.
“If it’s at all possible and compatible with your lifestyle and the pressures with your everyday life, you are better off sleeping in accord with internal clock.” -Alina Patke, research associate in the Rockefeller University lab of 2017 Nobel winner Michael Young
Another currently available option is Melatonin, a “darkness hormone” associated with sleep in humans, but that also exists in nocturnal animals. Studies have shown moderate effects on improving sleep for jet-lag sufferers and for night-shift workers taking melatonin, but not with insomnia and other sleep disorders. The effects of the hormone, which is available without a prescription, vary because each human body metabolizes it differently.
People who suspect they may have DSPD, and most people, should avoid late-night screen time and practice overall good sleep hygiene: Avoid caffeine before bedtime, turn off electronics, and avoid lingering in bed in the morning. Also skip late-night eating and keep to a meal schedule, Patke said, as the “clocks” in the liver and rest of the digestive system can also have a reciprocal effect on the sleep/wake cycle.
Medicine isn’t the only answer
Most people with DSPD often don’t get to live according to their internal clock because of the constraints of daily life, work and school, which can result in them not getting enough sleep. “If it’s at all possible and compatible with your lifestyle and the pressures with your everyday life, you are better off sleeping in accord with internal clock,” Patke said. Forcing yourself into society’s box may be a large part of what is causing these problems in the first place.
The CDC recommends starting school later, which was found to imrpove academic performance, quality of life and physical health in adolescents. They tend to need more sleep than adults and younger children, and their success may be hindered by early school start times.
Many scientists, including Patke, suggest that the solution may not be entirely medical but sociological. Schools and employers need to provide for more flexible start times – an idea that some in the world of work are beginning to embrace.
Bill Davis, vice president of operations at Boston-based Circadian, which dubs itself as a “human factors” consulting firm, said companies – especially those in 24/7, high-risk industries – are making adjustments to work schedules based on sleep factors. A major hazardous materials transporter changed its schedule based on bio-mathematical fatigue model and reduced accident rates, and costs, as a result. “Providing education on fatigue and getting better sleep as well as designing schedules that provide ample time for rest and sleep are in high demand,” Davis said.
Society will still run, as morning people take the morning shifts. But the up to 10 percent of the population that has DSPD and other sleep disorders will be able to function at their best, even if the latest breakthroughs in sleep genetics don’t turn into blockbuster sleep-aid drugs.
– By Roni Jacobson, special to CNBC.com