Sleep Science · Circadian rhythm
The clock within
At three in the morning and four in the afternoon, alertness drops, even if you have slept. It is not chance and it is not weakness. It is a clock the body carries in every cell, and no amount of willpower can move it. Pick a time and watch what happens.
OnlineScenario
Wide margin Past the threshold Asleep Peaks in sleep-related crashes
Up at 07:00, in bed at 23:00. The colour of the ring shows how much margin your body leaves you, hour by hour.
01Light
Morning sets the clock right
The internal clock does not run on an exactly 24-hour cycle. Measured in a laboratory, in very dim light, one cycle lasts slightly longer: 24 hours and 11 minutes on average. Left uncorrected, it would fall a little behind every day. Czeisler et al. 1999
What sets it right is light. In the retina, besides the cells we see with, there are others that contain a substance called melanopsin. They are not for seeing: they measure how much light there is, especially blue light, and send the signal straight to the clock in the brain. Berson et al. 2002 Hattar et al. 2002
Light comes in, the clock resets
At the wheel
Evening light pushes the clock later. People who read on a tablet before bed fall asleep later and are less alert the next morning. A study in Basel found that a computer screen in the evening also lowers melatonin. Chang et al. 2015 Cajochen et al. 2011
02The brain
The conductor
The light signal reaches a small group of neurons at the base of the brain, just above the point where the optic nerves cross. This group is called the suprachiasmatic nucleus, and it is the master clock. Mohawk et al. 2012
From there it keeps time for the rest of the body: for temperature, hormones, hunger and alertness. In the evening it starts the production of melatonin, the hormone of the biological night. During the day it pushes to keep you awake. Mohawk et al. 2012 Arendt & Skene 2005
From the clock to the body
At the wheel
The clock does not know you are driving. At three in the morning it says night, even in the car, even with the radio on. Mohawk et al. 2012
03The two forces
Two forces, one sleepiness
The sleepiness you feel comes from two forces. The first is sleep pressure: it builds with every hour you are awake and only drains away with sleep. One of the molecules that signal it is adenosine, which builds up in the brain while you are awake. Porkka-Heiskanen et al. 1997 Landolt 2008
The second is the clock, which acts as a threshold: by day it raises the threshold and keeps you awake even under heavy pressure; at night it lowers it, whatever you have done. The model that brings the two forces together was developed in Zurich by Alexander Borbély, and for more than forty years it has helped explain how sleep works. Daan et al. 1984 Borbély et al. 2016
You can see it clearly in the laboratory: eight men lived for over a month without knowing what time it was, on 28-hour days. Sleep and wakefulness followed both forces at once. Dijk & Czeisler 1995
Sleep pressure against the clock’s threshold
At the wheel
In the dead of night the two forces push the same way: pressure is high and the clock is falling towards its minimum, which it reaches before dawn. Coffee helps for a while because it stops adenosine from acting, not because it removes it. Landolt 2008 Philip et al. 2006
04The cell
A clock in every cell
Inside almost every cell in the body there is a small clock made of genes and proteins. Two proteins, CLOCK and BMAL1, switch on the PER and CRY genes. The PER and CRY proteins build up, enter the nucleus and switch CLOCK and BMAL1 off. Then they are broken down, the block lifts and the cycle starts again. Takahashi 2017
One cycle takes about a day. The discovery of this mechanism won the 2017 Nobel Prize in Physiology or Medicine: first studied in the fruit fly, the mechanism works in a very similar way in mammals. Takahashi 2017
In Geneva, Ueli Schibler’s group showed that the clock also runs in cells grown in the laboratory, far from the brain. The brain is not the only part of the body that knows what time it is. Balsalobre et al. 1998
The gene cycle
C = CLOCK · B = BMAL1 · ◆ = PER and CRY proteins · lines = gene messages
- 1CLOCK and BMAL1 switch the genes on
- 2PER and CRY build up
- 3they enter the nucleus and switch CLOCK and BMAL1 off
- 4they are broken down: the cycle restarts
At the wheel
Night-time sleepiness is not a thought you can push away. It is written in a cycle of genes that runs in every cell, even while you drive. Takahashi 2017
05Chemistry
The chemistry of the night
The clock can be read in three curves. Melatonin rises in the evening, as the light fades, and stays high through the biological night. Body temperature falls during the night and reaches its minimum before dawn. Cortisol climbs again towards morning and prepares you to wake up. Arendt & Skene 2005 Hofstra & de Weerd 2008
These are the signals researchers use to find out what time a person’s clock is showing. The shapes shown are typical; the values vary a great deal from person to person. Hofstra & de Weerd 2008 Dijk & Czeisler 1995
Three curves, one clock
At the wheel
Before dawn, low temperature and high melatonin tell the body it is the dead of night. It is also when driving is at its worst. Dijk & Czeisler 1995 Lenné et al. 1997
06The body
The body’s clocks
The liver, gut, pancreas and fat tissue have clocks of their own too. They follow the brain, but they also respond to meals. In mice, eating only during the day, the hours when they normally sleep, shifts the liver clock by up to twelve hours, while the brain clock does not move. Damiola et al. 2000
In humans, delaying meals by five hours shifted the blood sugar rhythm by almost six hours and the fat tissue clock by about an hour. The brain clock and sleepiness did not move. Wehrens et al. 2017
Gut bacteria also change over the course of the day, and jet lag disrupts them. This has been seen mainly in mice. When work and school run against the clock, as in social jet lag or shift work, the body is caught between two timetables. Thaiss et al. 2014 Wittmann et al. 2006
Meals delayed by five hours
At the wheel
The afternoon dip is not caused by lunch: it comes from the clock. A large lunch after a short night can make it worse. Reyner et al. 2012 Lenné et al. 1997
07The road
On the road
Crashes in which the driver fell asleep are not spread at random across the day. In England, police data show three peaks: around two in the morning, around six in the morning and around four in the afternoon. Horne & Reyner 1995
In a driving simulator, driving gets worse at two and at six in the morning, and in the early afternoon there is a dip of similar size. Lenné et al. 1997
And at night the road is not empty. On the A2 at three in the morning, an average of 185 vehicles an hour pass through the Gotthard tunnel, 229 at Biasca and 315 at Lugano.
Three peaks, and a road that never empties
At the wheel
The clock cannot be fooled: not by the open window, not by the radio. You can know where it stands, and stop. On real roads at night, a coffee or a thirty-minute nap let most young drivers drive almost as well as in the daytime. Philip et al. 2006
What you can do
The journey in seven sentences
- Morning light sets the clock right, through cells in the retina that are not for seeing.
- A small group of neurons at the base of the brain keeps time for the whole body.
- Sleepiness comes from two forces: sleep pressure, which builds while you are awake, and the clock, which acts as a threshold.
- In almost every cell, one cycle of genes and proteins takes about a day.
- Melatonin, temperature and cortisol follow the clock and tell the body whether it is day or night.
- Organs have clocks of their own, which also respond to mealtimes and can drift out of step with the brain’s.
- At the wheel, alertness drops most before dawn and in the afternoon, and the clock cannot be fooled.
The words
- Circadian
- From the Latin circa diem, “about a day”: a rhythm that repeats roughly every 24 hours.
- Suprachiasmatic nucleus
- The master clock, at the base of the brain.
- Melanopsin
- The pigment in some retinal cells: it measures light for the clock.
- Adenosine
- A molecule that builds up in the brain while you are awake and signals sleep pressure.
- Sleep pressure
- The need for sleep that grows with every hour awake. In the model it is called Process S.
- Melatonin
- The hormone of the biological night, made by the pineal gland when it is dark.
- Peripheral clocks
- The clocks of the liver, gut, pancreas and other organs.
- Social jet lag
- The gap between the clock’s timetable and the one set by work and school.
What we know, and what we do not know yet
We know
- Alertness follows a rhythm of about 24 hours, with its lowest point before dawn and a dip in the afternoon.
- Sleepiness depends both on how long you have been awake and on the time of day.
- Evening light pushes the clock later.
We do not know yet
- How far each person differs from the average curves: chronotype, age and work matter a great deal.
- How much meals affect sleepiness at the wheel. In humans, shifting meals did not change measured sleepiness.
- Many findings about the body’s clocks come from mice, rats and cats. In humans they are only partly confirmed.
Sources
About the model
The curves at the third stop come from the two-process model, with the time constants published by Daan, Beersma and Borbély. They show the typical pattern for someone who gets up at 07:00 and goes to bed at 23:00. They do not measure your sleepiness and do not replace the question “Am I sleepy?”
01 · Light
- Berson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cells that set the circadian clock. Science 2002;295(5557):1070-1073. DOI 10.1126/science.1067262 · study in rats
- Hattar S, Liao HW, Takao M, Berson DM, Yau KW. Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 2002;295(5557):1065-1070. DOI 10.1126/science.1069609 · study in rats and mice
- Czeisler CA, Duffy JF, Shanahan TL, et al. Stability, precision, and near-24-hour period of the human circadian pacemaker. Science 1999;284(5423):2177-2181. DOI 10.1126/science.284.5423.2177 · study in people, in the laboratory
- Chang AM, Aeschbach D, Duffy JF, Czeisler CA. Evening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness. PNAS 2015;112(4):1232-1237. DOI 10.1073/pnas.1418490112 · study in people
- Cajochen C, Frey S, Anders D, et al. Evening exposure to a light-emitting diodes (LED)-backlit computer screen affects circadian physiology and cognitive performance. Journal of Applied Physiology 2011;110(5):1432-1438. DOI 10.1152/japplphysiol.00165.2011 · study in people, Basel
02 · The brain
- Mohawk JA, Green CB, Takahashi JS. Central and peripheral circadian clocks in mammals. Annual Review of Neuroscience 2012;35:445-462. DOI 10.1146/annurev-neuro-060909-153128 · review
03 · The two forces
- Borbély AA, Daan S, Wirz-Justice A, Deboer T. The two-process model of sleep regulation: a reappraisal. Journal of Sleep Research 2016;25(2):131-143. DOI 10.1111/jsr.12371 · review, Zurich and Basel
- Daan S, Beersma DG, Borbély AA. Timing of human sleep: recovery process gated by a circadian pacemaker. American Journal of Physiology 1984;246(2 Pt 2):R161-R183. DOI 10.1152/ajpregu.1984.246.2.R161 · mathematical model
- Dijk DJ, Czeisler CA. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. Journal of Neuroscience 1995;15(5 Pt 1):3526-3538. DOI 10.1523/JNEUROSCI.15-05-03526.1995 · study in people, in the laboratory
- Porkka-Heiskanen T, Strecker RE, Thakkar M, et al. Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Science 1997;276(5316):1265-1268. DOI 10.1126/science.276.5316.1265 · study in cats
- Landolt HP. Sleep homeostasis: a role for adenosine in humans? Biochemical Pharmacology 2008;75(11):2070-2079. DOI 10.1016/j.bcp.2008.02.024 · review, Zurich
04 · The cell
- Takahashi JS. Transcriptional architecture of the mammalian circadian clock. Nature Reviews Genetics 2017;18(3):164-179. DOI 10.1038/nrg.2016.150 · review
- Balsalobre A, Damiola F, Schibler U. A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 1998;93(6):929-937. DOI 10.1016/s0092-8674(00)81199-x · rat cells, Geneva
05 · Chemistry
- Arendt J, Skene DJ. Melatonin as a chronobiotic. Sleep Medicine Reviews 2005;9(1):25-39. DOI 10.1016/j.smrv.2004.05.002 · review
- Hofstra WA, de Weerd AW. How to assess circadian rhythm in humans: a review of literature. Epilepsy & Behavior 2008;13(3):438-444. DOI 10.1016/j.yebeh.2008.06.002 · review
06 · The body
- Damiola F, Le Minh N, Preitner N, Kornmann B, Fleury-Olela F, Schibler U. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes & Development 2000;14(23):2950-2961. DOI 10.1101/gad.183500 · study in mice, Geneva
- Wehrens SMT, Christou S, Isherwood C, et al. Meal timing regulates the human circadian system. Current Biology 2017;27(12):1768-1775. DOI 10.1016/j.cub.2017.04.059 · study in people
- Thaiss CA, Zeevi D, Levy M, et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell 2014;159(3):514-529. DOI 10.1016/j.cell.2014.09.048 · study in mice and people
- Reyner LA, Wells SJ, Mortlock V, Horne JA. 'Post-lunch' sleepiness during prolonged, monotonous driving - effects of meal size. Physiology & Behavior 2012;105(4):1088-1091. DOI 10.1016/j.physbeh.2011.11.025 · driving simulator
- Wittmann M, Dinich J, Merrow M, Roenneberg T. Social jetlag: misalignment of biological and social time. Chronobiology International 2006;23(1-2):497-509. DOI 10.1080/07420520500545979 · questionnaires
07 · The road
- Horne JA, Reyner LA. Sleep related vehicle accidents. BMJ 1995;310(6979):565-567. DOI 10.1136/bmj.310.6979.565 · police data
- Lenné MG, Triggs TJ, Redman JR. Time of day variations in driving performance. Accident Analysis & Prevention 1997;29(4):431-437. DOI 10.1016/s0001-4575(97)00022-5 · driving simulator
- Philip P, Taillard J, Moore N, et al. The effects of coffee and napping on nighttime highway driving: a randomized trial. Annals of Internal Medicine 2006;144(11):785-791. DOI 10.7326/0003-4819-144-11-200606060-00004 · road, at night
- FEDRO, A2 hourly counts, 2022-2025 · driveawake.ch
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