The constant oscillation of life

On a cosmic scale, most bodies oscillate. Stars and planets rotate (which is a kind of oscillation). Observing the spots on the sun some 400 years ago, Galileo first made the discovery that our star rotates on its axis every 25 days — an observation which even now is not fully understood. Of course the rotation of the sun does not affect us nearly as much the rotation of earth.

All life on our planet, down to its very simple forms, cyanobacteria, have adapted to the daily rotation and regular light changes. Living organisms anticipate transitions, adapt their physiology, and perform activities at advantageous times during the day.
We humans do not escape the rule. The daily rotation of the earth influences the rhythm of our existence, determines our activities, shapes our lives and has a critical influence on our physiology.

This fine tuning of our physiology and behaviour to the night-day cycle is critical. “It probably helps conserve our functions for when we need them most – a variation on the hibernation theme in animals,” commented Prof Garret FitzGerald, Professor of Medicine & Pharmacology at the University of Pennsylvania.

Speaking at the inaugural Joan Kearney Science Lecture held in the Science Department of Alexandra College in Dublin, Prof FitzGerald explained how circadian rhythms (‘around a day’ rhythms) regulate the physiological functions that occur in the body within a 24-hour period.

“All of us have a periodicity. The existence of a circadian pattern of sleep-wake cycles, fasting/feeding rhythms, fluctuations in body temperature, but also heart rate, blood pressure, platelet counts, lung function and hormone release has long been known,” he said.

“And we have also observed the periodicity of a number of related conditions such as asthma and heart attack.”

But the question that had for long remained unanswered is how all those rhythms were established and maintained. The recent development of molecular biology provided some elements of answer.

The master clock
Most cells are incapable of receiving direct input from light. They rely on a ‘master clock’ to provide time cues. In humans this circadian pacemaker is located in the hypothalamus, more specifically in a cluster of nerve cells called the suprachiasmatic nucleus (SCN).

“There are specialised cells in the retina that connect directly to the SCN and transmit the resetting signal from sunlight,” Prof FitzGerald explained. Neurons in the SCN entrained by light thus control the sleep/wake pattern, and indirectly influence the daily cycle of feeding and starvation. “The SCN is the conductor of the circadian orchestra,” Prof FitzGerald said.

However, we now know that the SCN is far from being the only player in our physiological rhythms.

“The peripheral clocks have the capacity for autonomy,” Prof FitzGerald said.

Single cells and single organs, as well as tissues from SCN-lesioned mice, all display circadian rhythms even when placed in culture. Moreover, it is well known that people isolated from light still express a circadian pattern in their daily activity and behaviour – even though this is a bit longer than 24 hours (somewhere between 24 and 25); it is easier to reset a clock that has a longer cycle than extending a shorter one.

Rhythms in physiological functions must therefore be directly influenced by some internal molecular clockwork, independent of the SCN.

What are these molecular oscillators contained in our cells?

Clock genes
The molecular basis of peripheral clocks is beginning to be unravelled. This involves core clock genes – named BMAL1 and CLOCK – and a number of feedback loops.
These circadian clock genes undergo cyclic expression in the suprachiasmatic nucleus and in peripheral tissues to regulate physiological pro-cesses periodically (see box).

“Roughly 10 per cent of genes in any tissue oscillate on a 24- hour period,” Prof FitzGerald indicated. In fact, almost every cell in the body contains such molecular clocks.

“The oscillations in the brain relate to a clock in all our tissues, including gut lining, blood vessel lining, lungs (a famous exception to the rule being the testis which for some reason exhibits constant rather than cyclical expressions of these genes…).”

The result is oscillating protein expression producing cyclical cell/tissue function. And this clever mechanism exists in humans, rodents, and even in fruit flies!

Coordinator
Though autonomous, most tissues still require synchronisation signals from the SCN to retain periodicity. As Prof FitzGerald pointed out: “The oscillatory pattern of the SCN antecedes the others, and if you ablate it, many (but not all) peripheral rhythms are shut down.”

The SCN is thus thought to coordinate and synchronise the phase of peripheral oscillators. The question is: how? Scientists have actually just identified the signal the master clock might send to control these biological rhythms.

A new study which appears in the October 9 issue of Science showed that some cells in the SCN work themselves into a frenzy and then fall silent in the middle of the afternoon. This unexpected pattern (that would kill most brain cells) may help the SCN use light cues to reset circadian rhythms to a 24-hour cycle.

What’s more, synchronisation by the SCN could involve humoral signals. Prof FitzGerald points in that direction: “We propose that circadian or periodic availability of nuclear hormones may play a critical role in resetting a peripheral clock,” he said.

His team found that the action of retinoic acid on nuclear receptors was capable of controlling clock gene expression and resetting a vascular clock. For the first time scientists were able to phase shift a biological clock with just a single hormonal signal!

Clock network
Oscillations are an essential component of nature. Not only living systems, but most systems in the universe oscillate. Even fundamental particles, the very heart of matter, are associated with an oscillating wave. Why is this?

A core reason is that constant parameters are much more difficult to maintain than oscillating ones. Oscillations are more robust; when perturbed they always tend to go back to their original state of equilibrium, which stands as a sort of attractor.

However, the circadian rhythms in the body would appear less related to homeostasis and more to optimising behaviour (e.g., minimising energy expenditure) with respect to a periodically varying environment. In fact, circadian patterns are far from being the only oscillations which give rhythm to our physiology and behaviour. There are also longer period rhythms – including menstrual cycles and seasonal variations – and shorter rhythms including respiration and heart beat. All these rhythms are interconnected allowing integrated tissue function. “The clock network is the most robust interconnected network that ties up tissues together,” said Prof FitzGerald.

Molecular clocks
Unravelling the mechanism underlying the body’s central pacemaker and its peripheral molecular clocks is critical for the full understanding of our body functions – from our hearts and lungs to our sleeping patterns and our ageing processes.

It is a fundamental step in our effort to treat numerous prevalent conditions influenced by the internal clock, including cardiovascular diseases, obesity, cancer, and mood disorders. This could also point to new ways to correct problems like insomnia and jet lag.

The Science Bit will return to the subject of the physiological consequences of all this clockwork and how their understanding could improve disease management in a future column. – Irish Medical Times