The 'third eye' that affects night work and jetlag
Health professionals warned on link between body clock disruption and disease
17 July 2009
When you fly to New York from London how do you adapt to local time? At 5 hours behind GMT, it wouldn't be much fun shopping when your body says it’s dinnertime, and even less falling asleep into your dinner.
Biological activity is tied to an internal clock. Image: Jupiter
Thankfully, our bodies do adapt to local time because we have internal, genetically-driven biological clocks that can be reset by environmental cues, principally daylight. Our clocks, which we share with other animals and plants, have more fundamental uses than enabling us to eat, party, and sleep at local time – they are essential for happiness and good health, workplace productivity, and literally keep us sane by inducing sleep.
Animals’ clocks also regulate their sleep-wake cycles, appetites, breeding cycles and other seasonal functions such as moulting. In plants, that flowering and moving toward the sun are anticipated, not reactive, actions was deduced by the Greek geographer Androsthenes in the 4th century BC.
It has taken more than 2000 years to unravel the principal mechanisms behind biological clocks, or the "adaptations to life on a rotating world", as Neurologist William Schwartz remarked, but research has never been more important. Disrupted sleep-wake patterns have been implicated in health problems including depression, neurodegenerative diseases like Alzheimer’s disease (AD), schizophrenia, and more controversially have been linked with higher incidences of some cancers and heart disease risk factors.
The remains of the day
Biological clocks are expressed in organisms as circadian rhythms (from the Latin circa meaning ‘around’, and dies meaning ‘day’) whereby behaviours such as waking, eating and sleeping are induced at certain times. Clock genes run the show, but just as an alarm clock needs adjusting from time to time so does the body clock as the seasons change for example. Hence, clock gene activity is in turn governed by the timing of light entering the eye.
Circadian rhythms are "adaptations to life on a rotating world".
For years it was assumed that the light-sensitive rod and cone structures in the eye’s retina were responsible for resetting the clock. But diseased mice that lacked rods and cones still kept good time (ref 1), leading some researchers to seek evidence for a mysterious third class of receptor, or ‘third eye’.
The breakthrough came from Russell Foster and colleagues at Oxford University. Foster says that even after they had demonstrated a third light receptor in fish (ref 2), the idea that it would be found in the mammalian eye – which had been studied in detail for more than 150 years – provoked fierce resistance. "In one presentation someone stood up, swore, and walked out," Foster says. Only when a mouse was engineered to be completely free of rods and cones (ref 3, ref 4), but the circadian system was still aligned to the light-dark cycle, was the idea accepted. He adds that BBSRC did all the initial enabling funding for the discovery.
By 2007 Foster had demonstrated the results in humans. "In a case study of a man and woman who also lacked rods and cones, everything we showed in the mouse translated to humans," he says.
It was soon realised that research on the ‘third eye’ had direct healthcare implications. "The problem with a defunct body clock is that you get internal desynchronisation and that’s related to a whole raft of pathologies," says Foster. "Not only in terms of our cognitive abilities, but serious health consequences in our metabolic responses to stress and the ability to fight disease."
Some diseases such retinoblastoma result in complete removal of the eyes as the aggressive cancer can spread quickly via the optic nerve into the brain. Sufferers, who are few but often young, then experience severe sleep-wake cycle disruption because their endogenous (internal) clocks cannot be reset. "It’s like putting people in a dark cave for the rest of their lives," says Foster. "Because of the sleep disruption these children have difficult and often unmanageable mood problems."
The daily clock is located in the suprachiasmatic nuclei (SCN) of the brain's hypothalamus. Red filaments are retinal projection to the SCN. Green dots indicate gene activation via light stimulation.
Image: Daniela Lupi
But after 3mg of the hormone melatonin given just before bedtime, Foster says their behaviour "is transformed". Melatonin works because it regulates the body’s reaction to the dark side of the day-night cycle and administering it at the right time can bring back stability to sleeping patterns.
Melatonin is just one useful compound. New drugs can also be designed to target the pigment (melanopsin) that lies at the heart of the new photoreceptors – called ‘photosensitive retinal ganglion cells’ or pRGCs (ref 5). "Stabilizing sleep with these new drugs will have a huge impact. From helping shift-workers adjust to the demands of working at night to stabilizing the sleep patterns of the elderly," says Foster. He adds that better sleep-wake cycles in age-demented individuals have recently been shown to have a significant improvement on their cognition.
Sleep disruption is also a common problem in mental health and contributes to multiple co-morbidities, including the social isolation typical of conditions such as schizophrenia. "Many of us now view the sleep and circadian timing systems as a new therapeutic target to improve the quality of life of both patients and their carers," says Foster.
The regulation of circadian rhythms is not the only physiological function of the pRGCs where melanopsin is found. BBSRC research has shown it partly controls our level of arousal, pupil constriction, and the onset of sleep (ref 6, ref 7). In less than a decade, Foster’s work has therefore gone from fundamental new biology toward medical arenas, including mental health and neurodegenerative diseases.
Year in, year out
Foster’s research focuses on daily cycles, but as it rotates the planet orbits the Sun so there are yearly cycles too. They drive seasonal behaviours such as breeding, feeding and migration in animals, which are important to farmers and consumers.
"We know there is a daily clock controlled by clock genes, but I’m trying to understand the molecular basis of the annual clock," says Gerald Lincoln of Edinburgh University. He adds that if found in animals then there is certainly one in humans.
In fact, we don’t even know where the annual clock is. Unlike the daily clock, which ticks in specialised cells – the suprachiasmatic nuclei – in a part of the brain called the hypothalamus, Lincoln says no-one in the world can tell you where the annual clock resides. "My opinion is that it’s made up of a number of pieces which are not all in one site in the body. It’s an integrated clock."
Soay sheep help unravel the mystery of the annual clock. Image: Gerald Lincoln
Are we certain then, that an annual clock exists at all? Long-lived animals like sheep kept under constant light will free-run a 10-month seasonal cycle. So just as in daily rhythms, there is an internal timer that can respond to environmental cues (ref 8). In this case, sheep use the long, bright summer nights. "Animals don’t breed at certain times because the environment tells them too," Lincoln explains. "They have internal timing and the environment gives them an annual prompt."
He also cites experimental evidence from the University of Michigan, US, where sheep lacking their own melatonin have been given melatonin at the correct dose and daylight time to mimic mid-summer, which can induce a winter breeding season (ref 9).
This BBSRC-funded research has present and future applications in animal welfare and husbandry. With animals’ appetite, growth, breeding and coat all influenced by annual clocks, in the future we could use breeding to knock out one aspect of seasonality without affecting another because all long-lived animals are hard or soft-wired to be seasonal due to their temperate origins.
People also show seasonal traits and behaviours, such as Seasonal Affective Disorder (SAD). The nature of this widespread malady of the dark and depressing winter months are only now being revealed.
Biological clock research thus flirts between the practical and the theoretical. Lincoln and colleagues research has revealed shock evidence that the melatonin-producing pineal gland – which controls the complex symphony of hormonal secretions known as the endocrine system – can dictate the tune that the brain dances to and not the other way around: a fundamental shift in our understanding of hormonal control (ref 10).
"The pituitary gland was always believed to be a slave to the brain," Lincoln explains. "Now we discover that the long-day effect of summer is triggered by the pituitary gland first, driven by a cue from melatonin, which then tells the brain to turn on its cascade of regulatory mechanisms." Remarkably, in birds this system responds to light passing directly through the skull, while in thick-skulled mammals the signal is received via melatonin.
First found in birds has confirmed in mammals by Lincoln’s group, he says it makes sense because with the arrival of longer days in spring the first genes to switch on in the entire genome are in the pituitary gland. "This is clearly a fundamental timing system just being discovered."
Saturday nightshift fever
Biological clocks affect every living organism on the planet – even bacteria show temperature-compensated rhythms – and yet there is more that we don’t know than we do.
For instance, why are the internal clocks such bad time-keepers? A sheep’s endogenous clock is telling it that a year is 10 months long, and a person’s free-running clock measures a day at 25 hours. This is why Monday mornings can be so bad: our clocks are reset by morning light, so by lying in over the weekend on Monday your body wants an extra 2 hours sleep.
Shiftwork could affect health
But more important matters are looming. Some scientists now believe that disrupted sleep patterns can have severe impacts on otherwise healthy individuals that cannot be cured by going back to bed. In early 2009 the Danish government began a compensation process for 38 nurses who had developed breast cancer that was attributed to years of night-shift work (ref 11).
The pay-outs follow the 2007 publication of a International Agency for Research on Cancer monograph that rates prolonged night shifts at the same risk level as industrial chemicals and declares: "shiftwork that involves circadian disruption is probably carcinogenic to humans.”
Such links are controversial, but Professor Andrew Watterson from the University of Stirling believes that the breast cancer-nightshift link will be established beyond reasonable doubt for those working over many years.
Funded by his university and various charities, Watterson’s research interests (ref 12) relate to how evidence is used, particularly to the operation of the precautionary principle in public health: balance of probabilities versus beyond reasonable doubt. "Some studies are also flagging possible prostate cancer and Non-Hodgkin's lymphomas as presenting a possible risk too," he says.
Watterson admits that this approach does not map neatly against much scientific research, but more is needed. "I certainly think research on circadian rhythms is important and the sort of science BBSRC should fund."
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- Novel retinal photoreceptors (external link), Nature 394, 27-28, 1998
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