In a strict sense, circadian rhythms are endogenously generated, although they can be modulated by external cues such as sunlight and temperature. The first endogenous circadian oscillation was observed in the 1700s by the French scientist Jean-Jacques d'Ortous de Mairan who noticed that twenty four hour patterns in the movement of plant leaves continued even when isolated from external stimuli. Circadian rhythms may be defined by three criteria:
i) The rhythm persists in constant conditions (for example constant dark) with a period of about 24 hours
ii) The rhythm period can be reset by exposure to a light or dark pulse
iii)The rhythm is temperature compensated, meaning that it proceeds at the same rate within a range of temperatures.
    The circadian "clock" in mammals is located in the suprachiasmatic nucleus (SCN), a distinct group of cells located in the hypothalamus. Destruction of the SCN results in the complete absence of a regular sleep/wake rhythm. The SCN receives information about illumination through the eyes. The retina of the eyes contains not only "classical" photoreceptors but also photoresponsive retinal ganglion cells. These cells, which contain a newly-discovered photo pigment called melanopsin, follow a pathway called the retinohypothalamic tract, leading to the SCN. It is interesting to note that, if cells from the SCN are removed and cultured, they maintain their own rhythm in the absence of external cues.
    It appears that the SCN takes the information on day length from the retina, interprets it, and passes it on to the pineal gland (a pea-like structure found on the epithalamus), which then secretes the hormone melatonin in response. Secretion of melatonin peaks at night and ebbs during the day.

    Although biological clocks have been the focus of intensive research over the past four decades, only recently have the tools needed to examine the molecular basis of circadian rhythms become available. Early studies pointed to an area of the brain, the hypothalamus, as the location of the circadian pacemaker in mammals. More recent findings show proteins called cryptochromes, located throughout the body, are also involved in detecting changes in light and setting the body's clock.   
    Genes that code for the clock protein, PER (Period), glow in the head and other body parts of a fruit fly. Researchers made the clocks glow by engineering transgenic strains of flies in which the same genes that illuminate a jellyfish and a firefly's tail are attached to PER. The gene for luciferase, the enzyme that glows intermittently in fireflies, was expressed along with PER to reveal when the clock protein was being produced. Flies were also molecularly altered to brightly mark the clock sites with Green Fluorescent Protein, which glows constantly in jellyfish. 
    The first circadian gene was discovered in 1971 in the fruit fly; a second circadian gene was detected 13 years later. Following these discoveries, however, the search for clock genes in other organisms faltered. Not until 1997 was the first circadian gene found in a mammalian model, the mouse. This discovery immediately accelerated the search for other clock genes, and findings in higher order animals are yielding a consistent picture of the role and function of circadian rhythms in organisms from bacteria to plants to mammals.
    Today, we know the most about the workings of the biological clock in the fruit fly and a peek inside its mechanisms illustrates the complex elegance of the rhythms of life. The fly's clock consists of a core system of four regulatory proteins that interact to give the clock periodicity. The cycle begins when two of these proteins, CLOCK and CYCLE, bind together and increase the production of two other proteins, PER and TIM (Timeless), the levels of which slowly accumulate over time. When enough PER and TIM are made, they inactivate the CLOCK-CYCLE complex, slowing their own production (by negative feedback mechanism) and signaling the end of the cycle.
    Fruit fly clock cycle—interaction of four regulatory proteins, entrained by light, creates the daily rhythm of the fruit fly's clock. The binding of CYCLE and CLOCK turns on genes that make PER and TIM, which accumulate over several hours until they reach levels that turn off CYCLE and CLOCK. This, in turn, slows down the production of PER and TIM, which begins the cycle all over again. 
    Although parts of the puzzle still are missing, discoveries stimulated by this progress are yielding intriguing findings. Proteins such as DBT ("Double-Time") that act to fine tune the mechanism have been identified. Recently, variations have been found in the human Clock gene, which may predispose people to be "early birds" or "night owls" (I've always wondered where the Doyle Owl Reed-lore comes from!). Other research has linked academic and behavior problems in adolescents to irregular sleep patterns.
    Researchers have found that imposing too early school start times on children requires unrealistic bedtimes to allow adequate time for sleeping. Early school start times for adolescents are frequently associated with significant sleep deprivation, which can lead to academic, behavioral, and psychological problems, as well as increased risk for accidents and injuries, especially for teenage drivers. Completing our understanding of biological clockworks will lead to better treatments for diseases affected by circadian rhythm, as well as to methods of coping with disrupted sleep patterns.

Fig.3: Circadian systems. Cycles within the circadian systems of the fruit fly Drosophila, mammals, and the fungus, Neurospora. Elements in gray are educated guesses.
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