What is chronobiology?

Science and Profession

Chronobiology refers to the study of various cycles or rhythms that are fundamental to living organisms, including human beings. Many of the early observations were made on plants and nonhuman animals, but the basic concepts also apply to human biology and medicine. In the twentieth century, early findings about cyclical changes in symptoms, body weight, pulse rate, and body temperature were substantiated and broadly expanded to include numerous aspects of human biology and medicine. Well-informed physicians now expect rhythms in their patients’ behavior, physiology, and response to therapy. The extensive research on biological rhythms in diverse organisms makes up the specialized field called chronobiology. The presence of circadian, menstrual, weekly, seasonal, and other rhythms in humans necessitates a consideration of these cycles in any comprehensive approach to medical practice.

Despite their importance, the exact nature of these rhythms has not been resolved. Living organisms behave as though they have internal oscillators or biological clocks that time their activities. Some research provides evidence that many of the body’s cells each have such internal timers. Until the exact causes for the various biological rhythms have been identified, there will be some limitations to the benefits derived from knowledge of their characteristics. An unsettled dispute concerns whether the actual timing information for circadian and other rhythms comes from within the organism (endogenous) or from the environment (exogenous). It is expected that travel to space beyond the moon may ultimately answer this question. Astronauts may have sufficient internal timing information to survive, or it may be necessary to create a rhythmic environment of change in light-dark cycles and perhaps magnetic field variations to provide vital timing information. In the meantime, there is much that is known in chronobiology.

In mammals, an important circadian timing mechanism resides in a cluster of cells called the suprachiasmatic nuclei, or SCN, which are located in the hypothalamus of the forebrain. From studies on laboratory mammals, it has been learned that removal of the SCN abolishes many of the body’s circadian rhythms. In humans, chance tumors in this area are often found to disrupt the circadian rhythms of the patient. In laboratory mammals, it has been shown that there is a separate pathway from the eyes to the SCN that allows information about changes in the light-dark schedule to reach this part of the brain. Therefore, there is intense interest in learning more about the SCN and how they regulate circadian rhythms.

Additionally, the pineal gland, a small gland attached to the epithalamus of the forebrain, receives information from the SCN about the light-dark schedule. A hormone produced by the pineal gland called melatonin is released into the bloodstream at night and suppressed during daylight. Melatonin plays a significant role in the timing of body rhythms and sleep cycles. When melatonin levels rise, the brain interprets this as bedtime, a factor that has led to its increasing use as a treatment for jet lag.

The general physiology of the other tissues of the body is organized according to rhythmic processes. The exact question of whether such rhythms are dependent on the SCN is still a point of controversy. Nevertheless, the greater application of chronobiology to medicine does not have to await the solution of such theoretical questions. Even now, a wide variety of examples can be cited of the utility of chronobiologic principles in medicine.

Diagnostic and Treatment Techniques

Four medical applications of chronobiology will be discussed. One area from psychiatry is the treatment of seasonal affective disorder. Three from other areas of medicine are the chronobiological treatment of asthma, cancer, and jet lag.

Seasonal affective disorder, or SAD, is characterized by depression beginning each year as daylight shortens and fully remitting when days start to lengthen, sometimes switching to mania. The condition is related to where people live and the corresponding hours of sunlight; the condition remits in a few days when sufferers travel to sunnier climes and worsens as they travel to areas where the days are shorter. As many as one in four persons in the northern latitudes may suffer from SAD, and female sufferers outnumber male ones. Although the disorder has been recognized only recently, for years writers and poets have noted seasonal depression in themselves and others.

Some patients take a midwinter vacation to a sunny climate to alleviate the condition. For those who cannot travel, the use of artificial lights has been introduced. Glow lights are placed in the homes of SAD patients and used early in the morning as well as after sunset to lengthen daylight hours. Morning lights appear to bring particularly prompt relief. Relapses have been reported when light is withdrawn. Research is currently under way to determine when during the day light is most effective, how much light is needed, and the mechanisms by which light works to fight SAD.

Some details are emerging about this process. The human forebrain contains a small organ about the size of a pea that produces the hormone melatonin according to a circadian schedule. Melatonin is usually released into the bloodstream during the night. The use of bright light therapy seems to inhibit the release of melatonin and thereby to cause other changes in the brain chemistry. In some mammals, this mechanism may be important in regulating their seasonal behavior. In humans, the situation is more complex, and an adequate theory for the neurochemical basis of SAD and other mental disorders has yet to be advanced.

Asthma sufferers have long known that their symptoms worsen at night. This increase in coughing, wheezing, and breathlessness at night has been identified only recently with circadian rhythms rather than environmental factors. At first, some researchers thought that asthma was worse at night because the patients were lying down. It has been shown, however, that the symptoms show their circadian periodicity whether the person is lying down or not. The normal nightly decrease in airway passage diameter in the lungs of normal persons is exaggerated in the asthmatic. The most dangerous hours for the asthmatic are the very early morning hours, a time when there are more deaths among asthmatics. Interestingly, asthmatics who become adapted to a nighttime work schedule shift their most severe asthma symptoms to the daytime sleep period.

Experts in the field such as Michael H. Smolensky of the University of Texas contend that much more research needs to be done on the role of circadian rhythms in asthma and its treatment. For example, adrenocortical hormones, which are powerful anti-inflammatory agents, have been used successfully to treat asthmatics. It was discovered that the time of day when the hormones were given was of great importance. If the hormones are given in the evening, the patient’s own adrenal gland is inhibited. Therefore, the best time to give such hormones is in the early morning, near the time when they are normally released in the body.

Theophylline is a drug that has been very successful in ameliorating the symptoms of asthmatics. It has been found that certain types of sustained-release theophylline are effective in reducing the early morning symptoms if the drug is taken the night before. In the study of asthma, the benefit of considering chronobiology has become obvious, and any new products to treat asthma need to be evaluated chronobiologically before they are made available to the general public.

Cancer diagnosis and treatment are aspects of medicine that are receiving increased consideration by chronobiologists. The normal growth of tissues occurs by cell division, or mitosis, a rhythmic process that is normally precisely regulated. Cancer is essentially unregulated mitosis, resulting in the growth of a tumor that is no longer subject to the control mechanisms of the body. Yet even this breakdown in regulation has its seasons. In human males, some types of testicular cancer are more often diagnosed in the winter, and in females some types of cervical cancer have a peak occurrence in the summer.

The treatment of cancer involves the use of surgery, radiation therapy, or chemotherapy in an attempt to remove or kill the cancerous cells without substantial damage to the normal tissues. Early studies in animal models demonstrated that there are often specific times of the day that these types of cancer treatment can be most effective. In a few cases, the tumor may have a rhythm of mitosis that is no longer synchronized to the rhythm of the surrounding tissue. In these cases, it may be possible to administer drugs or radiation that inhibits mitosis according to a schedule that will affect the cancer cells but will not harm the host tissue. More often, there will be a mixed effect of the timed treatment, so that some suppression of mitosis occurs along with some side effects.

The application of chronobiology to the treatment of breast cancer has raised hopes that there can be a marked improvement for survival rates of women who undergo breast surgery. William J. M. Hrushesky of Albany Medical College found that women who had breast surgery near the time of menses had a higher risk of recurrence and death than those patients who had surgery near the middle of the menstrual cycle. It has also been observed that the diagnosis of breast cancer in the United States has a two-peaked seasonal rhythm in the spring and the fall. There is also evidence that the body temperature of the breast in normal women has a circadian rhythm along with perhaps an additional seven-day periodicity, whereas breasts with tumors have abnormal temperature rhythms of about twenty hours. This information may help in the early diagnosis of breast cancer if suitable automatic monitoring devices are used to measure breast temperature.

Jet lag may appear to be more of an inconvenience than a serious medical problem until one considers the disastrous consequences of a plane crash caused by pilot error or a poorly made decision by a diplomat in an international crisis. Wiley Post and Harold Gatty, on their 1931 plane trip around the world, were the first persons to suffer from this disorder. Essentially, the body is subjected to a shift in the day-night schedule, with sleep and meal times shifted earlier or later depending on the number of time zones crossed and the direction of the flight. The symptoms are general malaise, headaches, fatigue, disruptions of the sleep-wake cycle, and gastrointestinal disorders. There are individual differences in the time required to overcome jet lag. In general, younger and healthier people are better able to cope with such change.

A shift of six hours, such as a flight between New York and Paris, requires a substantial reorganization of one’s circadian rhythms. It can take from two days to two weeks to resynchronize. Adaptation is slowest when one stays indoors and continues on a “home-time” schedule. Eastward flights are less easily tolerated than westward flights; the delays in resynchronization can take almost twice as long. The reason for the difference is that when one flies east, the sun comes up earlier relative to “home time.” It is easier for most people to “advance” than to shift “backward”—that is, to go from day to night than to go backward from night to day. For this reason, it is suggested that travelers fly early in the day when flying east and later in the day when flying west.

Unfortunately, little consideration has been given to chronobiology in scheduling work time and time off. Pilots, diplomats, businesspersons, and other time zone travelers often perform poorly when their body rhythms are disturbed by jet lag. Similarly, people who must change their work shift every few weeks often find their performance levels dropping.

It should be realized that the living body has myriad hormones, enzymes, and other important constituents that have rhythms of several different periods. Maintaining the correct time relationship between the rhythms can be critical for normal health. In the diagnosis of disease, chronobiology has to be taken into account. Erhard Haus of the St. Paul-Ramsey Medical Center has spent many years detailing the circadian and other rhythms that must be considered. What is normal for the morning hours may be pathological for the evening hours. These rhythmic values are yet to be determined for many important diagnostic measurements.

In 2005, a research study by the Feinberg School of Medicine and Northwestern University confirmed previous findings that school start times for adolescents are too early. In adolescents, melatonin, the hormone that helps induce sleep, increases later in the evening, causing melatonin levels to stay at high levels until approximately 8:00 a.m. There is no known way to change melatonin levels; for example, going to bed earlier does not cause melatonin to decrease earlier. The researchers encouraged parents and school districts to start later, as research consistently shows that adolescents have their poorest academic performance in the morning and have consistently better cognitive functioning later in the day. The researchers noted that school start times are easily modified. Many previous studies have shown the same effect, and some school districts have instituted later start times, with many schools reporting improved cognitive functioning and mood among students.

Perspective and Prospects

One of the earliest written observations of a biological cycle was by Androsthenes, a soldier marching with Alexander the Great in the fourth century BCE, who recorded that the tamarind tree opens its leaves during the day and closes them at night. In experiments on similar leaf movements in other plants, the astronomer Jean Jacques d’Ortous de Mairan in 1729 found that plants held in the dark continued to open and close their leaves on a roughly twenty-four-hour schedule. Thus, circadian rhythms in plants were shown not to be simple responses to the rising and setting of the sun but rather internal oscillations.

Early observers more interested in humans also identified rhythms. In the fifth century BCE, Hippocrates reported that his patients had twenty-four-hour fluctuations as well as longer-term rhythms in their symptoms. Herophilus of Alexandria in the third century BCE observed a daily change in the human pulse rate. The Italian scientist Sanctorius in 1711 made repeated measurements of his own body weight and the turbidity of his urine, both of which he found to vary during the month. Later, he went to the extreme measure of constructing a giant scale and living on its huge pan so that a frequent record could be made of his changing weight. The French scientists Armand Seguin and Antoine-Laurent Lavoisier in 1790 did research that revealed circadian rhythms in the body weight of men. These researchers suggested that men who did not show such circadian rhythms in body weight should be suspected of being ill. The British scientist John Davy in 1845 reported that he had found both circadian and seasonal rhythms in his own body temperature.

The historical citations of persons taking an interest in chronobiology in past centuries were of only passing concern and did not, in most cases, help to establish this field. Chronobiology as a discipline has received attention from the medical community only since about the 1970s, and many of its contributions to improving health are yet to be realized. The foremost student of chronobiology as applied to medicine has been Franz Halberg of the University of Minnesota. He has repeatedly called the attention of the medical community to the importance of biological rhythms in maintaining health and in the diagnosis and treatment of disease. Halberg has promoted the use of “autorhythmometry,” or the self-measurement of one’s physiological variables to monitor one’s changing health. It has been shown that this method can be used effectively even by groups of schoolchildren.

The phase or the timing of the peaks and troughs of circadian rhythms is germane in both diagnosis and treatment. The advent of portable automatic recording devices that store physiological data on computer chips is opening up a means of documenting a patient’s circadian rhythms around the clock for weeks at a time.

The diagnosis of diabetes mellitus has been shown to depend to an extent on the time of day that the various tests, such as the glucose tolerance test, are administered. Some diabetics are “matinal” diabetics and do not have trouble regulating their blood glucose levels until the afternoon. These persons need to have glucose tolerance tests administered in the afternoon in order to reveal their diabetes. Many additional examples of the importance of chronobiology in diagnosis and treatment exist. As more physicians and health professionals become familiar with the concepts and application of chronobiology, the effectiveness of health care will be enhanced.

Bibliography

Coleman, Richard M. Wide Awake at 3:00 A.M.: By Choice or by Chance? New York: W. H. Freeman, 1990.

Columbus, Frank, ed. Frontiers in Chronobiology Research. New York: Nova Science, 2006.

Dunlap, Jay, Jennifer Loros, and Patricia Decourse, eds. Chronobiology: Biological Timekeeping. Sunderland, Mass.: Sinauer, 2003.

Endres, Klaus-Peter, and Wolfgang Schad. Moon Rhythms in Nature: How Lunar Cycles Affect Living Organisms. Translated by Christian von Arnim. Edinburgh, Scotland: Floris Books, 2002.

Garaulet, Marta, and Jose M. Ordovás, eds. Chronobiology and Obesity. New York: Springer, 2013.

Lee-Chiong, Teofilo L., ed. Sleep Medicine Essentials. Malden: Wiley-Blackwell, 2011.

Palmer, John D. The Living Clock: The Orchestrator of Biological Rhythms. New York: Oxford University Press, 2002.

Roenneberg, Till. Internal Time: Chronotypes, Social Jet Lag, and Why You're So Tired. Cambridge: Harvard University Press, 2012.

Rosenthal, Norman E. Winter Blues: Everything You Need to Know to Beat Seasonal Affective Disorder. New York: Guilford Press, 2006.

Sehgal, Amita. Molecular Biology of Circadian Rhythms. Hoboken, N.J.: Wiley-Liss, 2004.

Waterhouse, J. M., et al. Keeping in Time with Your Body Clock. New York: Oxford University Press, 2003.