”Our entire history is only the history of waking men”
Georg Christoph Lichtenberg
Hamsters don’t need alarm clocks. In the strange world of circadian rhythms - the 24-hour cycle that governs almost every biological process in every living thing, from body temperature to digestion to sleeping and waking - the hamster is the Swiss watch. ”You can predict within a minute when they’re going to wake up. Whereas humans, we’re more like the Wal-Mart wall clock,” says Professor Michael Antle from the University of Calgary’s Department of Psychology.
Antle is prying apart the group of 20,000 cells in the brain that make up the circadian clock. He’s hoping to explain something astonishing that’s happening to his hamsters. If he turns on their light for 15 minutes in the middle of the night, he can make them wake up an hour earlier the next day. But if he gives them the experimental drug NAN190 and then does the same thing, they’re up and about eight hours early. They will still need their 14 hours’ sleep, but their biological clocks appear to have been set back. ”When I saw the effects initially in my lab, I was shocked at how big it was. An eight-hour adjustment is something that is useful.” An eight-hour adjustment could get a hamster from its home in Canada to London without jetlag.
Researchers are beginning to unravel the secrets of sleep, that everyday but exquisitely mysterious state that, as lamented by Macbeth after he had lost it forever, ”knits up the ravell’d sleeve of care”. By tinkering with the main biological driver of our urge to sleep - the circadian clock - researchers are opening up the possibility of a drug that can reset it to suit our time zone and work hours. They have found ways of maintaining alertness in air-force pilots who have not slept for a day and a half. They are trying to create a drug that promotes the deepest, most restorative form of sleep; a pill that can give a concentrated dose of rest. Some even speak of a future in which a tablet, or even a computer program, might mimic the labyrinthine processes of sleep while allowing us to remain fully awake.
Behind this buzz are breakthroughs in genetics and molecular biology and a lot of money. Hypnotics are the second-highest-selling category of drug after painkillers. Part of the reason is that there is a widely held belief that western society is in the midst of an epidemic of sleeplessness. ”We have the opportunity to pack more and more into our day and there is simply not enough left in the day to do all the things that we crave,” says Russell Foster, an Oxford university circadian neuroscientist. ”So what are our options? Well, we just invade the night.”
Our conquest of the night has been gathering force since the invention of the light bulb, described by Canadian sleep researcher Stanley Coren as ”Edison’s curse”. Still, the idea that we sleep much less than we used to is controversial. The US National Sleep Foundation - which receives funding from drug manufacturers, among others, but stresses its scientific independence - claims that before the invention of the light bulb in the late 19th century Americans slept on average 10 hours a night. The foundation’s 2002 ”Sleep in America” survey concluded that the average had dropped to 6.9 hours on week-nights and 7.5 on weekends. ”There is a fair amount of evidence that suggests that we are, at least in the United States, getting less sleep than we did 50 or 100 years ago,” says Dr James Walsh, president of the foundation’s board and a leading researcher in the field.
Researchers on the European Union-sponsored Enough Sleep programme - which links university sleep research across Europe - believe Europeans sleep on average an hour less today than they did 30 years ago. But others are sceptical. Jim Horne, the director of Loughborough university’s Sleep Research Centre, believes much of the talk of a chronic sleep deficit is fear-mongering by pharmaceutical companies. ”There are people who have inadequate sleep, that’s for sure,” he says. ”But the sign of insufficient sleep is whether you are sleepy throughout much of the day, not just after lunch. On that basis, when you start looking at the evidence, certainly in the UK, the average amount of sleep for a healthy adult has been about seven hours, seven and a quarter hours a night for the last 40-odd years at least.”
There seems little doubt that our sleep patterns have changed over the centuries, partly in response to technology. Research by Virginia Tech history professor A. Roger Ekirch suggests most western Europeans before the industrial revolution enjoyed ”segmented sleep” - they woke midway through the night to reflect on their dreams, smoke tobacco and even visit neighbours. Candles were the preserve of the wealthy, so everyone else followed the dictates of light and dark. As for how many hours they slept each night, Ekirch cites a common aphorism of the period: ”Nature requires five, custom takes seven, laziness nine and wickedness 11.”
Arguments over the extent of sleep loss have important public health consequences. Dr Eve Van Cauter at the University of Chicago believes a decline in average sleep hours in the US since 1960 is one of the contributing factors to a rise in obesity over that period. Apart from reducing the desire to exercise, sleep loss appears to have a profound effect on appetite hormones. Her research restricted a group of young men to four hours a night for two nights and found that they showed a 28 per cent increase in the hormone ghrelin, which makes us feel hungry, and an 18 per cent decrease in leptin, which makes us feel full. The men responded by loading up on sweets, carbohydrates and salty foods. Several studies have also linked restricted sleep to type-two diabetes and diminished immune response. ”It lends support to your grandmother’s idea that you are more likely to catch a cold if you haven’t slept enough,” says Van Cauter.
This is a new field. Sleep has traditionally been seen as benefiting the brain. But evidence is building that those who are regularly denied it, particularly shift workers, are damaging their physical health. Several studies have shown that shift workers have higher rates of cardiovascular and gastrointestinal disease. Two US studies show higher rates of breast cancer in women who regularly work nights. ”A shift worker, the majority of them, have a permanent sleep debt,” says Van Cauter. But it is also possible that the misalignment of the shift worker’s biological clock with their environment is, of itself, harmful. ”Humans are programmed to eat during the day and fast overnight. If you eat during the night, you will not process the food in the same way.”
Until fairly recently, sleep had been largely considered an inert state. In Greek mythology, it was closely associated with death. The twin sons of Nyx, the goddess of night, were Hypnos (sleep) and Thanatos (death). Things got more animated further down the family tree, when Hypnos had a son, Morpheus, the bringer of dreams, who slept surrounded by poppy flowers and gave his name to morphine, another bringer of dreams. Physicians in the Renaissance clung to the Aristotelian belief that sleep originated in the abdomen. Thomas Cogan’s 1584 text The Haven of Health explained that fumes from digesting food ascend to the head ”where through coldnesse of the braine, they being congealed, doe stop the conduits and waies of the senses, and so procure sleepe.” It was the artists of the time who suggested a more subtle, and modern, view of sleep. In the literature of the period, sleep is a tumultuous place, full of transformations, bizarre visions and danger (see box). In the words of William Sherman, professor of Renaissance/Early Modern Studies at York university, sleep was a place where ”nothing happens and where everything happens or, more importantly, can happen”.
We now know that the brain is busy when it appears to be resting. We also know that sleep is regulated by two distinct drives; the circadian and the homeostatic. The former uses light as its primary signal to create an internal representation of the day, adjusting most aspects of our physiology accordingly. This is why Antle’s hamsters reacted so dramatically to a pulse of light, aided by a drug that apparently increased the amount of information from the eye that reached their biological clocks. The homeostatic drive is more intuitive. ”The longer you’ve been awake, the greater your need for sleep,” says Foster. The systems need to be in synchrony. What happens when they are not is demonstrated by the ill-effects of shift work and jetlag.
Beneath the stillness of sleep is a riot of electrical charges. We descend in four stages from the fast brainwave pattern of wakefulness to the slow pattern of deep sleep. Then we rapidly cycle back up into rapid eye movement sleep, or REM, in which we do our most florid dreaming. After REM sleep we cycle back down through the stages. Each cycle takes up to 90 minutes and we go through about four or five of them a night. It is still unclear what role each stage performs and how they interact.
Much research interest is focusing on deep sleep - stages three and four. This period of slow brainwave activity appears to play a critical role in allowing the cortex - the large outer portion of the brain - to recover from the day’s exertions. Researchers at Loughborough’s Sleep Research Centre are studying an apparent correlation between very slow-wave sleep and how well the cortex performs during wakefulness. They see an association between levels of this kind of sleep and the natural deterioration of the brain through ageing.
”What is interesting is that the elderly person who has more of this very, very slow-wave activity seems to have a better functioning brain,” says Horne. His team has mimicked the ageing process in the brains of young test subjects by depriving them of sleep for 36 hours. At this point, the decline in their ”executive function” - the ability to think in a flexible way, to learn, converse or deal with the unexpected - is similar to that of a 55-year-old. This deterioration is reversed immediately by deep sleep. It is unclear if enhancing this form of very slow-wave sleep would have similar benefits on the elderly, and would probably take many months of medication. Walsh has performed tests which appear to show that increasing slow-wave sleep can compensate for shorter overall sleep periods, as well as improving memory. ”I believe that, during normal sleep, slow-wave sleep is more restorative than other types of sleep and I’m beginning to feel more comfortable with my belief that pharmacologically enhanced slow-wave sleep also has aspects of enhanced restoration.” But Horne stresses that sleep mechanisms are dauntingly complex. He warns that pharmacologically induced slow-wave sleep may, in fact, be caused by the drug having some adverse effect from which the brain is attempting to recover. ”This very, very slow-wave activity does seem to be restorative... But whether if you jack it up more by a drug, you’ll get improved performance, no one really knows,” says Horne.
Pharmaceutical companies are trying. They are pouring millions into university research and their own research and development to develop better sleeping pills. Last year $5.1bn in hypnotics were sold around the world - mostly in the US - an almost 20 per cent increase on the year before, according to pharmaceutical data specialist IMS Health. Several companies already have slow-wave sleep promoting substances in trials. But there have also been high-profile failures. Early testing implied that Gaboxadol, an experimental drug from Merck and Danish company Lundbeck, might mimic natural sleep processes more closely than existing sleeping pills, enhancing deep sleep without disturbing the balance between REM and non-REM states. Later on in the trials, however, the drug revealed troubling side effects: hallucinations, dizziness and vomiting, at only twice the recommended dose. Merck and Lundbeck discontinued Gaboxadol’s development, a move which Datamonitor, the research company, predicts will leave the field clear for Sanofi-Aventis, which controls more than half the world market for hypnotics.
Competition in the sleeping aid market is fierce. Sepracor spent $298m advertising its Lunesta sleeping pill last year in an effort to win some of the market share of the world’s biggest-selling hypnotic, Sanofi-Aventis’s Ambien, according to TNS Media Intelligence. Its slightly creepy television ad featuring a lunar moth hovering over sleepers apparently had some soothing effect - its sales leapt more than 200 per cent from the year before.
But as the market expands, the regulatory environment for sleeping pills is getting tighter. In March the US Food and Drug Administration (FDA) instructed drug manufacturers to warn consumers that their products could lead to ”complex sleep-related behaviours, which may include sleep-driving, making phone calls, and preparing and eating food (while asleep)”. It named 13 drugs, including four of the five top-selling sleeping pills in the world. These behaviours are, indeed, ”complex”. Bizarre side-effects reported by people who have taken Ambien, which last year controlled 55 per cent of the market with $2.8bn in sales, range from hallucinations and violent outbursts, to binge-eating and driving while asleep. One Australian woman reportedly climbed back into bed after a nocturnal wandering with an electric heater, which she then turned on.
Part of the reason for our improved understanding of sleep is advances in our ability to monitor it, particularly in animals. It is now established that even cockroaches and fruit flies exhibit sleep-like states. But as technology peels back one layer it reveals a new one beneath. It’s not entirely clear why a giraffe sleeps only two hours a day but a two-toed tree sloth sleeps for 20. It’s yet to be discovered why some species of migratory birds can go for weeks without sleep with apparently no ill effects. Dolphins sleep half a brain at a time (so that they can swim, surface to breathe and avoid predators), but no one really knows how. ”The whole idea of a restorative function to sleep is not altogether clear,” says Foster. ”You would think that an athlete would need more sleep than a couch potato. In fact, couch potatoes sleep more than athletes.”
Not all of the body rests during sleep, and some parts of the brain are more active during REM sleep than while awake. Sleep may have evolved as a way of conserving energy, explaining why small mammals are more inclined to snooze than large ones. ”The big Nobel-prizewinning answer to the question of why we sleep isn’t clear, but it is emerging,” says Foster. One theory is that sleep allows us to consolidate new memories in the brain - a sort of nocturnal clearing of the desk - allowing us to adapt to new experiences. Most researchers believe it has a key role in learning. This seems particularly true of REM sleep.
It was not until 1953 that scientists discovered that our nocturnal brains, rather than remaining on standby, demonstrate two distinct states during the night. REM sleep was discovered by a graduate student at the University of Chicago who at first thought the drastic changes in the electroencephalograms - which record the brain’s electrical activity - he was monitoring were down to equipment failure. Most sleep researchers had turned off their polysomnograph machines after the subject had been asleep for a time to save paper. What they missed were periodic bursts of intense electrical activity in which the body is paralysed but the eyes dart backwards and forwards. In many ways, it is more like being awake than in deep sleep, which is why researchers refer to it as ”paradoxical sleep”. The discovery of REM sleep seemed to confirm the belief in ancient Indian philosophy that there are three modes of existence - sleep, dreams and wakefulness.
To the Renaissance physician, dreams gave clues to the dominant humour of the patient: choleric dreams were bright and noisy, while the melancholic patient saw death and darkness. Some artists dissented. The 16th-century English pamphleteer Thomas Nashe thought dreams ”a bubbly scum or froth of the fancy which the day hath left undigested”. This view recurred in the 1980s, when British scientists Francis Crick (co-discover of the DNA double helix) and Graeme Mitchison proposed that REM sleep was the brain’s way of discarding unwanted memory traces to allow new ones to fix. This was roughly the opposite of Freud’s contention that dreams served to prevent emotions, traumas and desires from waking us up, and of Aristotle’s that the sleeper saw things that he wished or intended to do ”for it is on these things that our thoughts and fancies most often dwell.” Many of those who study REM sleep today look for some accommodation between the idea of dreams as meaningful and their dismissal as psychic effluent: dreams as the narrative reflection of sleep’s work in laying down consolidated memory, and of using those stored bits of knowledge in novel ways to solve problems.
If the drive to master our circadian rhythms has created a bonanza for those selling a better night’s sleep, the same is true for its flipside, wakefulness. One great pharmaceutical success story of recent years has been Provigil, Cephalon’s blockbuster alertness agent. Originally approved for the treatment of narcolepsy - a disorder characterised by excessive daytime sleepiness and spontaneous ”sleep attacks” - the FDA has now cleared it for night shift workers and victims of sleep apnea - in which sufferers repeatedly stop breathing through the night.
Cephalon sold $727m worth last year, a 32 per cent increase on the year before. Eric Schmidt, senior analyst at Cowen and Company, predicts sales of Provigil and its longer lasting successor Nuvigil will more than double in the next five years. He estimates that half of Provigil sales are for ”off-label” uses, suggesting a massive demand for wakefulness promoters in otherwise healthy people. Yet no one really knows how the drug works - even the company that sells it. (Cephalon was sent a warning letter by the FDA this year for a piece of promotional material that recommended Provigil for uses other than those it was indicated for. Cephalon spokeswoman Jenifer Antonacci said the company had severed its involvement with the distributor of the material and that it fully complied with FDA requirements.)
One group eager for what Provigil appears to offer is the military. ”The big drive in western armies at the moment is to develop the metabolically dominant soldier; a soldier that can go anywhere, anytime and fight effectively without the downside of sleep,” says Foster. In 2004 researchers at the Air Force Research Laboratory at Wright-Patterson air force base kept F-117 pilots awake for 37 hours and gave them the active agent in Provigil, modafinil. The drug maintained their flight performance to within 27 per cent of baseline levels, against 82 per cent for those who had not taken it.
The demands of modern warfare are such that soldiers’ own biological clocks can be their enemy. ”The requirement of getting deployed [is that] all of a sudden I’m in another part of the world, maybe my sleep cycle is disrupted. I conduct military operations at night and I’m required to get my rest during the day.” explains Dr Amy Kruse, who runs the Preventing Sleep Deprivation programme at the US Department of Defense Advanced Research Project Agency. ”Under certain conditions, someone might be sleep-deprived for a day or more in order to carry out an operation.”
The agency has been funding research into how to restore a soldier’s cognitive performance in these situations. One of the most promising solutions is a compound that makes modafinil look like a very blunt instrument. CX717, developed by Cortex Pharmaceuticals in Irvine, California, acts on a receptor in the cortical areas that are thought to be involved in cognitive processing. Early tests in monkeys at Wake Forest University in North Carolina have had startling results.
The monkeys were given a mental exercise similar to a video game, and were subsequently deprived of sleep for 30 to 36 hours. When they were tested again, their results plummeted. But after being given CX717, their performance was restored to normal, wakeful levels. Brain scans showed that the drug had reversed most of the changes in electrical activity caused by the sleep deprivation. Lack of sleep had caused a big dip in activity in each monkey’s frontal cortex - which is associated with higher mental processing - while increasing activity in the temporal lobe, which deals with recent memories. Researchers believe this is how the brain compensates for sleep deprivation. The drug had returned both areas to normal. ”If you look at the primate data from CX717, they have some really nice activity data in the brain showing these areas are brought down by sleep deprivation but those areas are actually restored by administration of a compound,” says Kruse. Testing on humans is at an early stage.
The military is not the only group experimenting with how to stay sharp without sleep. Modafinil has become a popular and readily available nootropic, or smart drug. Generic versions of Provigil such as Modalert, from India, are sold on online pharmacies without prescription. Recreational users swap experiences in chatroom forums. Many who have used these versions for all-night study sessions, long work hours or just partying report increases in energy and alertness, but warn that it in higher doses it can cause anxiety, decreases in creativity and a loss of verbal fluency that one user described as ”being like a very short silent stutter”. One 27-year-old IT company owner who has both taken and sold generic modafinil online has stopped using it. ”I accidentally took 800 mg (four times the daily dose),” he told the FT in an e-mail. ”After a few hours I felt extremely energised, both mentally and physically. I felt like I was on top of the world. In the afternoon, I went to the gym and had one of the most intense workouts ever. After I came back from the gym, I felt anxiety and I don’t ever have anxiety. By the night it had become so intense that I thought I would have a panic attack and had to use Diazepam for the first time in my life... That night I didn’t sleep much, if at all.”
For researchers in the field, the demand for substances that can tailor sleep to our needs is a sign of the times. Foster predicts that within a decade we will have genuine insight into the biological control of sleep. That will open up new and - to some - unsettling possibilities further into the future: a pill that can biologically mimic sleep; a way of hooking up to a computer which could take parts of the brain ”off-line”, consolidating memory and coming up with new ideas while you stay awake. ”What you could say is that what we need to do is go back 100 years and embrace more natural sleep patterns, but that’s not going to happen,” says Foster. ”So while I feel uneasy about advocating these sorts of interventions, I think frankly there is almost no alternative.”
Sleeping beauties
Surrouned by hushed spectators, Tilda Swinton lies in state in a glass box.
But look closely and her chest rises and falls, her eyelids twitch. The British actor’s 1995 collaboration with artist Cornelia Parker at London’s Serpentine Gallery was a monument to the third of our lives that we spend in ”non-productive” sleep. ”There was a weird thing going on with the public because she was there and she was vulnerable,” says Parker. ”I realised when we were doing it that Tilda had been thinking of doing it in costume, which would have protected her. But because she was sleeping as herself it made her much more vulnerable.”
Long before scientists began looking seriously at sleep, artists and writers offered insight into its hidden universe. In representing sleeping as an act of relinquishing power, Parker’s The Maybe was picking up a common theme. In the Middle Ages Saint Augustine wrote of the incubi who ”often made wicked assaults upon women and satisfied their lust upon them” while they slept. In Edmund Spenser’s 1590 epic poem The Faerie Queene sleeping is never good for you. The wizard Archimago, who commands sleep, ”leads the Redcrosse Knight, the hero of the story, on the wrong path and separates him from his lover,” says William Sherman, professor of Renaissance/Early Modern Studies at York university.
In Shakespeare’s The Tempest Caliban promises that Prospero’s afternoon nap is the right moment in which to murder him and seize his books. ”Particularly when the figure who is sleeping is a figure of power, sleep opens up possibilities for negative transformations,” says Sherman.
This association of sleep and danger presages modern theories on the evolutionary origins of sleep cycles. Creatures may have evolved to sleep at times when they are less vulnerable to predators. The fact that all animals appear to sleep in stages may itself be an inbuilt safety mechanism, punctuating deep sleep with lighter slumber in which we are more responsive to threats.
