Target Health Blog

The Biological Clock

July 30, 2018

History of Medicine

A mosaic of Hippocrates on the floor of the Asclepieion of Kos, with Asklepius in the middle, 2nd-3rd century.Photo credit: This file is licensed under the Creative Commons Attribution-Share Alike 2.5 Generic license. Wikipedia Commons

Hippocratic medicine was humble and passive. The therapeutic approach was based on the healing power of nature. "If we could give every individual the right amount of nourishment and exercise, not too little and not too much, we would have found the safest way to health". Hippocrates, 460 BCE. 

The earth rotates on its axis every 24 hours, with the result that any position on the earth's surface alternately faces toward or away from the sun -day and night. That the metabolism, physiology, and behavior of most organisms changes profoundly between day and night is obvious to even the most casual observer. These biological oscillations are apparent as diurnal rhythms. It is less obvious that most organisms have the innate ability to measure time. Indeed, most organisms do not simply respond to sunrise but, rather, anticipate the dawn and adjust their biology accordingly. When deprived of exogenous time cues, many of these diurnal rhythms persist, indicating their generation by an endogenous biological circadian clock. Until recently, the molecular mechanisms by which organisms functioned in this fourth dimension, time, remained mysterious. However, over the last 30 or so years, the powerful approaches of molecular genetics have revealed the molecular underpinnings of a cellular circadian clockwork as complicated and as beautiful as the wonderful chronometers developed in the 18th century.


Circadian rhythms are the subset of biological rhythms with period, defined as the time to complete one cycle of~24 hours. This defining characteristic inspired Franz Halberg in 1959 to coin the term circadian, from the Latin words “circa“ (about) and “dies“ (day). A second defining attribute of circadian rhythms is that they are endogenously generated and self-sustaining, so they persist under constant environmental conditions, typically constant light (or dark) and constant temperature. Under these controlled conditions, the organism is deprived of external time cues, and the free-running period of ~24 h is observed. A third characteristic of all circadian rhythms is temperature compensation; the period remains relatively constant over a range of ambient temperatures. This is thought to be one facet of a general mechanism that buffers the clock against changes in cellular metabolism.

The first writings, at least in the western canon, to recognize diurnal rhythms come from the fourth century BCE. Androsthenes described the observation of daily leaf movements of the tamarind tree, Tamarindus indicus, that were observed on the island of Tylos (now Bahrein) in the Persian Gulf during the marches of Alexander the Great. There was no suggestion that the endogenous origin of these rhythms was suspected at the time, and it took more than two millennia for this to be experimentally tested. The scientific literature on circadian rhythms began in 1729 when the French astronomer de Mairan reported that the daily leaf movements of the sensitive heliotrope plant (probably Mimosa pudica) persisted in constant darkness, demonstrating their endogenous origin. Presciently, de Mairan suggested that these rhythms were related to the sleep rhythms of bedridden humans. It took 30 years before de Mairan's observations were independently repeated. These studies excluded temperature variation as a possible zeitgeber driving the leaf movement rhythms. 

The observation of a circadian or diurnal process in humans is mentioned in Chinese medical texts dated to around the 13th century, including the Noon and Midnight Manual and the Mnemonic Rhyme to Aid in the Selection of Acu-points According to the Diurnal Cycle, the Day of the Month and the Season of the Year. As early as 1880, Charles and Francis Darwin suggested the heritability of circadian rhythms, as opposed to the imprinting of a 24-hour period by exposure to diurnal cycles during development. This was initially explored in the 1930s by two strategies. In one, plants or animals were raised in constant conditions for multiple generations. One of the most grueling among such studies demonstrated the retention of stable rhythms among fruit flies reared in constant conditions for 700 generations. In a second strategy, seedlings or animals were exposed to cycles that differed from 24 hour in an effort to imprint novel periods; such studies could sometimes impose the novel period length during the novel cycles, but upon release into continuous conditions, the endogenous circadian period was restored. The inheritance of period length among progeny from crosses of parents with distinct period lengths was first reported in Phaseolus; hybrids had period length intermediates between those of the parents. In 1896, Patrick and Gilbert observed that during a prolonged period of sleep deprivation, sleepiness increases and decreases with a period of approximately 24 hours. In 1918, J.S. Szymanski showed that animals are capable of maintaining 24-hour activity patterns in the absence of external cues such as light and changes in temperature. In the early 20th century, circadian rhythms were noticed in the rhythmic feeding times of bees. Extensive experiments were done by Auguste Forel, Ingeborg Beling, and Oskar Wahl to see whether this rhythm was due to an endogenous clock. The existence of circadian rhythm was independently discovered in the fruit fly Drosophila melanogaster in 1935 by two German zoologists, Hans Kalmus and Erwin Bunning.In 1954, an important experiment was reported by Colin Pittendrigh who showed that eclosion (the process of pupa turning into adult) in D. pseudoobscura was a circadian behavior. He demonstrated that temperature played a vital role in eclosion rhythm, the period of eclosion was delayed but not stopped when temperature was decreased. It was an indication that circadian rhythm was controlled by an internal biological clock. The term circadian was coined by Franz Halberg in 1959. Genetic analysis identifying components of circadian clocks began in the 1970s. Although now it seems axiomatic that circadian clocks are composed of the products of genes, just how this might be so was the source of considerable controversy. It was argued that forward genetic efforts would be fruitless because clocks were sufficiently complex to reasonably be expected to exhibit polygenic inheritance and would not yield easily to standard genetic approaches. However, mutations conferring altered period length were identified and characterized in the fruit fly Drosophila melanogaster, the green alga Chlamydomonas reinhardtii, and the filamentous fungus N. crassa. It took more than a decade to clone the first clock gene, the Drosophila period (per) gene, and another 5 years to clone the second, the Neurospora frequency gene. However, the decade of the 1990s saw rapid progress toward the identification of clock components and the elucidation of oscillator mechanisms central to the circadian clock in a number of organisms, most notably Drosophila, Neurospora, and mice.

Ron Konopka and Seymour Benzer identified the first clock mutant in Drosophila in 1971 and called it "period" (per) gene, the first discovered genetic determinant of behavioral rhythmicity per gene was isolated in 1984 by two teams of researchers. In 1977, the International Committee on Nomenclature of the International Society for Chronobiology formally adopted the definition, which states:

Circadian: relating to biologic variations or rhythms with a frequency of 1 cycle in 24 + 4 h; circa (about, approximately) and dies (day or 24 h). Note: term describes rhythms with an about 24-h cycle length, whether they are frequency-synchronized with (acceptable) or are desynchronized or free-running from the local environmental time scale, with periods of slightly yet consistently different from 24-h.

Joseph Takahashi discovered the first mammalian circadian clock mutation using mice in 1994. However, recent studies show that deletion of clock does not lead to a behavioral phenotype (the animals still have normal circadian rhythms), which questions its importance in rhythm generation. Konopka, Jeffrey Hall, Michael Roshbash and their team showed that per locus is the center of the circadian rhythm, and that loss of per stops circadian activity. At the same time, Michael W. Young's team reported similar effects of per, and that the gene covers 7.1-kilobase (kb) interval on the X chromosome and encodes a 4.5-kb poly(A)+ RNA. They went on to discover the key genes and neurones in Drosophila circadian system, for which Hall, Rosbash and Young received the Nobel Prize in Physiology or Medicine 2017. Sources:; Wikipedia

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