The Royal Society of Edinburgh Cellular Clocks Professor Ole Laerum CorrFRSE, President, Norwegian Academy of Science and

Letters and Professor of Experimental Pathology and Oncology, The Gade Institute, University of Bergen Monday 3 December 2007
Professor Laerum began by saying that since there has been life on earth, organisms have had to adapt to variations in light, temperature and the changing seasons. For many years it was observed that plants, animals and humans responded to changes in light and temperature, but the reason for this was unknown. Then, around 1015 years ago it was discovered that every single cell, not only in insects and higher animals, but also in the human body, has a clockwork mechanism that can keep the time. The process is controlled by specific genes. This led to an explosion in research and it was found that cellular clocks can be found in all types of organisms. This is an evolutionary development that dates back 700 million years. There are nerve cells in the middle of the brain the suprachiasmatic nucleii that Professor Laerum described as the master clock which controls time regulation in the body. This master clock is re-set every day by pulses received from the retina of the eye in response to daylight. Without this light stimulus, the cyclical processes within the body would slowly start to drift. Exposure to daylight is necessary to maintain equilibrium in the rest of the body. Light is, however, not the only factor, as genetic and environmental factors, such as temperature, also influence these processes. Every organ in the body has its own way of regulating time. The needs of the liver, for example, are totally different from the needs of the brain. Individual responses are thus required, but they all have to be co-ordinated with the rest of the body. The result is that each single cell in the body is co-ordinated with the others. Social behaviour can also influence the workings of this clock. Professor Laerum said it is a very complex mechanism, but the end result is a person who is in equilibrium with the outer world and all the cues to which he/she is exposed. Melatonin, which is secreted by the pineal gland during the night, plays an important role in this regulatory process. Production of melatonin results in, amongst other effects, a reduction in blood pressure and pulse rate and feelings of drowsiness. Its main function is to prepare the body for renewal during sleep. Practically all the functions of the body operate in different time phases. For the heartbeat, it is a rhythmic process repeated every second, whilst others follow a day/night pattern and some are seasonal. So-called circadian rhythms are governed by cellular clocks through specific genes. There are eight main genes involved which act by either suppressing, stimulating or modifying circadian functions in the cell. Around 10% of the nearly 30,000 genes in each human cell are directly controlled by these clock genes, whilst many others are under less direct secondary control. Cellular clocks act in most tissues and their main function is to help the body adjust to the external environment. There are two types of main time function in the body cyclic time where processes are repeated periodically and linear time where activity is induced but then is halted, such as the growth phase at adolescence. Professor Laerum said his talk would concentrate on cyclic variations. This has developed into an extensive area of research which is now called chronobiology the study of biological functions related to time, in its broadest sense. The gene suppression, stimulation or modification within cells means there are both negative and positive elements controlling functions in the cell. Professor Laerum considered why this should be important. He said cells are complex systems with more than 5,00010,000 different chemical process taking place, all of which need to be co-ordinated. Most of the time regulation that takes place is for the internal use of cells. He illustrated the variation that can happen over time by examining changes in body temperature throughout the day. It is at its lowest between 3 am and 5 am, starts to increase as we wake up

and reaches a peak between 6 pm and 8 pm. There is a difference of 0.6 degrees centigrade between the maximum and minimum, which he described as quite a substantial variation. These variations are important, as there are many daily functions that are dependant on temperature. However, experiments that have involved raising body temperature to try to influence certain functions have proved unsuccessful, as these variations only occur in a restricted temperature range. Research has shown substantial circadian variations in many functions, including feelings of well-being and happiness. A group of psychologists have even examined when humans are at their happiest and have concluded that it is at 3.20 in the afternoon! Professor Laerum went on to describe the different cyclic variations of a number of hormones in the human body which rise and fall at various times of the day and night. His own research has involved trying to discover if stem cells vary in the same way as other cells. This has found that cell division in the bone marrow does vary throughout the day and night and follows a similar pattern to body temperature. Professors Laerums team has also shown that it is possible to induce clock gene activity in stem cells which, he said, may be important for the treatment of various diseases. There is evidence that clock gene activity can also be influenced in cancer cells. This is important, as it has been shown that clock function is disturbed in malignant cells, which may be why they divide in an uncontrolled fashion rather than at defined time periods. Most diseases also have a periodic component. They are not constant throughout the day or the year. Cardiac infarction and angina, for example, mostly occur at around ten oclock in the morning. This has been observed throughout the world and may be connected to changes in blood pressure and heart rate that occur around that time. Resistance to pain is lower throughout the night and doctors and nurses need to be aware of this, said Professor Laerum. Asthma is worst during the night and peaks in the summer months. Most children are born throughout the night, as the onset of labour most commonly occurs at that time. Most people also die during the night, although the reasons for this are not entirely clear. People who are deprived of normal cues provided by exposure to daylight can also suffer symptoms such as depression, sleep disorders and stress. This can occur in people who are exposed to continuous daylight in summer and continuous darkness in winter. In conclusion, Professor Laerum said traditional rural life was much more in tune with cyclic variations in nature. People started work when it got light and finished when darkness fell. Now modern society had turned this upside down. People today are becoming more and more dependent on electronic communication and losing touch with the traditional pattern of living. This may be a disadvantage, but it may also have advantages and Professor Laerum said that discussion would be best left to the audience. A short question session followed in which Professor Laerum was asked about the potential to give chemotherapy at specific time periods to maximise its benefit. He said a large European trial of colon cancer has shown that such a strategy delivered substantial improvements compared with conventional therapy. However, since then, new drugs have been developed and the question would have to be re-tested before a final answer was produced. The next question related to the implications for blind people whose brains do not receive any cues from exposure to daylight. Professor Laerum said people who are totally blind usually get disturbances. However, light is not the only factor, as variations in temperature can have an impact on an individuals perception of the environment. Regular habits can also help. Professor Laerum was asked if there is a connection between circadian rhythms and epileptic seizures. He said that there is some evidence that strong light stimulates the brain and can induce epileptic seizures. In addition, manic depressive illness is more common in summer months when light is strong. Another question asked how complex organisms have to be to have these clock functions. Professor Laerum said clock genes have been found in uni-cellular organisms. It seems to be a universal system in all types of cells, he concluded.
Bryan Christie

Opinions expressed here do not necessarily represent the views of the RSE, nor of its Fellows