Column: Rhythms

by flaunt

One of the foremost researchers in circadian rhythms gives us his take on getting in tune with our cycles

The day is done, and the darkness

Falls from the wings of Night,

As a feather is wafted downward

From an eagle in his flight.

– Henry Wadsworth Longfellow

There have been over a trillion dusks and dawns since life began some 3.8 billion years ago. During that time the Earth’s daily rotation has slowed to a shade less than 24 hours—or 23 hours 56 minutes and 4 seconds to be precise. This predictable daily spin results in regular and profound changes in environmental light; temperature; food availability and a host of other key environmental features that influence survival. In response to this dynamic world, almost all life—including some forms of bacteria—have evolved an internal biological timer that anticipates this daily change. Organisms effectively “know” the time of day and employ a biological clock to fine-tune physiology and behavior in advance of the environmental change. In humans, for example, blood pressure, metabolic rate, cortisol, alertness, and kidney function all begin to rise several hours before we wake. Then in the early evening, prior to sleep, this physiology moves to a more physically inactive state. Such internally generated daily rhythms are called “circadian rhythms” from the Latin circa (about) and dies (day).

But why anticipate, why not merely respond to altered levels of dark and light? The answer is that biochemistry and physiology cannot be switched from one state to another instantly. For example, it takes about 30-40 minutes to switch the visual system from day to night vision, and more than four hours to fully adapt physiology from the sleep to wake state. Using environmental change as a stimulus to drive biological change would result in sub-optimal levels of performance at critical times of the day. For animals this transition would make it more difficult to avoid predators or catch prey, and for plants the biochemistry of photosynthesis would not be optimized to convert carbon dioxide and water into sugars. In humans the loss of an hour as a result of the clock change in spring means we are not fully adapted for activity when the alarm drives us out of bed for the commute to work. Our impaired alertness is almost certainly a significant factor in the increase in traffic fatalities on the Monday after the shift (~17% increase in the US). Evolution is uncompromising and will select only those individuals who make the most efficient use of their time. As a result almost all life seems to utilize some form of circadian timer to adjust biology in advance of the dynamic change imposed by the Earth’s rotation. Indeed, the demonstration of circadian timing is now considered as one of the signatures of life itself.

A circadian clock also stops everything happening at once, ensuring that biological processes occur in the appropriate sequence or “temporal framework.” For cells to function properly they need the right materials in the right place at the correct time. Thousands of genes have to be switched on and off in order and in harmony. Proteins, enzymes, fats, carbohydrates, hormones, nucleic acids, and other compounds have to be absorbed, broken down, metabolized, and produced in a precise time window. Energy has to be obtained and then partitioned across the cellular economy and allocated to growth, reproduction, metabolism, locomotion, and cellular repair. All of these processes, and many others, take energy and all have to be timed to best effect by the millisecond, second, minute, day, and time of year. Without this internal temporal compartmentalization of physiology, biology would be in chaos and survival compromised.

Human physiology is organized around the daily cycle of activity and sleep. In the active phase, when energy expenditure is higher and food and water are consumed, organs need to be prepared for the intake, processing, and uptake of nutrients. The activity of organs such as the stomach, liver, small intestine, pancreas, and the flow of blood to these organs need internal synchronization—which a clock can provide. Sleep may be the suspension of most physical activity, but during sleep many essential activities occur including: cellular repair, the removal of toxins, and in the brain, memory consolidation and information processing. Disrupting this pattern, as happens with jet lag or shift work, leads to internal desynchrony and the failure to do the right thing at the right time. But what is the circadian clock; how is it locked onto the Earth’s rotation, and what happens to health when circadian rhythms become disrupted?

In mammals the master body clock is located within a small, paired structure called the “suprachiasmatic nuclei,” abbreviated to “SCN.” The SCN consists of approximately 50,000 neurons and is located deep within the hypothalamus, just above where the optic nerves enter the brain and fuse—the optic chiasma. If the SCN is damaged in humans (e.g. from a brain tumor) or ablated in rodent models, then 24-hour patterns of sleep and wake are abolished. Remarkably, isolated SCN cells can generate a 24-hour rhythm of electrical activity, showing that circadian rhythms arise from a subcellular molecular process located within an individual SCN neuron. This molecular clock arises from about 14 key “clock genes” which encode different proteins that interact in various ways to generate a 24-hour oscillation of protein assembly and then degradation. This cycle of clock protein production and destruction is translated into 24-hour patterns of physiology and behavior.

At first it was assumed that SCN neurons are the only cells capable of generating circadian rhythms. However, we now know that most, if not all, cells of the body have this capability. It seems that the SCN acts like the conductor of an orchestra, providing a rhythmic signal from which the countless peripheral clocks within the organs of the body take a cue and align their circadian activity appropriately. If the SCN is destroyed this synchronizing cue is lost and the peripheral clocks begin to drift apart. 24-hour patterns of rhythmicity are lost at the tissue and organ level, but cells tick away on their own for many days. As a result the “day within” arises from a complex network of billions of autonomous circadian oscillators, synchronized to each other and somehow aligned to the outside world.

The eye detects the dark/light cycle and this signal acts to synchronize (entrain) the SCN to the rotation of the Earth. It has long been known that the rod and cone photoreceptors within the eye allow image-forming vision. Until recently, however, it was unclear which photoreceptor(s) provided input to the SCN. Was it rods or cones or perhaps both? The answer that emerged surprised everyone—it was neither. We showed that circadian rhythms in mice would remain entrained to the light/dark cycle after all the rods and cones had been genetically ablated, but eye loss prevented entrainment of the circadian system to light. The only possible conclusion was that there was another non-rod, non-cone photoreceptor that was supplying information about ambient light levels to the SCN. These findings in mice were also replicated in humans suffering from genetic diseases that led to the loss of all rod and cone photoreceptors. These and other data allowed us to show that this novel photoreceptor is based upon a small number of directly photosensitive retinal ganglion cells (pRCGs). The ganglion cells of the eye give rise to the optic nerve and this nerve tract conveys light information from the eye to the brain. The pRGCs comprise only about 1% of all ganglion cells and their photosensitivity is provided by the blue-light sensitive photopigment melanopsin. The key point is that the pRGCs respond to light without any inputs from the rods or cones.

The announcement in 1999 of the existence of a third photoreceptor type in the mammalian eye was met with widespread skepticism and even hostility. Until the late 1990s it seemed inconceivable to most vision biologists and ophthalmologists that there could be an unrecognized class of photoreceptor within the eye. After all, the eye was the best understood part of the central nervous system. One hundred and fifty years of research had explained how we see: Light is detected by the rods and cones followed by advanced visual processing in the brain. This understanding left no room for an additional class of photoreceptor. The discovery of the third photoreceptor not only shocked vision biologists but also led to the realization that the definition of clinical blindness must incorporate both visual and circadian light regulation. Ophthalmologists now appreciate that the eye provides us with both our sense of space and a proper sense of time.

Because circadian rhythms are embedded across all physiology, disruption of the circadian system can have very marked and far-reaching health consequences that are only now being appreciated. Circadian rhythm disruption (CRD) can arise exogenously as a result of conflicting environmental signals (e.g. jet lag, shift-work, or poor light exposure) or endogenously as a result of diseases or pathological states that alter circadian mechanisms (e.g. mental illness, neurodegenerative disease or eye loss). But irrespective of the cause, CRD can lead to profound cognitive defects and ill health as summarized in Table 1. For example, the degeneration of the SCN during Alzheimer’s disease (AD) causes major sleep/wake disturbances. This disruption in patients also affects the sleep patterns of carers, and disturbed sleep is the key reason why AD sufferers are committed to residential care by carers. The earliest description of Parkinson’s disease (PD) included a reference to disturbed sleep. Today, it has been estimated that 80-90% of PD patients have disrupted sleep/wake timing problems. A disrupted body clock is also a characteristic feature of mental illness, and significantly the partial stabilization of sleep/wake patterns in patients with depression and schizophrenia has been shown to improve the severity of symptoms. Significantly, many of the health problems associated with CRD (Table 1) are reported routinely as co-morbid with neuropsychiatric illness and neurodegenerative disease, but are rarely linked to the disruption of the circadian system.

CRD, of the sort experienced by shift workers, can lead to an increased risk in both short-term and long-term health (Table 1). Nurses are one of the best studied groups of night shift workers. Years of shift work in these individuals has been associated with a broad range of health problems including type II diabetes, gastrointestinal disorders, and even breast and colorectal cancers. Cancer risk increases with the number of years of shift work, the frequency of rotating work schedules, and the number of hours per week working at night. The correlations are so strong that shift work is now officially classified as “probably carcinogenic [Group 2A]” by the World Health Organization. Other studies of shift workers show increased heart and stroke problems, obesity, and depression. A study of over 3,000 people in southern France found that those who had worked some type of extended night shift work for ten or more years had much lower overall cognitive and memory scores than those who had never worked on the night shift.

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Under laboratory conditions circadian rhythm and sleep disruption has also been shown to impair glucose metabolism and apatite, which may be the explanation why shift workers have a higher risk of weight gain, obesity and type II diabetes. Significantly, night shift workers have elevated levels of the stress hormone cortisol, which has also been shown to suppress the action of insulin and raise blood glucose. It is now abundantly clear that CRD is not simply an inconvenience but a condition that exacerbates or causes serious health problems across the spectrum of all health (Table 1), and developing better educational and management programs to allow individuals to manage CRD, along with the development of new pharmacological and light interventions to help stabilize CRD, will have a global impact upon the economics of health care, and at an individual level, improve the quality of life for countless patients and their caregivers.

The study of circadian rhythms has become a unifying branch of scientific enquiry. The old concept of a constant, homeostatically defended optimum for a biological system that remains stable across the 24-hour-day has been replaced by an understanding that daily variation, driven by the circadian system, provides an immense advantage in the struggle for existence. Furthermore, understanding how circadian rhythms are generated and regulated is providing us with new mechanistic insights into the nature of key biochemical and physiological processes, and significantly, how these systems interact. In addition, we are also beginning to appreciate the impact of disease and the 24/7 society on circadian rhythm disruption, and the serious consequences of this disruption on overall health and wellbeing. When I, along with a relatively small number of researchers, started to work on circadian rhythms well over 30 years ago we were warned that this was not a serious subject for a career in science. Such advice was rejected by our fascination to know more, but I doubt that any of us would have predicted that the study of circadian rhythms would have moved from a peripheral curiosity to a discipline that is now becoming embedded within every branch of biomedicine.

Written by Russell Foster