Thursday, April 01, 2004

Are We Trying to Banish Biological Time?

By: Russell G. Foster B.Sc., Ph.D.

Can we—should we—vanquish biological time? With or without our participation the decision is already being made, argues the author.

Timing may not be “everything,” but it is instructive to ask how the following facts and observations could be related: Almost half of all medication the space program uses in orbit is intended to help astronauts sleep. The accident at Three Mile Island began at night, as did those at Chernobyl and the Union Carbide plant in India. The side effects of chemotherapy could be reduced several-fold if doctors would time the treatment. Heart attacks are not randomly spaced throughout the day; they are concentrated between 6 a.m. and noon. Some soldiers in combat situations now take a drug that keeps them on their feet for three days and nights— with few evident side effects. What is all this about? Timing, explains the author: specifically, the biological clocks that control our “circadian rhythms,” exerting their influence at the cellular (and even molecular) level, often against our embrace of the 24/7 world.

Clocks instruct us to go to bed, wake up, and eat. But even as we are driven by the motions of a mechanical device, hacking our day into hours, minutes, and seconds, our bodies are answering to another, more persistent beat—one that probably started ticking shortly after life appeared on Earth. Embedded within our genes and those of almost all living things are instructions for a biological clock, one that still harkens to the passage of approximately 24 hours.                     

This conflict between mechanical and biological time is not new, but in advanced industrial societies it is intensifying, and rapidly. Round-the-clock activity is now the norm in utilities, transportation, manufacturing, finance, leisure, retailing, emergency services, media, and education, where employees work to the beat of an artificial rhythm. Indeed, all of us in the developed world now live in a 24/7 society. That this imposed structure is in conflict with our basic biology can be seen in the way that time and its demands contribute to stresses on our physical health and mental well-being—in the fundamental tension between the way we want to live and the way we evolved to live.

It was not always like this. Before the invention of sundials by the Babylonians, people lived by natural time. The sun, moon, and stars determined the pattern of life. The Earth turned on its axis and split time into day and night. Its tilt gave us seasons. People rose at dawn, tended their animals, and went about their activities until sunset. In that world, people knew the time by the sun and by what they were doing. A harmony existed between their daily bodily rhythms and the external world.

Not that the harmony was ideal, of course. In the latter part of the second century BC, the Roman playwright Plautus had one of his characters in a comedy complain about the tyranny of time, showing an implicit understanding of the internal rhythms that drive behavior.

The gods confound the man who first found out

How to distinguish hours. Confound him too,

Who in this place set up a sundial,

To cut and hack my days so wretchedly

 Into small pieces! When I was a boy,

My belly was my sundial—one surer,

Truer, and more exact than any of them.

The dial told me when ’twas proper time

 To go to dinner, when I ought to eat:

 But nowadays, why even when I have,

I can’t fall to unless the sun gives leave.

The town’s so full of these confounded dials.

Until we turned our nights into days and began regular air travel across multiple time zones, we were largely unaware of our internal clocks. Still, some of us may have noticed the striking impairment of our abilities in the early morning, reminding us that we are slaves to our biology. In fact, our ability to perform mathematical calculations or other intellectual tasks between 4 a.m. and 6 a.m. is worse than if we had consumed several shots of whisky—enough to classify us as legally drunk.

Welcome to the world of circadian rhythms (circa about, diem a day), those near 24-hour rhythms that persist when we or other living things are isolated from all environmental time signals such as the daily change in light or temperature.

CIRCADIAN RHYTHMS

As far as we know, the first person to study circadian rhythms was the French astronomer Jean Jacques d’Ortous de Mairan. Interested in the effects of the Earth’s rotation, de Mairan was curious why the leaves of some plants were raised during the day and drooped at night. In 1729, he put a mimosa plant in a cupboard to see what happened to it in constant darkness. Peeking in at various times, he noted that the plant’s leaves still moved rhythmically, as though the plant had its own representation of the 24-hour day. This simple experiment showed that daily rhythms were not a response to changing amounts of light; they were endogenous (internal). De Mairan had unknowingly identified the first circadian rhythm, although the term would not be used for more than 200 years.

The rigorous investigation of biological rhythms began in earnest in the 1930s, when Erwin Bünning in Germany found that the leaf movements of the common bean plant oscillated even when in constant darkness and constant temperature, with an average oscillation period of 24.4 hours. Bünning thus established a salient property of circadian clocks: When kept in constant conditions, they run with a period close to, but never exactly, 24 hours. The near 24-hour pattern of rhythmic activity under constant conditions of darkness or light is known as a “free-running” rhythm. It is life’s internal, unconstrained rhythm, the beat it keeps when free from other factors. A light-dark cycle or other time cues can synchronize or entrain these rhythms, but they do not cause them.

We are like the plants that de Mairan and Bünning studied. In experiments, volunteers have stayed underground in constant light for weeks on end. Under such constant conditions, human circadian rhythms average 24 hours, 11 minutes. With no way of knowing day from night, the volunteers’ body rhythms start to drift from synchronization with the outside world. After about two weeks, they go to bed at midday and wake at around 8 p.m. After about a month, however, they are back, more or less, in synchrony with the outside world—before they drift off again.

By the late 1970s, scientists had shown that many organisms had free-running rhythms under constant conditions. With a period close to, but not exactly, 24 hours, these free-running rhythms could be entrained to exactly 24 hours by some time-giver in their environment, such as night and day. Like all good clocks, these rhythms compensate for the effects of temperature. All other biological processes speed up and slow down with a rise and fall in temperature, but a clock would be useless if its period were not constant.

But if a clock drives these biological rhythms, where is it located and what does it look like? How does it work? How does it synchronize with local time? Is there just one clock?

THE HUNT FOR BIOLOGICAL CLOCKS

Under normal conditions, our inner clock uses the 24-hour cycle of light and dark to align biological time to day and night. Set to this rhythm, the clock then anticipates the differing demands of the 24-hour day and fine-tunes our physiology and behavior to prepare our body for changing conditions. Thus, body temperature drops, blood pressure decreases, and tiredness increases in anticipation of going to bed. Then, before dawn, metabolism gears up in anticipation of increased activity when we wake. But where in the body is the circadian mechanism located?

Under normal conditions, our inner clock uses the 24-hour cycle of light and dark to align biological time to day and night. Set to this rhythm, the clock then anticipates the differing demands of the 24-hour day and fine-tunes our physiology and behavior to prepare our body for changing conditions.

During his long life, the pioneering physiologist Curtis Richter carried out some of the earliest studies on rhythmic behavior in an attempt to locate the mammalian biological clock. He died in 1989, at age 95, after working in the same laboratory at Johns Hopkins University for 63 years. In a series of experiments, Richter removed the adrenals, gonads, pituitary, thyroid, pineal, and pancreas from experimental animals. He gave his rats electroshock therapy, induced convulsions, and prolonged anesthesia. Through it all, the rats remained rhythmic. Only when he looked further into their brains was he able to eliminate 24hour rhythms, inducing arrhythmicity (irregular rhythm). In 1967, Richter reported that lesions in the front part of the brain’s hypothalamus—he was not able to get any more precise—caused this arrhythmic behavior. 

In the early 1970s, Fredric Stephan, Ph.D., a graduate student of Irving Zucker, Ph.D., at the University of California, Berkeley, picked up where Richter left off. Carefully lesioning the front of the hypothalamus, he identified a small paired cluster of cells known as the suprachiasmatic nuclei (SCN) as playing a critical part in organizing rhythms of behavior such as drinking and locomotion. At about the same time, Robert Moore, Ph.D., M.D., at the University of Pittsburgh was following a different path to locate the clock, relying on the intimate relationship between the clock and light. Moore tracked a light beam as it came in through the eye and discovered that it traveled from the eye through the optic nerves and along a projection into the SCN in the brain. The new-found pathway from the eye to the SCN was called the retinohypothalamic tract. 

Amazingly, just 20,000 or so cells— an almost infinitesimal cluster— seemed to be responsible for controlling the timing of a mammal’s internal rhythms.

Among them, Moore, Stephan, and Zucker established that removing the whole of the SCN (but not just part of it) appeared to destroy all circadian rhythms. Amazingly, just 20,000 or so cells—an almost infinitesimal cluster—seemed to be responsible for controlling the timing of a mammal’s internal rhythms.1, 2 A model for the circadian timing system of mammals seemed to be emerging: The eye sensed light, and a dedicated pathway captured this information and delivered a sensory input to the SCN, which, in turn, was linked with the neural and endocrine systems. But was the SCN itself the clock—or merely part of a relay that linked external information with circadian timing? 

Finding the 20,000 cells of the SCN among billions in the rat brain was tough enough. Proving that this structure was also the seat of the biological clock was even tougher. Shin-Ichi Inouye, Ph.D., and Hiroshi Kawamura, Ph.D., at the Institute of Life Sciences in Tokyo performed critical studies demonstrating that the circadian pattern of rhythmic electrical activity in the SCN was high during the day and low at night. They then isolated the SCN by cutting around it with a tiny rotating knife, severing its neural connections to the rest of the brain. The rhythmic pattern continued within the SCN itself, but rhythmicity was abolished in neurons outside the cut. This suggested that not only was an electrical rhythm produced within the SCN, but also electrical signals from the SCN provided timing information to other brain regions. Still more evidence for the SCN clock came from Bill Schwartz, M.D., at the University of Massachusetts, when he discovered that the SCN is metabolically active during the day but relatively inactive at the night. Significantly, no other brain region exhibited such a dramatic rhythm.

 art_v6n2foster_2
After decades of searching for the mammalian “master” clock, scientists zeroed-in on a tiny cluster of cells in the brain, the suprachiasmatic nuclei (SCN), that seemed to be responsible for our internal circadian rhythms. The SCN comprises just 20,000 or so cells in the front of the brain’s hypothalamus, connected to our eye (and therefore sensed light), and linked with our hormonal systems. Circadian rhythms appear to exist even at the level of individual SCN cells. © 2004 Christopher Wikoff
 

The final piece of evidence came from experiments with SCN transplantation— and from the lucky discovery of a mutant hamster. Martin Ralph, a Ph.D. student in the laboratory of Michael Menaker, Ph.D., (at the University of Oregon and later the University of Virginia), noticed that one hamster shipped to the lab had a short free-running rhythm. Ralph discovered the hamster carried a mutant gene (allele). A single copy of the gene resulted in a free-running rhythm of about 22 hours, but two copies produced a rhythm near 20 hours. Ralph and Menaker realized that the mutant gene, which was named tau, provided a way to test whether the SCN was unambiguously the body’s master clock. If the SCN was removed from the mutant hamster and transplanted into another in which the SCN was destroyed, would the recipient then show a circadian period of the donor—or retain its own? If the period were that of the donor, not that of the host, then the SCN must contain the oscillator. Ralph and Menaker, along with Fred Davies, Ph.D., and me, transplanted the SCN from tau mutant hamsters into normal hamsters after their SCN was destroyed. In every case, the restored rhythm showed a period close to 20 hours. Likewise, when the transplantation was performed from normal to mutant, again it was the period of the donor that was restored. Here was unambiguous proof to satisfy even the severest skeptic. The SCN contained a circadian oscillator.3 

Soon after these tau mutant studies, other researchers found that even individual cells from the SCN had circadian rhythm. Steven Reppert, M.D., and his team at Harvard discovered that the overall activity of individual rat SCN neurons showed a marked circadian rhythmicity averaging 24.35 hours.4 Not only was the SCN the anatomic site of the oscillator, but it also was composed of cells that themselves oscillated and that somehow coordinated their individual firing to give an overall rhythm of just more than 24 hours. Thus, by 1995, circadian organization appeared to rest exclusively on the collective activity of single SCN neurons that drove the rhythmic timing of drinking, feeding, sleeping, and so on. We now know, however, that this description of mammalian circadian organization is incomplete. 

LOOKING FOR CLOCK MOLECULES

If, as had been shown, individual SCN neurons, like single-celled organisms, could generate a circadian rhythm, then the basic mechanisms had to reside within the cell, not in the interactions of cells. The search that ended in discovery of clock genes in mammals started with the Nobel Prize winning work by Seymour Benzer, Ph.D., on Drosophila, the fruit fly. In the 1960s, scientists established that different physical forms (phenotypes) of Drosophila, given descriptive names like “Curly wings” or “Bar eyes,” were the product of defects in single genes. In other words, a direct link existed between some specific genes and specific phenotypes. Now, Benzer wanted to see what effect a change in a single gene might have not on an organism’s physical features, but on its behavior. 

The very idea was heresy. At that time, scientists thought it would be far too complicated to ascertain the effect of a single gene on even the simplest behavior. By using the analogy of a mechanical clock with its hundreds of parts, behavior was thought to depend on the interaction of dozens, hundreds, perhaps even thousands, of genes. Examining a single cog would tell you little about how the clock worked. 

A young graduate student, fascinated by the way organisms seemed to sense time, went to Benzer’s laboratory to explore the possibility of genetic influence on such behavior. Although the undergraduate thesis of Ronald Konopka, Ph.D., was on circadian rhythms in plants, he became particularly interested in the genetic basis for circadian regulation of behavior in Drosophila. Konopka exposed flies to chemical agents that caused random mutations in the DNA carried by the sperm of the fly. He then bred these individual mutant flies and studied their circadian behavior. Skeptics said it would not work: Even if Konopka found clock mutants, he would be unable to find out what had gone wrong at the level of the gene. After all, thousands of mutations might affect the clock. All Konopka was doing was making flies sick, and, even if there was a single mutation of the clock gene, the fly might not live long enough to breed. 

Konopka confounded them all. He found what he was looking for in the 200th fly. Normal wild-type Drosophila have a free-running period a little longer than 24 hours, but he found a mutant with a period of around 19 hours, another of 29 hours, and a third mutant that showed random (arrhythmic) behavior. Crossing the mutants with wild-type flies revealed that the three different mutant flies (short, long, and arrhythmic) had mutations in the same gene. Because mutations in this gene altered the period of the fly’s circadian rhythm, Konopka called it the period (per) gene; he and Benzer had identified the first clock gene to be found in any species. Nobody knew yet whether other genes were involved in the molecular clockwork, and, if so, how they might interact; but an all-important first step had been taken in the long journey to disassemble the molecular clockwork.5 

Because mutations in this gene altered the period of the fly’s circadian rhythm, Konopka called it the period (per) gene; he and Benzer had identified the first clock gene to be found in any species. 

Genes send a message in the form of mRNA, which is decoded to generate proteins within the cell. It is proteins that perform most of the functions of an organism, acting as regulators, enzymes, signaling molecules, and structural components of the cell. By convention, genes are written in lowercase italics and their protein product in uppercase. So if per was the gene, then there had to be a protein called PER. What and where was PER, and what did it do? 

The first real key to understanding how PER might be involved in clock function came some years after Konopka and Benzer’s work. At Brandeis University, Kathy Siwicki, Ph.D., and Jeff Hall, Ph.D., (another of Benzer’s students) detected PER within individual cells of the fly’s body. They showed that, although PER was present in many different tissues, a small group of cells in the fly’s brain (the lateral neurons) and eyes showed 24-hour rhythms in the amount of PER protein. These patterns of protein abundance mirrored circadian behavior. In normal flies, protein levels peaked early at night (around 8 p.m.) and then dropped to undetectable levels in the middle of the day. In 19-hour mutants, PER peaked much earlier, in 29-hour mutants it was greatly delayed, and no PER protein could be detected in arrhythmic flies. The likeliest explanation for this oscillation in protein was that rhythms of per mRNA drove the rhythmic production of PER protein. Sure enough, per mRNA showed a 24-hour cycle, with the peak in mRNA occurring some four to six hours before the peak in PER protein. 

With this information, Paul Hardin, Ph.D., and Jeff Hall in 1990 proposed a possible mechanism for the rhythmic expression of PER. Perhaps, they hypothesized, PER protein was involved in a kind of negative feedback loop, whereby it inhibited its own production. First PER levels would build up, then reach a point at which they would inhibit the production of per mRNA, which would, in turn, result in lowered production of PER. Eventually, though, when all PER production stopped, the per gene would once again go into action, and PER proteins would be produced. The dynamic tension between the positive and negative elements of the loop created the rhythm. Hardin wrote, “feedback of the per gene product regulates its own mRNA transcription, there is a protein ‘tick’ and an RNA ‘tock.’”6

But this model still does not answer the question of how a stable rhythm is generated. Negative feedback typically keeps a system in equilibrium within defined limits, like the thermostat on the heating system. The nature of oscillation is different, characterizing a system that moves away from equilibrium before returning. Realizing PER could not act alone stimulated the hunt for additional components. To date, more than 10 genes and their protein products have been identified that participate in this molecular oscillation in Drosophila, and there are probably many more. 

Many genes of the circadian clock are similar in both mice and Drosophila, suggesting that a circadian clock existed in the common ancestor of insects and mammals some 700 million years ago. 

But what about mammals? The mouse genome is fairly well understood. Using the Drosophila model of the clock genes as a guide and fishing for similar (homologous) mouse genes, scientists developed a reasonably comprehensive picture of the mouse clockwork mechanism. Many genes of the circadian clock are similar in both mice and Drosophila, suggesting that a circadian clock existed in the common ancestor of insects and mammals some 700 million years ago. But looking beyond that, before the animal branch of the evolutionary tree, what similarity will we find in the molecular basis of the clock? The answer is not a lot. The genes identified to date in plants, fungi, and bacteria bear no real resemblance to any of the known clock genes in animals, suggesting the biological clock could have evolved multiple times. Nonetheless, although different sets of genes seem to generate the clock, the same fundamental mechanism—a self-regulated feedback loop involving proteins— is at work. 

MASTER CLOCK—OR CLOCKS?

A decade or so ago, the idea that the mammalian circadian system was regulated solely by a “master clock” in the SCN started to unravel. Scientists knew that insects had multiple circadian oscillators. For example, the abundance of clock genes in the wings, legs, oral regions, and antennae of Drosophila is evidence of circadian rhythms outside the nervous system. But mammals were thought to be different, and even the discovery of clock genes in tissues outside the mammal SCN did not ring many alarm bells. Then, in a series of experiments at the University of Geneva, Ueli Schibler, Ph.D., demonstrated decisively a 24-hour pattern of clock gene expression in cultured cells from connective tissue. These and later experiments with liver and heart tissues led to the realization that cells throughout the body not only express clock genes but also can drive circadian rhythms for several cycles when isolated from the SCN. 

So is the body composed of billions of independent clocks? Ah, but there is a critical difference between a peripheral, or organ, clock and the SCN. Only transplanted SCN cells can restore rhythmicity to an animal whose original SCN cells were destroyed. Transplanting cells from other regions of the brain will not make an arrhythmic animal rhythmic. This discovery leads to the idea that the SCN may be the regulator of a circadian organization based on multiple oscillators, rather like the system that generates “standard time.” 

At the beginning of the 19th century, there were 144 official times in North America. A town could reckon its local time from noon, when the sun was highest in the sky, so, for example, New York’s day started and ended five minutes before Philadelphia’s. None of this mattered too much when transportation was limited to 20 or so miles a day by horse-drawn coach. But when the railways came along and journey times shortened, precise coordination of timing became important, particularly when the railways began publishing timetables. In 1848, Britain standardized time across the mainland to Greenwich Mean Time. As the pace of global communication increased, the need increased for a master clock to bring all the local times into line. We still tell the time locally, saying 2 a.m. in London while knowing that it is noon in Sydney and 9 p.m. in New York City. But a standard time signal locks all the local times together. 

Under normal circumstances, the mammalian circadian system probably works in the same way. Rather than the simple linear model, our timing mechanism is a complex network. All the organs are linked to a central time signal within the SCN, and their activities can therefore be coordinated. 

SHIFT WORK AND SHEDDING LIGHT ON THE CLOCK

To perform its function, a clock must be set to local time, and the near 24-hour molecular rhythm in the SCN is normally adjusted every day by exposure to darkness and light. Even with total loss of sight, this adjustment continues, but loss of both eyes in any mammal, including humans, results in both visual and circadian blindness.  

An unexpected result of studying the light-detecting mechanisms that adjust the circadian system was discovery of the previously unknown group of light-sensing cells within the eye. When my colleagues and I proposed the existence of such cells, a little more than a decade ago, we met considerable skepticism. Could something as important as an unrecognized photoreceptor in the eye possibly have been overlooked? The eye was the subject of serious study for more than 150 years, and its functions were thought to be well understood. The rods and cones of the outer retina detect light, and the cells of the inner retina filter the information before signals travel the optic nerve for advanced processing elsewhere in the brain. 

We showed, however, that, although the circadian-related photoreceptors of mammals are located in the eye, neither the rod nor cone photoreceptors are involved. We discovered this while studying mice, but others were subsequently encouraged to study the circadian function in blind people. Two research groups identified blind individuals who had eyes but lacked conscious light perception. Despite this anomaly, some individuals were able to regulate their circadian responses to light. One practical result of this discovery is that every attempt is now made to preserve an intact eye in people with certain forms of eye disease so that the eye can perform its circadian function. 

The strong effect of light on our biological clock presents a problem for night-shift workers. Normally, even after 20 years of night-shift work, individuals will not have shifted their circadian rhythms. Their metabolism, alertness, and performance are still high during the day (when they are trying to sleep) and low at night (when they are trying to work). This physiologic misalignment has been associated with increased death from heart disease and an eight-fold higher incidence of peptic ulcers. Other physical problems in night-shift workers include chronic fatigue, excessive sleepiness, difficulty sleeping, higher rates of substance abuse, and depression. Shift workers are also vulnerable when driving home after a night shift, especially on quiet, monotonous roads. After four successive night shifts, the risk of a single vehicle crash at 3 a.m. increases 50 percent.7 

So why don’t shift workers shift their clocks? After all, if we travel across multiple time zones, we recover from jet lag and adjust to local time. The explanation seems to be that the photoreceptor mechanisms that adjust our circadian system are fairly insensitive to light. 

So why don’t shift workers shift their clocks? After all, if we travel across multiple time zones, we recover from jet lag and adjust to local time. The explanation seems to be that the photoreceptor mechanisms that adjust our circadian system are fairly insensitive to light. Thus, our clock will always respond to bright natural sunlight in preference to the dim artificial lights commonly found in the workplace. Shortly after dawn, natural light is some 50 times brighter than normal office and factory lighting, and at noon natural light can be 500 to 1,000 times brighter—even in Britain. So exposure to strong natural light on the journey to and from work, and perhaps during the day, normally prevents night-shift workers from adjusting their circadian system. But if the night-shift worker hides from bright natural light during the day and is exposed to brighter light in the workplace, then a shift in the body clock can be achieved. 

Many major maritime and industrial accidents have happened at night. The nuclear accident at Three Mile Island began at 4 a.m., and the one at Chernobyl started at 1:23 a.m. The chemical explosion at the Union Carbide plant in Bhopal, India, occurred at 12:15 a.m. The Exxon Valdez disaster also took place at night, but not, as is often supposed, because the ship’s captain had been drinking. He was not on duty at the time of the accident. The problem was a combination of poor shift-work scheduling, human error, excessive overtime, crew fatigue, inappropriate sleep schedules, inadequate shift changes, alcohol, insufficient training, and reduced crew sizes. 

Space travel is undoubtedly the most extreme shift-working environment. Crews on space missions sleep poorly. On some shuttle trips, up to half the crew take sleeping pills, and, overall, about half of all medication used in orbit is intended to help astronauts sleep. Even so, astronauts average about two hours less sleep each night in space than on the ground. That problem will have to be solved before the manned fiight to Mars, a round trip that will take more than two years. 

WITH MEDICATION, TIMING IS EVERYTHING

Many important functions of our bodies vary, sometimes greatly, over the course of a day. One of the standard tests for asthma is to measure airway function, which is usually higher in the afternoon than in the morning. An early-morning appointment with the doctor can confirm the severity of the condition, but the same person seeing the same doctor later in the day could well have a different result. Same person, same doctor, same disease—different time.

It would make sense to deliver a drug when it will be most effective, but most medications are not prescribed to intersect with the changing physiology and biochemistry of the patient. Instead, to make it easier to remember, patients are instructed to take drugs at regular intervals. 

It would make sense to deliver a drug when it will be most effective, but most medications are not prescribed to intersect with the changing physiology and biochemistry of the patient. Instead, to make it easier to remember, patients are instructed to take drugs at regular intervals. Doctors hope to maintain a stable drug level in the patient, trusting that the drug manufacturers have balanced therapeutic dosages with toxicity levels so the drug will work despite variations in how the patient processes it. A more effective approach would balance the circadian variation in what the body does to the drug (pharmacokinetics) with the circadian variation in what the drug does to the body (pharmacodynamics). 

Unfortunately, little has been done in clinical practice to acknowledge the importance of timing, despite, for example, experiments almost 20 years ago that showed a change in the daily scheduling of chemotherapy for ovarian cancer could reduce side effects such as hair loss and nerve damage by half. The report on the experiment said: “Every toxicity was markedly diminished several-fold simply depending on what time of day the drugs were given.”8 

What was going on here? The big challenge in cancer treatment is to kill the tumor without killing the patient, and the goal of most nonsurgical therapies is to attack the cancer cell’s replication machinery. Many drugs used in cancer therapy act at specific points in the cell-division cycle to destroy or inhibit the growth of rapidly dividing cells. Unfortunately, they also affect rapidly dividing noncancerous cells, such as those in bone marrow, hair follicles, and stomach lining. But the circadian variations in the cell cycle are different in cancerous and non-cancerous cells. Therefore, toxicity can be reduced if most of the daily treatment is confined to times of lowest cell division in the noncancerous cells, so higher doses can be given to target the cancerous cells. Unfortunately, this approach is far from typical. 

Francis Levi, Ph.D., M.D., at the Hospital Paul Brousse near Paris, and his associates in other European hospitals, treated more than 1,500 patients with colon cancer by infusing a rhythmically oscillating level of medication. The precise schedule depends on the drug. Levi found that, using this method, the dosage of chemotherapy can be much higher than the maximum the body can tolerate under a “flat-rate” regimen. As a consequence, about a three-fold increase was seen in the proportion of tumors that shrank by at least half. “All the side effects are reduced by chronotherapy,” Levi reported. “And this despite the fact that the dose which could be delivered was higher by 40 percent.”9 

Why is such a seemingly commonsensical and therapeutically beneficial approach still outside mainstream medicine? Cost is an issue, and the messy practicalities in the complicated, time-sensitive administration of the powerful, toxic drugs used in chemotherapy do not fit well with the shift patterns and work schedules of busy hospitals. Second-generation, multichannel ambulatory pumps, with simplified programmability and reduced volume, weight, and cost, should allow timed chemotherapy to be given to any patient cost-effectively. Such devices will help, but only when the medical community is convinced that such timed treatments are beneficial—currently this is not generally the case. 

Consider another application of circadian rhythms to clinical practice. The risk of heart attack from 6 a.m. to noon is 30 to 40 percent higher than would be expected if heart attacks occurred randomly throughout day and night. The risk of stroke heightens during the same time period. The most likely reason for these variations is the timing of the body’s changes in blood pressure and heart rate. Blood pressure is at its lowest during the night and rises about 10 to 25 percent from 6 a.m. to noon. Pulse rate also has a nighttime low and increases before waking, again by about 10 to 20 percent. The surge in blood pressure puts stress on arterial walls. If an unstable coronary or carotid plaque is there, it is more likely to be dislodged and then block a coronary artery, causing a heart attack. 

If the most dangerous period is during the morning, it would seem sensible to ensure that drugs being taken to reduce blood pressure are maximally effective at that time. If such a drug is taken at night, it reaches its peak concentrations just as morning circadian variations begin to appear. But a recent survey showed that, although more than half of U.S. primary care physicians know that blood pressure peaks in the morning, only one in seven patients is advised to take blood pressure medication before going to bed. 

Although more than half of U.S. primary care physicians know that blood pressure peaks in the morning, only one in seven patients is advised to take blood pressure medication before going to bed. 

Two other diseases that have profound circadian rhythms in both the manifestation and intensity of symptoms are rheumatoid arthritis and osteoarthritis.10 Rheumatoid arthritis can be distinguished from osteoarthritis by the time of day when the patient’s joints are most painful; morning stiffness is characteristic of rheumatoid arthritis, whereas with osteoarthritis symptoms often are worse in the afternoon and evening. Consequently, certain medications effectively relieve osteoarthritis symptoms when taken in the morning, but better results are obtained in rheumatoid arthritis when part of the dose is taken in the evening. 

Some diseases and disorders are specifically related to circadian malfunctions. Tiny changes in a human per-like gene can have a profound effect on our own behavior. One family studied by Louis Ptacek, M.D., and his colleagues at the University of Utah included a grandmother, daughter, and grandchild with the same sleep disturbance. Regardless of work schedules or social pressures, they cannot stay up much later than 7:30 p.m., and they tend to wake up around 3:30 a.m. By studying the family relationships, a small mutation was identified. This “familial advanced sleep phase syndrome” is exceedingly rare, but scientists are discovering that circadian malfunctions can be involved in depressive illnesses, as well. Also, schizophrenics and people with bipolar disorder have difficulties with timing activities —perhaps a symptom related to a circadian defect rather than dysfunctional behavior. 

THE FUTURE

The 24-hour variation in how we perform is increasingly at odds with the demands of a 24/7 lifestyle. In our society, many people are expected to perform with equal efficiency throughout the 24-hour day, and sleep tends to be regarded as a problem—almost an illness—to be minimized or even eliminated. The race is on to create the “metabolically dominant soldier,” a warrior who can fight 24 hours a day, seven days a week, without rest. British troops used stimulants to keep them awake during the Falklands conflict, and U.S. Air Force crews took amphetamines during the Libyan air strikes. Soldiers, sailors, and aviators must make instant decisions based on incomplete information. Even a slight drop in cognitive performance makes all the difference between life and death. But amphetamine use has side effects, ranging from agitation and irritability to nausea and sexual impotence. Also, when the drug wears off, a rebound effect of extreme fatigue or depression can occur. 

Pharmaceutical science has come to the “rescue” with modafinil, a so-called eugeroic (“good arousal”) drug. The French government admitted that its crack troops in the Foreign Legion used modafinil during covert operations inside Iraq in the first Gulf War. The U.S. military seems to have great hopes for modafinil, allegedly spending $100 million for research because soldiers who sleep less can provide a military edge. Michel Jouvet, M.D., an authority on sleep, claimed that “modafinil could keep an army on its feet and fighting for three days and nights with no major side effects.” Police, hospital staff, pilots, other people who work all night, and even students taking exams are among the tens of millions in our 24-hour society who might be tempted to take modafinil if it becomes generally available. But until we know exactly how it works and what the effects of its long-term use might be, I urge extreme caution.

We can keep pushing toward the 24-hour society and attempt to use pharmacological intervention to counteract the biological downside of working around the clock. Or we can reject that trend and embrace biological time. Those would at least appear to be our options—if we have not already gone too far to be able to make a truly free choice.

Based on our insights into circadian rhythms and sleep, it is not far-fetched to imagine that in the next few years we will fashion a whole range of drugs to manipulate these rhythms, drugs that could usher in a world that sleeps only two hours a night and is active during the other 22 hours. We have difficult choices to make. We can keep pushing toward the 24-hour society and attempt to use pharmacological intervention to counteract the biological downside of working around the clock. Or we can reject that trend and embrace biological time. Those would at least appear to be our options—if we have not already gone too far to be able to make a truly free choice. 

If we continue in our current direction, we would become the first species to dominate both the day and night. People say that we cannot “turn back the clock,” that “the 24/7 genie will not return to its bottle,” and, as a result, many believe that we have no alternative but to wage total war on the night. But as a society we have not bothered to ask about the costs and what we actually expect and hope to gain. 

Perhaps one answer is that we do not yet fully understand what it would mean to embrace biological time. We still have but a tenuous grasp of that aspect of our biology —we do not even know why we sleep. Solving that mystery will be one of the great challenges of the coming decades. Until it is solved, we should be wary of casually tossing sleep into the trash. 

Yes, I think it likely that technology will help us to cope with 24/7, but is coping the same as living? Unfortunately, that difference may matter less and less as many of us become too numb to appreciate it. Surely our future can be better than that, but only if we learn far more about the nature of biological time and, in particular, pose serious questions about how we can adjust society to its constraints instead of trying to adjust 3.5 billion years of evolution to the demands of a few generations of technological and societal change.

References

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About Cerebrum

 
Bill Glovin, editor
Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board
Joseph T. Coyle, M.D., Harvard Medical School
Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine
Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital
Robert Malenka, M.D., Ph.D., Stanford University School of Medicine
Bruce S. McEwen, Ph.D., The Rockefeller University
Donald Price, M.D., The Johns Hopkins University School of Medicine

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