Keeping Time

A deep dive into how organisms keep time, and why that matters

Why Oscillate?

From birth to death an organism experiences a myriad of different stimuli, many of which are cyclical. Migration, mating, courtship behaviours, hunting, and sleep-wake cycles are all cyclical processes repeating in a regular manner i.e a rhythmic manner. Ranging from minutes to days and even months, these biological rhythms help the organism cope with its environment’s physical rhythms like the seasons, light-dark cycles, tidal movements etc.

Circa Diem

Of particular interest are rhythms that repeat daily. Also called Circadian rhythms (from the Latin words “Circa”(about) & “Diem”(a day)). These rhythms influence numerous vital physiological, biochemical, and behavioural processes, from body temperature, feeding behaviour, sleep-wake cycles to hormone secretion, and glucose homeostasis.

What makes a rhythm

Circadian Rhythms present three main characteristics:-

1. Circadian rhythms are free-running — When shielded from all outside stimuli, and placed in a constant light environment, the organisms still show a circadian rhythm, referred to as free-running. This in turn displays the endogenous nature of the rhythm, it continues running even in the absence of environmental rhythms, albeit at a frequency slightly different than 24 hours. Thus in a way these rhythms are a way for the organism to generate an estimate or measure of time independently of geophysical cycles(known as biological time).
2. Synchronisation — In natural conditions, the rhythm is attuned to the light-dark cycles. This adaptive nature depends on the process of entrainment which refers to matching the period of the circadian rhythm to the period of the external cycle. This in turn establishes a constant time relation between a particular event of the circadian rhythm (such as awakening) and a specific event of the environmental cycle (such as dawn or dusk).
3. The speed of the clock is temperature compensated so that changes in the temperature do not affect it.

The Beatmaker

The circadian rhythms in vertebrates are controlled by the Supra-Chiasmatic Nuclei(SCN), located in the hypothalamus, SCN acts as a master clock synchronising local clocks present in tissues throughout the body. The SCN itself is synchronised by inputs from specialised photosensitive cells in the retina.

At the molecular level, these oscillations are maintained by transcriptional and post-translational feedback loops involving a set of mostly conserved clock genes.

Surprisingly, circadian rhythms have also been reported in cyanobacteria. This might seem counterintuitive as prokaryotes generally have a lifetime smaller than a day(why bother keeping a timer for a cycle that is longer than your lifetime!?). However, prokaryotes are more like a mass of protoplasm that grows larger more so than separate organisms, so in that respect, while it won’t make sense for the individual, the mass of the protoplasm does need to adapt and respond to cyclical changes daily.

Thus we can see that these rhythms are an integral part of most organisms, now that we know how they work, we can talk about how we can use these to our advantage.

Hacking time

Circadian rhythms are ubiquitous when it comes to the control of bodily functions so it’s only natural that disorders and diseases disrupt it. Scientists have also been looking at ways to manipulate the clock to their advantage.

• A large number of drug targets seem to show a circadian variation in their gene expression. Many studies show that the timing of drug application very likely affects the efficacy and toxicity of a drug. Further research into this could help improve the efficiency of these drugs. Conversely, the evaluation of rhythmic expression of “off-targets”, as well as the drug clearance, could help reduce toxicity and side effects.
• Many cyclic genes were linked to the cardiovascular system, there is also evidence for cardiac disorders happening more frequently in the early morning hours. Thus the timing of the dosing has been shown to play a role in the efficacy of these drugs. An example being Simvastatin, whose efficacy is shown to be the greatest when taken before bedtime. Besides that, antihypertensive drugs such as nifedipine and angiotensin II receptor antagonists also elicit greater benefits in the evening.
• The circadian clock controls the “on” and “off” cycling of many functions that are important for cancer development. Disruption of the clock may cause these functions to get stuck on “on” or “off” state, creating the right conditions for tumours to develop and grow. Studies have shown that cancer cells often exhibit disruptions in the normal circadian clock of a cell. Moreover, targeting specific components of the clock in these cells might be a viable strategy for killing and controlling the malignant mass.
• The disruption of sleep-wake cycles has been linked with the development of metabolic disorders and diabetes. Animals that are forced to eat during their resting period show an increase in body mass and a change in the expression of clock and metabolic genes. In humans, shift work that favours irregular eating times is associated with altered insulin sensitivity and higher body mass.
• Studies show that drug abuse profoundly affects the circadian clock via the central pacemaker(the SCN). People suffering from addiction show disrupted rhythms and these are even shown to cause a greater risk of substance abuse and relapse.

Conclusion

The study of circadian rhythms and their effects is a burgeoning field. The myriad of ways organisms keep time and how it affects them is a fascinating subject. We’re only now beginning to realise the sheer impact that the circadian system has on our bodies, and further research will surely serve to cement that.