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Time After Time

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Rhythms of Life: The Biological Clocks that Control the Daily Lives of Every Living Thing

By Russell G. Foster and Leon Kreitzman

(Yale University Press, 276 pp., $19)

Man has invented many ways to measure physical time, from ancient sundials to water and sand clocks, from the pendulum to the wind-up pocket watch, all the way to the modern atomic clock. An example of this latter-day timekeeper, introduced in 1950, measures a second as 9,192,631,770 cycles in the energy radiation of the Caesium atom. This produces an atomic second, which is one-86, 000th of a solar day, and is accurate to one second in three million years. Not bad, if you care about promptness. Whether time is real or not (as philosophers continue to ponder), whether without our constructions it really does "flow," what unites all clocks is that they measure a well-defined, regular, and uniform physical change of one kind or another.

In their wonderful book, Russell G. Foster and Leon Kreitzman tell us that while our ability to measure time has improved over the ages, we have nevertheless "been steadily losing a battle with time. Instead of controlling our modern clocks, they control us." Think about it: when we want to know when it is time to eat, or to go to bed, or to plan a vacation, we look at watches and clocks and calendars. Increasingly, these tools become dictators. But consider nature for a moment: without a Rolex or even a Swatch, the monarch butterfly knows to migrate from North America to Central America at precisely the same time each year. With no calendar and no alarm clock, the cicada emerges from the ground after exactly thirteen or seventeen years for a few fleeting weeks of frenzied mating--and the squirrel knows where and when to return to each and every one of its buried stashes of perishable goodies precisely before they lose their value and must be abandoned like surplus cottage cheese in the grocery. Bears hibernate, swallows rise to catch the early worm, and even plants seem as if they are silently counting the hours. This last fact has been known for some time: Linnaeus suggested back in 1751 that two species of daisy, the hawk's-beard and the hawkbit, be planted in a circle, since each opens and closes within precisely half an hour of the other, creating the hands of a floral clock.

So do organisms have invisible clocks and calendars? Has the march of civilization alienated us from our once equally intimate familiarity with nature? A first clue about such perplexities presents itself when we fly across oceans and find ourselves helplessly watching B movies in our hotel room at four in the morning: the difficulties of overriding jet lag--or the "work lag" of the night shift--are also the fruits of civilization. There are nuisances that are to be found only in the human world. All this makes it more difficult to answer the above questions with any conviction. We live in a "24/7" world, and have cleverly invented the modern means--electricity, alarms, heating, pharmaceuticals--to overcome our ancient evolutionary rhythms. No longer bound to the cadences of nature, we need not shiver in winter and rise early in the summer months--or so most of us believe.

But it turns out that we are wrong. Just like all the living things around us, we are constitutionally defined by our internal rhythms, and it takes more than a few thousand years of culture to override a few billion years of evolution. Heart attacks and births, Foster and Kreitzman report, occur most often between four o'clock and six o'clock in the morning. Toothaches are calmest after lunch, urine is produced fastest in the evening, and you are most likely to develop an allergic reaction an hour before midnight. Body temperature, heart rate, and blood pressure are all lower at night and higher during the day, and dance to a regular daily meter. Even cognitive ability varies throughout the day: take an exam at eight in the morning and your score is likely to be different from the result you would obtain on a test taken in the afternoon. In nature, there are intertidal, lunar, annual, and circadian ("about a day") rhythms, along with the lesser-known infradian (longer than a day) and ultradian (shorter than a day) cadences.

It stands to reason that such rhythms should have been etched into living beings over evolutionary time, for although the week and hour and minute are human inventions, the Earth will rotate on its axis about every twenty-four hours for at least the next five billion years, and the moon will wax and wane every 29.5 days, and the tide will roll over the waves twice a day, and Sirius the Dog Star will rise with the sun every 365 of them. For humans, it is primarily the circadian rhythms that govern much of our behavior (though female readers will rightly protest that I have never experienced certain rattling lunar effects). Whether you shake a hand firmly depends on the time of day, and may not seem all that important; but consider that there is a favored hour of lovemaking for married and non-married, child-rearing and childless, working and unemployed people, and your ear for chronobiology (named for Cronus, the Greek harvest deity) may suddenly perk up. There is a relationship, in sum, between our internal clocks and the outside world, and figuring out how that works has been one of the more exciting rides in modern biology.

 

The tale of chronobiology has many heroes going back to the 1800s, but as the neurobiologist Foster (himself a protagonist) and his co-author Kreitzman relate, the modern story really only begins in the early part of the twentieth century. In different places and with different organisms, clues began gradually to accumulate. It started with August Forel, a Swiss doctor and naturalist, who noticed one day in 1910 that a group of bees came to feed on the remains of his breakfast. The bees would appear every morning at precisely the same time, even when he tricked them and set no food on his table. Next it was the German-American scientist Curtis Richter, working in the lab of John Broadus Watson at Johns Hopkins, who noticed in the early 1920s that when he soundproofed and blackened the windows of the lab, muting all possible external stimuli, his rats seemed to behave in a rhythmic fashion, eating and feeding and treadmilling at fixed times. This was something of an irony, since it was occurring in the lab of the man who thought all behavior was just a matter of stimulus and response. More importantly, it led to a search for the source of the rhythm. After all, if pure behaviorism was out (since organisms react differently to the same stimulus in different contexts, and behaviors persist regularly without them besides), and if motivation, too, failed to do the trick (since it cannot explain why rats eat at given times irrespective of how hungry they are), then some kind of an internal clock seemed more and more obvious.

Some years later, in 1930, Erwin Bunning in Germany showed that the leaf movement of the common bean Phaseolus oscillated in complete darkness at a period of 24.4 hours. He called this period the "free-running" rhythm of the plant, and it soon became evident that what was true for the bean was true for the sea anemone, the kangaroo, the spider, and the weasel: organisms on Earth, including humans, have a free-running rhythm that is close to, though never precisely, a twenty-four-hour cycle. It became evident that while external cues could synchronize this rhythm to fit the twenty-four-hour day, they did not cause it; the free-running rhythm looked more like the ticking of some kind of internal clock.

The notion of an inner clock again gained support from the bees. Karl von Frisch had been studying the way bees locate sources of food, and more importantly how they report its location to their friends back in the hive. Figuring out how their waggles and angles of dance conveyed azimuth and distance would ultimately win him the Nobel Prize, together with the century's two other great ethologists, Konrad Lorenz and Niko Tinbergen. But the observation that when there was a headwind the bee reported a greater distance to the source of food made it clear that it had to have some internal sense of time. After all, distance traveled is time multiplied by speed, and the headwind meant that the speed to the prize was lessened.

 

 

But if bees and beans and humans have internal clocks, what common features would they be expected to share? At the heart of the clock would be a self-sustaining oscillator, something that counted off beats in regular intervals in the absence of any external time cues. There would have to be a setting mechanism or time-giver (Zeitgeber) linking the internal oscillation to the outside world--to the predictable movement of the sun and constellations, maybe even to temperature, magnetism, or food. And there had to be a means of making the output biologically useful--something we could observe as regular, rhythmic, adaptive behavior. But how could a set of biochemical reactions produce rhythms with a period of about twenty-four hours? The problem is that biological molecules are highly sensitive to temperature: an enzyme works at entirely different speeds as the temperature of its environment changes. Mammals and birds use homeostasis to create a stable internal environment, but what about algae and coral, or insects, lizards, and plants? The body temperature of such ectotherms fluctuates with the sun and seasons, and yet the rhythms of their lives remain fixed.

When a small group of experts met at Cold Spring Harbor in 1960, most agreed that despite this serious problem, there had to be inner clocks that were not dependent on external cues, though in truth none of them yet knew how this could work. What Colin Pittendrigh, who studied the emergence at dawn of Drosophila flies, had to say was amazingly prophetic: "The student of rhythms protests he has no common mechanism to give his field the unity he would like," the authors quote him, and yet there "are common mechanisms--built of different concrete parts--in circadian systems and photoperiodic effects everywhere." Pittendrigh could not have known how right he was. After all, the molecular revolution was just beginning; there were even still a few important scientists here and there who doubted the significance of the recent working out of the structure of DNA. And how would such "common mechanisms" work? It made sense that billions of years of evolution would relate life to the planet: if this were not so, birds would migrate south instead of north, fish eyes would not "flip" to their night mode when the time came, and CroMagnon man would wallow away his mornings in deep slumber. But what kind of inner oscillator plus external setting device could possibly be common to the diatom and the jellyfish, the alewife, the red-throated loon, and humans?

The road to the answer led in two directions. Down one path, researchers followed the lead of Richter, who had been able to show that lesions of the frontal part of the hypothalamus in rats abolish rhythmic circadian behavior. In 1970, researchers located the specific target in the hypothalamus that was playing the leading role--a small group of twenty thousand cells called the suprachiasmatic nuclei (SCN). Another lab confirmed that this was the special location by injecting radioactive amino acids into the eyes of rats and following the tracer molecules as they made their way through the optic nerve to the brain. As structures analogous to the SCN were found in birds and reptiles, people began to get excited. And when researchers, including Russell Foster, transplanted the SCN of a mutant hamster with an internal clock with a period of twenty-two hours into the brain of a normal anucleate whose behavior now adopted that same rhythm, they were ecstatic. Soon people were evocatively calling this tiny speck, its volume only one-third of a cubic millimeter, the "mind's clock."

 

The second path to the solution of the mystery of biological time followed upon the heels of one of the molecular revolution's great heroes. The son of Jewish immigrants from Poland, Seymour Benzer was given a microscope in Brooklyn in 1934 as a bar mitzvah gift. At fifteen he was already a scholarship student at Brooklyn College, though no one in his family had previously gone beyond the twelfth grade. Considered the "egg with two yellows" of his family, Benzer combined what his biographer Jonathan Weiner called "a feeling for physics and a feeling for the study of life." It was this rare combination that ultimately set his goals: to discover the physical characteristics of genes to understand how genes explain behavior.

At Purdue, Benzer developed a system that allowed him to show that genes were not indivisible, as was believed, but could actually be cut up into pieces. Mutant flies with curly wings were often the result of a single nucleotide base being replaced by another. Just as with the atom before Rutherford, it was hard to believe that the gene was not indivisible--that was bad enough. Much more outrageous was the heretical suggestion that certain behaviors, as opposed to mere physical traits or diseases, would be altered if a single gene was damaged. So it is perhaps not surprising that when a graduate student named Ronald Konopka arrived at his lab in Cal Tech in the mid-1960s, the notoriously late-sleeping Benzer set him on a course studying the genetics of circadian rhythms. Before long, Konopka discovered a mutant fly with no sense of time.

Crossing the mutant with wild-type flies revealed that the responsible gene resided on the X chromosome. It was dully dubbed per, for "period." Shortly after Benzer and Konopka sent "Clock Mutant of Drosophila melanogaster" to the Proceedings of the National Academy of Sciences, the great man of molecular biology, Max Delbr

ück, came up to Benzer with a drink in his hand at a Pasadena party. "I don't believe it," he said in his thick German accent. "But Max," Benzer pleaded in his Bensonhurst drawl, "we found the gene!" Training his famous blue gaze right back at Benzer, Delbrück answered: "I don't believe a word of it." But it was real. And even though it was unclear whether there were other genes involved, and how precisely they coded for a timer, Benzer and Konopka had found the first-ever clock gene in any organism, firmly--some thought ominously--linking behavior to genetics.

In the decades that followed many details became clear, and while not all the cogs and pegs of the systems in all organisms have been fully worked out, the basic principle is simple: a clock can be constructed of a gene that codes for a protein which acts to inhibit its own production, and a second protein that delays this self-inhibition by a reliable amount of time. In the tiny mould Neurospora, for example, the gene frequency (frq) codes for the protein FREQUENCY (FRQ), which is regulated by another protein called WC-1. WC-1 is made eight hours later than FREQUENCY, which itself takes around sixteen hours to wind up back to its peak level, thereby creating a twenty-four-hour clock. It's as simple and as beautiful as that.

So how is the inner clock made to synchronize with the environment? How, in the end, does an organism's "free rhythm" match itself to the demands of the outside world? Here is an example from another organism. In Drosophila flies, the FREQUENCY and WC-1 equivalents are called PER and TIM. When light reaches TIM through the optic nerve of the fly, it degrades it in a regular, predictable fashion. In this way, with the help of a few other proteins, the PER/TIM feedback loop is aligned to the light/dark cycle, providing the crucial link between inner and outer worlds. This process is called "entrainment," and while cues such as temperature, food availability, humidity, and even social contact can act as triggers, light is nature's greatest entrainer of all.

This makes good evolutionary sense. Light is the most stable of these cues, and it can be used not only to signal dawn and dusk, but also, since the amount of light falling on the Earth varies precisely with latitude and season, to calculate the time of the year. This is how the salmon and the loon and the monarch know when to migrate, the roe deer and the wallaby and the cicada when to mate, the squirrel how to find its stash on time, and the tobacco plant and the evening primrose when to release their scents for pollinating nocturnal insects. It is how the internal private message becomes the external natural poem.

Sometimes the poem may be put to work for other purposes. Spanish farmers understood this centuries before latter-day tulip growers began manning their glowing tractors at night to expedite sales: over two hundred years ago, they were providing artificial lighting to increase egg production in chickens. Even NASA has been paying close attention: it is significant, and worrisome, in terms of astronauts' fatigue and performance, that there is no regular light in space, or that Mars has a day of 24.65 hours. Light has been such an important entrainer that evolution has even "invented" in mammals a whole new class of photoreceptors, different from the rods and cones used for vision, in order to bring it safely to the SCN in the brain. The surprise existence of such receptors, discovered in Russell's own lab six years ago, made it clear that even diseased eyes need to be kept intact in order to allow them to perform their circadian functions. Blind people, with no working rods and cones, still need their eyes for waking and sleeping.

 

 

As impressive as they may seem, these satisfying tales of scientific triumph are simplified versions of the story. How birds migrate, when animals decide to mate, even what precise proteins construct the Neurospora clock, are all difficult and complex problems. There is much that we still do not know. Still, figuring out the basic workings of the DNA "tick" and protein "tock" of all living beings' internal rhythms, and the external cues that entrain them, has been one of the most impressive journeys in the recent history of science. Showing that, since many of the genes and proteins that tell time are similar in mice and flies, there must have been an ancestral clock for insects and mammals going back seven hundred million years--and a much, much earlier one for bacteria--is an extraordinary accomplishment. What it all means is that, from the beginning, we have evolved to regulate our internal worlds, but also to keep in step with our planet. There is no inner without an outer.

There is also no single time for any given person, though this is not the subject of Foster and Kreitzman's book. We refer to time "flying" and time "crawling," even to time "freezing in its place." How we come to these judgments depends on our mental and emotional states, and on the ways they process information, rather than on a direct ability to sense or to perceive, as in feeling the heat of a candle advanced toward our face. A moment of remembered silence may be judged an eternity. Artists have depicted this: the description in The Magic Mountain of the tortured minutes experienced by tuberculosis patients in the sanitarium as their doctors take their daily temperature will not soon be forgotten by any reader who has a temperature, any temperature. Students of psychological time have shown that the perception of time is related to the degree to which we actually think about time, which is why amusement park lines snake around bends rather than extend infinitely backward, why mirrors are placed beside busy elevators and digital clocks on train platforms, and why a line into which someone cuts is judged longer by its slighted members than an equally long one where everyone behaves.

Time is an acquired concept, as any parent who has heard his toddler say "Let's go to Grandma yesterday" knows. In a famous experiment, the Swiss psychologist Jean Piaget presented two racing snails to three-year-old children. Even though the snails started and stopped at the very same moment, the one who had gone a longer distance was judged by the kids to have traveled for the longest time. The five-year-olds finally got it: our concepts of speed and of distance are primary to our concept of time.

But psychological time is not the only sister of the physical and biological sorts, as the Ugandan "milking time," the Quechua "time of the boiling potato," and the Bedouin "cigarette" make abundantly clear. (Time walking from place to place is measured by Bedouin by the number of cigarettes smoked on the journey. ) Generally speaking, in Western culture time is an independent variable that does not shrink or grow as a function of how one uses it (although this is far from how we perceive it), nor does it change from place to place. But the Hopi, by contrast, have no sense of simultaneity: two events cannot take place at the same time if they cannot be seen happening together. The ancient Chaldeans who invented astrology judged that time can be measured by the movements of celestial bodies. And because they believed that time determines destiny, the travels of stars were (and for many people still are) portents. Irrespective of the Rolex, molecular clocks, and the vagaries of the human psyche, cultural time is thoroughly and variously and colorfully constructed.

Besides physical, biological, psychological, and cultural time, there are of course the historical, evolutionary, geological, and cosmological time frames. This first one has since Herodotus been a subject of debate: do the events of the future really await their turn to appear? Should we imagine, as Collingwood quaintly asked us not to, that "the past and future exist in the same way ... in which, when we are walking up the High past Queen's, Magdalen and All Souls exist"? On this question there is not much agreement. But geological and evolutionary time are another matter: here the battles have been waged not between all forms of predestinarians and anti-determinists, but rather between men and women who lack religious faith and those who have it. When James Hutton, the eighteenth-century Scottish geologist who discovered deep time, said of the Earth that "we find no vestige of a beginning--no prospect of an end," or when Darwin wrote that primordial man and the sea cucumber had a common ancestor, many believed--and still do--that the floodgates to hell had opened. As for the contemplation of the vastest time frame of all: whoever it was who said that "eternity is a very long time, especially toward the end," when we think cosmologically all of us suddenly smile at each other with a kind of warm feeling of excited wonder. There is something about reflection on the limitlessness of time that renders our usual human squabbles rather petty.

 

 

But let us return to our own biology. Philosophers may argue over whether time is real, but the unlucky few who suffer from the incredibly rare familial fatal insomnia, or even just the rest of us who experience good old-fashioned jet lag, do not feel as though we need to penetrate the philosophical argument too deeply--for us, the answer is obvious. As Foster and Kreitzman show in the last chapters of their book, chronobiology is not only about how cicadas know when to burrow through the ground and monarchs when to migrate, but also about when to dispense important drugs and how best to treat disease and cancers.

Consider familial advanced sleep-phase syndrome, or FASPS, in which people have a shifted wake/sleep cycle, falling into bed at 7:30 p.m. and waking before the roosters at 3:30 in the morning. Louis Ptacek at the University of Utah has found that the disorder is inherited, and that in some patients it is due to a single amino acid change in the protein encoded by the per gene. To date this is the first example of the genetics of a complex behavior in humans, the sapiens equivalent of Benzer and Konopka's Drosophila discovery.

The authors quote a wry remark about the discovery: "It seems that our parents--through their DNA--continue to influence our bedtimes." But these are serious matters. In England, about 3 percent of the population suffers from Seasonal Affective Disorder (SAD), in which autumn and winter bring with them depression. SAD is much worse in the higher latitudes of Norway, where a frightening 27 percent suffer annually from the disorder, becoming sleepy, gaining weight, and often losing interest in life altogether. Rheumatoid arthritis, osteoarthritis, asthma, even cardiovascular troubles are all marked by strong circadian rhythms in the manifestation of symptoms. This last example is due to the fact that blood pressure and heart rate both peak in the early morning, which explains why most heart attacks occur at 6 a.m. (Heart attacks are also 33 percent more common in the winter than in the summer.) As if their days were not bad enough, sufferers of Alzheimer's have a disturbed circadian rhythm, making sleep at night an even more difficult prospect. A combination of bright-light and melatonin therapy may help relieve more general symptoms of this horrible affliction, an approach that doctors are now trying.

But there is a snag: chronotherapy is expensive and labor-intensive, and so it has yet to become a mainstay of the medical profession. Many of the drugs used to treat cancers, for example, attack rapidly growing cells at a particular phase of their division. The problem with chemotherapy is that such drugs also attack other rapidly dividing cells, such as hair follicles and bone marrow, resulting in baldness and pain. But the circadian rhythms of the healthy cells are often not the same as the rhythms of the cancers, so if the daily treatment is confined to the times when the cell cycle of DNA replication of the normal cells is lowest, anti-cancerous drugs may be dispensed in greater doses. It stands to reason, then, that patients should be treated with the body's clock in mind, and yet they usually receive their drugs at times that are convenient to the hospital employees, rather than at times that would be most effective in combating their diseases.

The larger issue is that we will be increasingly able to understand and to manipulate our rhythms. If you believe that necessity is the mother of invention and that money counts in this world, then the $40 billion annual tab for the effects of sleep disorders in the United States alone (through productivity loss, accidents, and medication) render the appearance of new targeted drugs, and eventually genetic intervention, more likely. Will we all want to take a pill or flip a gene that will free us altogether from slumber, or will we be content to limit its use to doctors, CEOs, busy moms, and fighter pilots? (The American military is already spending $100 million on research on a drug called modafinil, which cuts sleep requirements and is used in Iraq and Afghanistan today.)

We live in a maniacally fast and busy world, in which television and radio update our every minute and working hours and travel are increasingly heedless of the cadences of our planet. Evolution and chronobiology teach us that our inner and outer worlds are fundamentally connected. But finally how we view time is intimately connected to our dreams and aspirations--the way we would like to see the poem of our lives, and of our world, written. Will we wish to continue our growing detachment from the cycles of the sun and moon and tide and planets, or will nature more powerfully, or rudely, return us to its order? In the end, it may be up to us.

Oren Harman is the author of The Man Who Invented the Chromosome (Harvard University Press) and the co-editor of Rebels, Mavericks and Heretics in Biology (Yale University Press).

This article originally ran in the December 24, 2008, issue of the magazine.

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