Circadian rhythm

• 1. Introduction

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  Circadian rhythm is the roughly 24-hour biological oscillation ticking inside nearly every living thing on Earth, from the cyanobacteria coating ancient rocks to the sleeping human body. In the 4th century BC, Theophrastus recorded what a ship's captain named Androsthenes observed while sailing under Alexander the Great: a tree whose leaves opened at sunrise, fully unfolded by noon, then closed again at night. The locals said it went to sleep. That tree was later identified as the tamarind. What the sailors were watching, without any language for it, was one of the oldest patterns in biology. What drives this internal clock? How does a single cell know what time it is? And what happens to a body when that rhythm breaks?

• 2. Naming a Pattern

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  Franz Halberg coined the word "circadian" in 1959, pulling it from the Latin circa, meaning "about," and dies, meaning "day." His definition was careful: the term applied to rhythms close to 24 hours, whether slightly longer or shorter. In 1977, the International Committee on Nomenclature of the International Society for Chronobiology formalized the definition, pinning it to rhythms with a frequency of 1 cycle in 24 plus or minus 4 hours. Before that term existed, the phenomenon had been accumulating evidence for centuries. Chinese medical texts from around the 13th century referenced diurnal cycles in human physiology, including texts titled the Noon and Midnight Manual. In 1729, French scientist Jean-Jacques d'Ortous de Mairan ran what may be the first controlled experiment on the subject. He kept the plant Mimosa pudica in constant darkness and found its leaves still moved in a 24-hour pattern, demonstrating the rhythm came from inside the plant, not from sunlight. The criteria that eventually defined a true circadian rhythm required three things: the rhythm must persist in constant conditions, it must be resettable by external cues, and it must stay stable across a range of physiological temperatures, a property called temperature compensation. That last criterion turns out to matter because temperature changes the speed of nearly every molecular process in a cell. A clock that sped up in summer and slowed in winter would be useless.

• 3. The Genetic Machinery

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  Ron Konopka and Seymour Benzer identified the first clock mutation in the fruit fly Drosophila in 1971, naming it the "period" gene, written as per. That single discovery opened a door. The per gene was isolated in 1984 by two competing teams working simultaneously. One team, led by Konopka along with Jeffrey Hall and Michael Rosbash, showed that the per locus sits at the center of circadian rhythm, and that destroying it stops circadian activity entirely. At the same time, Michael W. Young's team reported that per spans a 7.1-kilobase interval on the X chromosome and encodes a 4.5-kb poly(A)+ RNA. The molecular mechanism in Drosophila runs through two interlocked feedback loops: the PER/TIM loop and the CLK/CYC loop. During daylight, the CLK/CYC loop kicks off transcription of per and tim, but the resulting proteins stay low because the protein DBT breaks down monomeric PER. After sunset, DBT disappears, PER binds stably to TIM, and the PER/TIM dimer enters the nucleus to shut down CLK and CYC. In the early morning, light activates the cry gene, whose protein CRY destroys TIM, the dimer falls apart, PER degrades, and the whole cycle starts again. Hall, Rosbash, and Young received the Nobel Prize in Physiology or Medicine in 2017 for mapping this machinery. A defect in the human version of the per gene was later identified as the cause of Familial Advanced Sleep Phase Syndrome, a condition in which affected individuals sleep and wake roughly four hours earlier than most people, traced to a single amino acid change at position S662 in the human PER2 protein.

• 4. The Master Clock in Mammals

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  In mammals, the body's primary timekeeper sits in a pair of tiny cell clusters in the hypothalamus called the suprachiasmatic nucleus, or SCN. Destroy the SCN, and a regular sleep-wake rhythm disappears entirely. The SCN receives light information from the eyes not only through the rods and cones used for ordinary vision but through a separate class of specialized ganglion cells. These cells contain the photopigment melanopsin and send signals along the retinohypothalamic tract directly to the SCN. When isolated and cultured outside the body, SCN cells maintain their own rhythm without any external input. The SCN passes time-of-day information to the pineal gland, a structure shaped like a pine cone located on the epithalamus. The pineal responds by secreting melatonin, which peaks at night and ebbs during the day. Researchers at Harvard showed that human subjects can be entrained to cycles as short as 23.5 hours and as long as 24.65 hours. A 1999 study from Harvard University estimated the natural human rhythm to be closer to 24 hours and 11 minutes. A 2010 study found a small sex difference: the circadian period for women averaged 24.09 hours, for men 24.19 hours, with women tending to wake earlier and showing a greater preference for morning activity. Joseph Takahashi and colleagues noted in a 2013 article that almost every cell in the body contains a circadian clock. Peripheral oscillators have been found in the adrenal gland, lungs, liver, pancreas, spleen, thymus, and skin, all synchronized through hormonal signals that radiate from the master clock.

• 5. When the Clock Goes Wrong

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  Clock-mutant mice become hyperphagic and obese and develop altered glucose metabolism. Deletion of the Rev-ErbA alpha clock gene in mice can result in diet-induced obesity and disrupts the balance between glucose and lipid use, predisposing the animals to diabetes. In humans, disrupted circadian rhythms decrease melatonin secretion, alter hormone patterns from the pituitary gland, and enhance oxidative stress that can induce neurodegeneration. Conditions associated with irregular circadian function include bipolar disorder, depression, delayed sleep phase disorder, and a reversal of the sleep-wake cycle that can signal acute kidney injury. Shift workers who routinely eat at irregular times show altered insulin sensitivity and higher body mass. Studies of shift workers found an 11% increase in 24-hour high-sensitivity C-reactive protein levels, as well as elevated systolic and diastolic blood pressure, compared to controls. High levels of the atherosclerosis biomarker resistin have been reported in shift workers, alongside elevated triacylglyceride levels, both of which contribute to arterial hardening and cardiovascular disease. Chronic night shift workers face increased risk of dementia, particularly those over 50 years old. Blue LED lighting suppresses melatonin production five times more than orange-yellow high-pressure sodium light. A metal halide lamp, which produces white light, suppresses melatonin at more than three times the rate of sodium light. The National Transportation Safety Board has cited pilot fatigue from crossing multiple time zones as a contributing factor in accidents, and has conducted research into countering it.

• 6. Beyond Animals

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  Circadian rhythms appear across all domains of life, and researchers believe they evolved independently in animals, plants, fungi, and cyanobacteria. The cyanobacterium Synechococcus elongatus has the simplest known circadian clock: just three proteins, KaiA, KaiB, and KaiC, can sustain a 22-hour rhythm in a test tube over several days when ATP is added. The previous assumption was that even bacterial clocks required DNA transcription and translation. In plants, circadian rhythms govern leaf movement, germination, stomatal gas exchange, enzyme activity, and fragrance emission. Two interlocking feedback loops drive the plant clock. The morning loop involves proteins CCA1 and LHY, which encode MYB transcription factors in Arabidopsis thaliana, and the regulators PRR7 and PRR9. The evening loop involves GI and ELF4, both connected to flowering time. In 2012, Andrew Millar and colleagues showed that TOC1 functions as a repressor of genes in both loops, suggesting the plant clock is better described as a triple negative-component repressilator than the positive-negative feedback model used for mammals. Experiments on three varieties of Arabidopsis found that plants grew best when their internal clock period matched their external light-dark cycle. The monarch butterfly Danaus plexippus uses a time-compensated sun compass based on a circadian clock located in its antennae to navigate its fall migration to overwintering grounds in central Mexico. Norwegian researchers at the University of Tromsø found that reindeer at 70 degrees North show circadian rhythms in autumn, winter, and spring, but not in summer; reindeer at 78 degrees North on Svalbard show such rhythms only in autumn and spring.