For nearly a century, UChicago scientists have explored the deep universe of sleep.
“I feel like a lab rat,” says Ruben Rodriguez. He looks a little beleaguered, smiling up from the bed where soon he’ll be asleep, while next door, in a room smelling of coffee and humming with computers, a sleep tech will spend long, small hours monitoring his breathing and brain activity, his eye movements and muscle tone, the oxygen and carbon dioxide levels in his blood. Rodriguez feels like a lab rat because he is one. Covered head to foot in wires and electrodes, he is spending his fourth night in as many months at the University of Chicago Medicine’s Sleep Disorders Center as part of a study on obesity hypoventilation syndrome. Also called Pickwickian syndrome—in The Pickwick Papers Dickens described a character with the classic symptoms—the disease usually combines severe sleep apnea with shallow waking respiration. “To the point where they’re not breathing enough to get rid of the carbon dioxide, so it accumulates in their bodies,” says Babak Mokhlesi, who directs the Sleep Disorders Center. “This is the extreme of the extreme.” Rodriguez, 39, knew he’d put on a lot of weight in the past few years—he reached 375 pounds before he started working it off this past January—and he knew he was waking up frequently at night. But he didn’t realize he had a problem until his boss called and told him. A driver for a handicap-accessible van service, Rodriguez kept nodding off at the wheel, a few seconds here, a few seconds there, whenever traffic slowed to a stop. The camera on the windshield caught him. “I never hit nobody, thank God,” he says. Going in for a diagnostic sleep study last fall, he found out that when he slept, his breathing periodically stopped for 20 seconds at a time, sometimes longer, before his brain lurched into action, sending an urgent signal for him to rouse up and gasp for air. (“Apnea” comes from a Greek word meaning “without breath.”) In the course of a night, this might happen dozens of times. Tonight is Rodriguez’s last in the sleep lab. Now outfitted with a CPAP device (the acronym stands for “continuous positive airway pressure”) that keeps him breathing normally through a mask that fits over his face, he sleeps soundly, solidly. Five minutes after sleep tech Greg Bild wishes him goodnight over the intercom, Rodriguez is asleep. A little more than an hour later, he’s in REM, the digital waves that track his eye movements picking up speed, rolling over each other as they undulate across the computer screen’s teeming, black cosmos. The University of Chicago has a long history with sleep. “I heard this was the place where they invented it,” Rodriguez joked the first time he came to the medical center. That’s not quite true, but it is the place where sleep science first took shape, and where the shape of sleep itself—how it works and what it’s for, and what happens when something goes wrong—began to emerge from the darkness. In 1925 Chicago physiologist Nathaniel Kleitman, PhD’23, established the world’s first sleep lab, on the second floor of Abbott Hall, which he filled with instruments and measuring devices he and his students had fashioned. Fourteen years later, he published a textbook, Sleep and Wakefulness (University of Chicago Press, 1939), which became the canonical volume for sleep researchers everywhere. Fourteen years after that, in 1953, Kleitman and graduate student Eugene Aserinsky, PhD’53, published a two-page paper in Science, documenting their discovery of REM sleep. Little noticed at first, it was nevertheless a breakthrough, a foundation on which the rest of sleep science would build. Rapid eye movements, the two reported, occurred regularly during sleep and were accompanied by faster heartbeats, quicker breathing—and dreaming. Subjects whom they awakened during or just after a REM cycle could describe vivid, detailed, visual dreams. With medical student William Dement, MD’55, PhD’58, Kleitman dispelled the idea that sleep was a single state. Recording subjects throughout the night, they used eye-motion measurements and EEGs of brain activity to chart shifting sleep patterns. A few years later, Chicago psychologist Allan Rechtschaffen, along with Dement and Chicago colleague Gerry Vogel, SB’51, MD’54, helped give scientific shape to narcolepsy, a disorder first described in the late 1800s. In a series of 1960s papers, the three researchers articulated the idea that narcolepsy is a form of dissociated REM sleep. Later Rechtschaffen, who led the sleep lab after Kleitman’s retirement, carried out some of the first research on insomnia and sleep apnea. He and Pennsylvania psychiatrist Anthony Kales developed a standardized method for classifying sleep stages that remained in use until 2007, when the American Academy of Sleep Medicine, building on Rechtschaffen and Kales’s system, released new guidelines. In those early years, when sleep science was still a wide-open field of deep and ancient mysteries, Rechtschaffen looked for clues wherever he could find them. He brought into the lab not only human subjects but also cats, alligators, tortoises, and lizards, hoping to pin down the common fundamentals of sleep. His experiments with rats, in which he kept the animals awake continuously, demonstrated the fatal effects of sleep deprivation. Growing scrawnier and weaker, even as they ate more, the sleep-deprived animals lost coordination and stopped grooming themselves. Finally their bodies failed completely, and after two to three weeks they died. Nearly a century after Kleitman first drew back the curtain on sleep, its mysteries remain vast and profound, although the field is more densely populated, at Chicago and elsewhere. Sleep researchers converge from across disciplines: physicians, neuroscientists, psychologists, physiologists. As David Gozal, who leads the University’s pediatric sleep program, says, “The universe of sleep here is expanding. There are lots of galaxies out there.” Most of those galaxies exist within UChicago Medicine, but some are farther flung. Social neuroscientist John Cacioppo has shown that loneliness can damage sleep quality, and biophysicist David Biron searches for clues to the genetic mechanism that regulates sleep in the “lethargus” behavior of roundworm C. elegans, a tiny primitive organism whose quiescent state resembles our own. For more than a decade, organismal biologist Daniel Margoliash and former psychology chair Howard Nusbaum, U-High’72, have investigated how sleep affects cognition in people and birds. Testing students as they learn complex video games or memorize new words, and starlings and zebra finches as they encounter new songs, Margoliash and Nusbaum have shown that sleep consolidates and protects new memories, that it fends off false ones, that it can even restore memories that seem to be lost. Tracking birds’ individual neurons, Margoliash discovered something not unlike dreaming: during sleep, the animals’ brains fire in patterns that mimic wakeful singing. Birds, he theorized, rehearse their songs at night, the way some scientists believe people revisit the day’s events in dreams. Most of the University’s sleep research, though, happens within the medical center, where the past two decades of discovery have leaned more toward the physiological than the psychological: how sleep—or lack of it—interacts with obesity, diabetes risk, hormone function, metabolism, and cardiovascular problems. In 2008 scientists led by epidemiologist Diane Lauderdale, AM’79, AM’81, were among the first to draw a conclusive connection to heart disease, calculating that for every hour of average sleep lost, coronary calcium buildup can increase by 16 percent. In a novel study this past January, internist Vineet Arora, AM’03, examined how hospital noise, which sometimes spikes to a chainsaw-loud 80 decibels, disrupts patients’ rest, and perhaps with it their recovery. “We have developed a theme that basically could be summarized as: the importance of sleep for physical health,” says Eve Van Cauter, who directs the University’s Sleep, Metabolism, and Health Center. “I mean, your grandmother would say, ‘I knew it all along, that sleep is important to stay healthy.’” Study by study, sleep researchers are proving it. In 1999 Van Cauter published a groundbreaking report in the Lancet. Chronic sleep loss, she found, strikingly alters hormone secretion in young, healthy adults. In some subjects who were sleeping only four hours a night, glucose metabolism came to resemble that of diabetics. Their blood cortisol rose to levels usually seen in much older people. The study was one of the first to explore the effects of sleeplessness on the body rather than the brain. Since then Van Cauter’s research has linked poor, irregular sleep to a multitude of chronic diseases: diabetes, obesity, and heart disease. She has studied shift workers and jetlag sufferers. Last year she and biomedical anthropologist Kristen Knutson, a frequent collaborator, reported that insomnia can worsen insulin resistence in diabetics. In another 2011 study, Van Cauter found that sleep loss can lower young men’s testosterone levels. Sleep apnea, she’s reported, can raise the risk and severity of diabetes. “Many of my colleagues in the sleep field will say that the function of sleep is still unknown,” Van Cauter says. “‘Why do we sleep?’” But the question, she argues, is itself a fallacy: there’s no single function. “If you sleep deprive an individual, basically nothing remains normal, whether mental or physical. Sleep is a basic need for function at every level.” Van Cauter still has big questions. Does restoring sleep to the sleep deprived repair mental and physical function? Is it possible, with longer, better-quality sleep, to walk back some of the damage done to blood pressure, diabetes risk, inflammation, the likelihood of Alzheimer’s disease? “There are some hints,” she says, that what she calls “good sleep hygiene” can offer those benefits, but what’s missing is a body of evidence, “strong well-designed studies.” Another open question for her is pharmacological. “We have so few drugs to treat people in sleep. For people with hypertension, there are 20 different drugs,” each targeting a different blood-pressure mechanism. “For sleep, we know there are different waking centers, so a person who has trouble sleeping, it could be because of too high histaminergic tone, or too high cholinergic tone, or too high neurogenic tone. The regulation of sleep is complex, and we know the neuronal groups and neurotransmitters involved. Yet the sleep drugs we have all target the exact same receptor,” a subunit of the benzodiazepine. “The pharmacology of sleep is really very poorly developed.” In another corner of the medical center, the pharmacology is a puzzle Nanduri Prabhakar is trying to solve, at least for one disorder whose numbers have been rising: obstructive sleep apnea, which happens when the soft tissue around the airway blocks off breathing. (Mokhlesi says that 70 percent of the clinical patients at the Sleep Disorders Center have sleep apnea.) Weight is a frequent contributing factor—it’s no coincidence that sleep apnea has increased along with obesity—but so are age and gender and genetics. Men are more likely to develop the condition. So are people over 40, those with a family history, or people with certain sinus conditions. Four to 9 percent of middle-aged men and 2 to 4 percent of middle-aged women have sleep apnea. An emergency-medicine professor, Prabhakar directs the Center for Systems Biology of Oxygen Sensing. His research focuses on the molecular mechanisms at work during intermittent hypoxia, the oxygen deficiency that accompanies sleep apnea and can contribute to high blood pressure, heart attacks, and other maladies. Using rodent and cell-culture models, Prabhakar is developing a drug to counteract the biological reactions that set those larger problems in motion. The need is urgent, he says. During a 2010 interview with the UK’s Physiological Society, he noted that for adults with sleep apnea, a hypoxia-fighting drug would make CPAP devices more effective and improve patients’ quality of life and cognitive function. He added that nearly one in two babies born prematurely suffer chronic intermittent hypoxia because of disrupted breathing during sleep. “If it’s not cured,” Prabhakar said, “eventually they develop sudden infant death syndrome.” Pediatric pulmonologist David Gozal has seen that happen. During his medical residency in Israel, a baby died from sudden infant death syndrome. The experience shook him. “Sudden infant death syndrome is a condition that occurs only during sleep,” he says. “I didn’t know anything about sleep, because at that time—this was the late 1970s—as a discipline it barely existed, and certainly not in pediatrics.” In 1981, while he was still a resident, Gozal established a sleep lab specifically for children at Haifa’s Rothschild Hospital (now called Bnai Zion Medical Center). “Looking back, I can’t overemphasize how primitive I was in my understanding of sleep, but it seemed like the right thing to do,” he says. “I thought we needed to understand why babies die suddenly and unexpectedly, and to understand that, I thought we needed to understand sleep in babies.” His research has helped illuminate the mechanisms that connect hypoxia and sudden infant death syndrome. Thirty years later, Gozal is still a rarity, running a pediatric sleep program he says is “more unique” than he would like. “Children are not little adults,” he says. Diseases can behave differently in one than in the other, and they often require different remedies, although children, like adults, suffer the full range of sleep disorders: sleep apnea, insomnia, restless leg syndrome, and “narcolepsy, which we now know—because we and others documented this—can occur very early.” Moreover, Gozal says, children need their own sleep research because the stakes are so high. “Alterations in sleep in early childhood can have huge lifelong consequences, and sometimes transgenerational consequences.” Sleep disorders in kids can modify their genomes and change the way they develop into adulthood. “Our job as pediatricians is not just to make sure that kids are healthy, but to make sure they become healthy adults.” Gozal came to Chicago in 2008, and since his arrival he’s assembled a team of nearly a dozen scientists and physicians doing what he calls “bench-to-bedside” work. Among them are Yang Wang, studying ways to protect children’s brains from the intermittent hypoxia associated with sleep apnea, and Shelley Zhang, investigating how immune function and metabolism are affected. Using animal models of sleep disorders, Abdelnaby Khalyfa examines the genomic pathways and gene interactions, and Vijay Ramesh looks for connections between childhood sleep disruptions and neurodegenerative diseases like Alzheimer’s and Parkinson’s. Rakesh Bhattacharjee studies how cellular particles—endothelial cells, monocytes, platelets—shed during sleep apnea, contribute to vascular dysfunction and, in turn, to childhood obesity. Leila Kheirandish-Gozal, Gozal’s wife, studies how specific immune cells may change and then contribute to atherosclerosis in children with sleep disorders, while Richard Li investigates the role endothelial cells and monocytes play in apnea-related atherosclerosis. In his own lab, Gozal examines the effects of disrupted sleep on children’s brains and bodies. In a 2011 study he tracked the sleep habits of four- to ten-year-olds and found that, on average, they slept eight hours a night—an hour and a half to two hours less than the recommended duration. Children with the poorest and shortest sleep were four times more likely to be obese, and their blood tests showed increased metabolic and cardiovascular risk factors. Currently Gozal studies how sleep apnea, obesity, and cognition interact. “So we’re imaging kids, doing cognitive function in kids, measuring vascular function in kids, doing metabolic assays in kids. And trying to put it all together and understand how genes could potentially affect these relationships.” He also studies how oxidative stress affects cognition, and how diet might modify those effects; how sleep disruptions can lead to changes in cancer behaviors; and how poor sleep can alter the genome. Because obstructive sleep apnea affects kidney function, he is developing a urine test for the disorder, so that children can skip the strenuous, difficult nights in the sleep lab. Just down the hall from the bed where Rodriguez is spending his final night in the sleep lab, a three-year-old girl, attached to her own set of electrodes and wires, struggles to get to sleep. (Children and adults share sleep lab facilities, if not medical and research programs.) She’s come in for diagnosis and treatment of a nighttime breathing disruption—the sleep techs suspect sleep apnea—and for two hours she whimpers and squirms. Her mother cajoles her with a blanket, a toy, and, in desperation, a cell phone. By the time she finally drifts off, her mother already passed out beside her, it’s long after midnight. Sleep disorders have genetic and biological underpinnings that researchers are just beginning to understand, but lack of sleep is also often environmental, and often in ways that are not within people’s control: Life’s responsibilities push back bedtimes. Stress keeps people awake. Children sleep irregularly because their parents do. There’s also something Gozal might call a modern lack of regard for sleep. “You look at the earth today,” he says. “It’s all light, all noise. The quality of our sleep, the regularity of sleep—it has disappeared.” People ignore the effects of sleep loss because they can. “It’s the only thing that doesn’t punish you immediately.” But sleeplessness does punish you. It’s not the “tradable commodity” it seems to be, Gozal says. “We spend one-third of our lives sleeping. If it weren’t important, why would we do this?” he says. “Every aspect of our lives essentially revolves around sleep. It is the dark matter that connects all the visible stars.”
Stanford professor William Dement, MD'55, PhD'58, explains the connections between healthy sleep and optimal performance as part of Google's Tech Talks lecture series.WATCH THE VIDEO AT YOUTUBE