Rhythms in red blood cells and the ever-present casein kinase

My latest research was published in Journal of Biological Rhythms this week. It is open access here: Casein Kinase 1 Underlies Temperature Compensation of Circadian Rhythms in Human Red Blood Cells.

How CK1 works in a RBC
Casein Kinase 1 modifies circadian rhythms in red blood cells

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Jet lag – the disadvantage of having a clock in the modern world

Air travel challenges our bodies in a way that has never before been encountered in our evolutionary history. It allows us to move rapidly across multiple timezones, quicker than we could have ever moved by foot or animal. Unfortunately, our bodies are unable to adjust quickly enough. We are constrained by our circadian clocks, the things that give our bodies a sense of internal time, which have evolved to coordinate our physiology to the rhythmic and predictable changes in the external environment (as well as other roles) like day and night. The clock keeps its original time when you move timezones like a watch before you’ve reset it. It’s resistant to rapid change, giving us jet lag. However, unlike a watch, the body clock can gradually reset itself over a period of days so that we become tuned to a new local time. Despite this inbuilt mechanism, in an era of global travel it is often too slow.

Is it possible to speed up the resetting process? Can we travel the world without jetlag?

Maybe.
Continue reading “Jet lag – the disadvantage of having a clock in the modern world”

Presentiment – circadian clocks giving plants and animals a sense of time

Presentiment is that long shadow on the lawn
Indicative that suns go down;
The notice to the startled grass
That darkness is about to pass.

Emily Dickinson

Sometimes you find in literature beautiful expressions of technical terms that are otherwise dry and stuffy. Presentiment, by Emily Dickinson, is one of those beautiful expressions. Why did she decide to write a few words about twilight, and at the same time so succinctly summarise one of the key features of the circadian clock? Apparently Dickinson spent much of her adult life withdrawn from the world and, in doing so, she was probably in a position to watch and notice the hidden-in-plain-sight details of the world, such as how the length of shadows allow you to approximate the time of day and how grass may tell time without watches.

Continue reading “Presentiment – circadian clocks giving plants and animals a sense of time”

Why have a circadian clock?

Almost every animal and plant on the planet has a circadian clock, even those that live in the depths of the sea and deep underground in caves.

The presence of clocks in almost all life-forms implies that it is a helpful or advantageous characteristic, an evolutionary adaptation, serving to improve the fitness of the organism. This argument makes apparent sense but, without testable hypotheses, has little to support it.

Two main hypotheses have been formed to explain the evolutionary benefit of having a circadian clock. The first is known as the External Synchronisation hypothesis – that the benefit to the circadian clock lies in being coordinated with the external environment, for example, the predictable daily change in light and dark that we call day and night. The second is the Internal Synchronisation hypothesis – here the clock benefits an organism by allowing it organise physiological processes in time in order to avoid conflict between incompatible processes, for example separating the process of photosynthesis from that of nitrogen fixation in the case heterocystous cyanobacteria.

These two hypotheses aren’t mutually exclusive. The internal synchronisation hypothesis doesn’t necessarily require a 24 hour clock; plenty of other periods would suit. But, timing pressure placed on an animal from the external environment could force biological processes to fit within the 24 hour day, for example, the reactions for photosynthesis. These are only necessary in the day when it is light. But since nitrogen fixation and photosynthesis are incompatible, nitrogen fixation gets restricted to the night and internal organisation has been forced on an animal from external pressure. Once established, internal synchronisation could become independent of external pressures. Perhaps, in the origin of circadian timing systems, external synchronisation came first and internal synchronisation second, but now, either one serves as a selective advantage. So, though the two hypotheses propose reasons for selective advantage a circadian clock might give to an organism, and therefore why Clocks may have evolved in the first place, arguments are complicated as whether these are the original selective pressure that formed a circadian timing system.

How might we test which which hypothesis is most important today? One way is to look at animals that live in non-rhythmic environments, those that do not experience the regular and predictable cycle of day and night. These animals offer the chance to directly test the first, external synchrony, hypothesis, since in a non-rhythmic environment, there is no need to synchronise to an absent cycle. 

The deep sea and caves are two environments that fit this description. Interestingly, most studies on organisms that live there give at least some hints that circadian clocks are present and working even here. Although, there are many difficulties interpreting and comparing this research due to the various experimental conditions used, this general observation lends weight to the internal synchronisation hypothesis – in the absence of a no cycling external environment, a ticking clock must be being used for something else, and internal synchrony is the most obvious.

My PhD research looked at one organism that lives in the depths of caves and is highly adapted to life there: the Mexican blind cavefish, Astyanax mexicanus. This fish shows wonderful daily patterns of behaviour and gene expression, confirming that it has a functional circadian clock. It also shows some interesting quirks, which give some insight into why an animal that lives in the dark and has done so for tens to hundreds of thousands of years might keep a system that generates 24 hours rhythms in physiology and behaviour.

What is a circadian clock?

Broadly speaking, the circadian clock is a cell and molecular feedback loop – inside the cell, a bunch of proteins that interact with genes and DNA, which in turn interact back with those original proteins. This cellular feedback loop controls those outward and apparent rhythms we are aware of, like jet lag and waking, as well as many more we may be unfamiliar with, but it isn’t just humans who have a body clock, all life on planet Earth has one, although its workings aren’t exactly the same in all life-forms.

The feedback loop. Proteins join together to activate gene transcription of genes that subsequently repress the original proteins. This feedback generates oscillations of gene expression.
The feedback loop. Proteins join together to activate gene transcription of genes that subsequently repress the original proteins. This feedback generates oscillations of gene expression. From Eckel-Mahan and Sassone-Corsi, 2013, Metabolism and the circadian clock converge.

In animals, the key players are genes called clock, bmal, period and cryptochrome. There are actually multiple versions of the genes, named numerically (clock1a, bmal2, period3 etc) and shortened to 3 or 4 letters (clk1a, bmal2, per3 etc). To explain the cycle, we need to start with clock and bmal and go twice around the feedback loop, each stage showing the effect of the previous.

Firstly, CLOCK and BMAL proteins (CLK and BMAL; by consensus gene names are in italics and PROTEIN names are in uppercase), interact in the cell, joining together to turn on period and cryptochrome genes. As the genes are turned on, they are transcribed by the cell, eventually begetting proteins, PER and CRY proteins. These proteins interact with CLK and BMAL proteins to make CLK and BMAL less activating, repressing CLK and BMAL.

Secondly, as CLK and BMAL are now repressed, the turning on of period and cryptochrome genes is stopped. Fewer PER and CRY proteins are generated by the cell. Fewer PER and CRY proteins means less repression of CLK and BMAL, and so CLK and BMAL are released to begin another cycle.

The overall effect is similar in plants and other organisms: Activator proteins turn on repressor genes, these repressor genes are translated into repressor proteins by the cell and repress the activator proteins and so on. These proteins and genes in the clock aren’t the same in all organisms, but they play similar roles turning on or off genes, modifying the activity of proteins, like how David de Gea and Manuel Neuer are not the same player, but play similar roles for their teams. The fact that clocks have a similar feedback mechanism but consist of different components in the different branches of life adds to the idea that circadian clocks must be evolutionarily adaptive. It is an example of convergent evolution, where two separate species look similar without being evolutionarily related, such as how dolphins and sharks look fairly similar and are adapted to the broadly similar environments but are completely different species. In this case, evolution has dictated that the best body shape for fast and efficient swimming in water is a streamlined oval. In the case of circadian clocks, we can suggest that evolution has dictated that the best way of organising your physiology and behaviour is through the use of a molecular feedback loop which acts within the cells of the body.

 

Two illustrations of how the molecular components make up the circadian clock. On the left - in zebrafish. Clock (CLK) and bmal (BMAL) proteins (there are 6 versions) interact to activate (green arrow) transcription of per and cry genes. PER and CRY proteins then interact with CLK and BMAL to repress (green line with flat on top) their activity. Per and cry are also activated by light. On the right - plants. CCA1 and LHY are the CLK and BMAL equivatlents, interacting to activate PRR7 and PRR9 which then repress CCA1 and LHY.
Two illustrations of how the molecular components make up the circadian clock. On the left – in zebrafish. Clock (CLK) and bmal (BMAL) proteins (there are 6 versions) interact to activate (green arrow) transcription of per and cry genes. PER and CRY proteins then interact with CLK and BMAL to repress (green line with flat on top) their activity. Per and cry are also activated by light. Taken from Vatine et al., 2011, It’s time to swim! Zebrafish and the circadian clock. On the right – plants. CCA1 and LHY are the CLK and BMAL equivatlents, interacting to activate PRR7 and PRR9 which then repress CCA1 and LHY. Taken from Harmer lab at UC Davis