Science: Under the microscope - Clocking on

NATURE'S TIMEKEEPERS REVEALED

CELLS ARE the true miracle of evolution, for their properties define life and they have such astonishing capabilities in addition to their ability to reproduce. They can, for example, tell the time. We know that our bodily functions depend on a daily rhythm which is upset when we travel east or west. This rhythm affects not only sleep/wake cycles but hormone secretion and liver and kidney function too. Light intensities set this circadian clock; light reaches the retina in our eyes, and signals are sent to a special region of our brain which is the body's major timekeeper.

But such mechanisms are not only present in animals. Japanese geneticists have discovered a biological clock in very primitive single-cell organisms, blue-green algae known as cyanobacteria, which controls their uptake of nutrients. In order to follow the oscillation, they altered the bacteria so that one of the genes whose activity is controlled by the clock produced a luminescent protein. This meant they could follow the algae's clock by looking at changes in its light emission. The emission oscillated, with a daily cycle of about 24 hours.

To discover how this clock works, the geneticists isolated over 100 strains of the cells in which the daily activity cycle had been lost or altered. Then, to find out which genes had been lost or mutated in these strains, they took DNA from normal cells, chopped it into little pieces, and introduced the pieces back into the mutant strains until they found a bit of DNA that would restore normal behaviour. They found that one DNA fragment which contains just three genes could restore normality - and that these three genes run the clock, and that all three are essential for its proper function. As you might expect of these genes, their own activity oscillates with a 24-hour cycle; indeed, their activity provided the clue as to how the biological clock works.

Early in the day the genes (called kaiA, B and C - kai is the Japanese word for cycle) are active and the proteins for which they code are made in the cell. Initially, protein kaiA turns on the activity of kaiB and kaiC but then after a while the kaiC protein accumulates and turns off all three genes. With time, the amount of kaiC decreases as it is degraded and so the genes come on again and the cycle is repeated ... That is the essence of the clock - a protein accumulates and turns off the gene necessary for its production so that its concentration falls and the gene comes on again.

This basic mechanism has also been found in other clock systems. But the genes involved in the algae's clock are quite different from those in animals, which means that clocks have evolved more than once in evolution. Further evidence of this is hinted at by new findings of a clock in plant cells, with yet another set of genes involved. Amazingly, clocks have evolved independently several times.

Now comes a further surprise. It is not just in your brain that there is a clock - it now seems as if every cell in the body may have a 24-hour clock ticking away. In tissues as diverse as liver and lung there are genes which oscillate with a daily cycle. Cells that have been in culture for 20 years can be made to oscillate again if given a boost of culture medium. The clock-like activity in our cells may be more relevant to our health than previously thought; one need only recall the sleep problems of depressed patients, and how awful jet-lag can be. Perhaps someone will find a clever way to reset all the clocks in all the cells.