How to Be on Time: Internal Clock Lessons from Blue-Green Algae

HERTEL AND REDIGER (Humboldt-Universität zu Berlin):

“Turn the night into day!” Are these not the mottos of our modern times? To party the night away or, for unfortunate individuals, to work at night is now the norm. In doing so, however, we encounter an opponent that should not be underestimated — the internal clock — which governs the daily rhythm, from gene expression and metabolism to behavior of not only humans but also insects, plants, and unicellular cyanobacteria (also known as blue-green algae). As such, the internal clock is biologically fundamental — a part of life like reproduction or cell divisions. Therefore, an understanding of the underlying mechanism is highly relevant to human health and quality of life.

The biological clockwork is an endogenously driven, roughly 24-hour oscillator, termed the “circadian clock” (Latin: circa = about, dies = day). The key role of this core oscillator is to sense the environment and relay environmental stimuli to specific cellular processes, such as gene regulation, cell division, and energy production, triggering them to occur at the correct time of day. This internal clock is trained to adapt to the length of the day and seasons. It also can maintain its approximate 24-hour rhythm even when the natural environment changes (for example, when the temperature changes) by constantly compensating for small random perturbations. Despite everything that is known about biological clocks, many questions remain to be solved even concerning the clock system’s most essential features. For example, it is not clear how the clock can produce an oscillation as long as ~24 hours.

The Inner Clock of Blue-Green Algae

Among living beings on earth, cyanobacteria appear to be the first to have developed the simplest known circadian clock (more than 3.5 billion years ago). Like plants, they use light as a source of energy and carry out photosynthesis. Concomitant with this biological process is oxygen production, which led to the creation of our oxygen-enriched atmosphere and is essential for supporting life on the planet. In the early development of life on our planet, cyanobacteria had to protect themselves against damage by ultraviolet (UV) light that was not filtered by the Earth’s atmosphere when early life emerged. The solution for this problem must have led almost automatically to temporal separation of biological processes at the molecular level.

Recently, cyanobacteria have become the model of choice for scientists to study the components and the mechanics of the circadian clock and its impact on biological processes.

Due to the work of many scientists, today we know the properties of the cyanobacterial watch and can isolate the few principle clock proteins involved in generating circadian rhythms. Several groups collected the so-called pendular, gears and pull springs of different cyanobacterial strains, and investigated them with regard to their interplay. Within our research project we also analyze the core clock of cyanobacteria. One can say we have become a kind of molecular watchmaker by extracting, decomposing and rearranging the clock components. We aimed to track down the most likely clock mechanism, which confers sustained oscillations of cellular processes, such as gene expression or metabolism. With our lab data we simulated potential mechanisms on the computer. Eventually, we arrived at one clock mechanism that reproduced the experimentally observed stability of oscillation of clock protein complexes. Thus, we propose the following mechanism: in contrast to the fixed gears of a mechanical clock, the clock proteins interact rhythmically with each other, form complexes and disassemble in a perfectly orchestrated way. The circadian period derives from a negative feedback induced by sequestration of one clock protein by two other clock proteins. The formation of these various protein complexes within 24 hours is a sophisticated mechanism that may coordinate cellular processes at a certain speed or behavior at the right time.

Although we only studied a simple clock mechanism in a simple organism, we can draw conclusions about the complex internal clock in humans. Effects on health might be expected when the clock system has deficiencies. Rhythm disturbances occur, for example, due to shift-work and can result in sleep disorders and in depressive syndromes; these disturbances are also connected with forms of cancer (read more in “Light, circadian, circannual rhythms” by Anders Johnsson).

The exact effects of not following the circadian clock are not yet fully understood. Knowing how biological clockworks in different organisms function are important milestones so that scientists in the future can, for example, restore the proper timing of the body rhythm when the internal clock of the body is malfunctioning. Last but not the least, night birds and party lovers will eventually benefit from this better understanding.

Stefanie Hertel and Anne Rediger
Humboldt-Universität zu Berlin

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