The ticking of the clock

2015 L’Oréal-UNESCO UK & Ireland Women In Science fellowship winner Dr Aarti Jagannath has the molecular mysteries of the circadian clock in her sights…

All life on earth has evolved in an environment where there are daily rhythmic changes caused by the rotation of the earth on its axis. Light levels, temperature and even the availability of food change constantly every day, with a predictable rhythm. As a result, most life forms have evolved a timekeeping mechanism, known as a circadian clock, which anticipates these changes in the environment and allows them to prepare accordingly.

For plants, this would mean timing photosynthesis during the day. For us humans, the most obvious expression of the clock is the sleep wake cycle, but pretty much all that our body does occurs with a 24 hour rhythm. For example, blood pressure and body temperature fluctuate with a daily rhythm.

This extends to alertness and cognition; we are primed to be most alert during the day, a few hours after we wake up. At night, these levels naturally dip. Indeed we are seven times more likely to be involved in a road accident during that 3 am drive to the airport, as that is when the clock has set alertness levels to be the lowest.

As with most of our physiology, the clock exists at the level of genes and is found in nearly all cells of our body. It consists of protein factors whose production and degradation occur with a 24h rhythm and downstream of these proteins are thousands of other genes that go on to regulate different aspects of physiology.

The circadian clock is therefore a master regulator of gene transcription.

Naturally, when this clock is disrupted, the consequences are quite serious. Studies on shift workers show they are at a far higher risk for diabetes, obesity, depression and even cancer. In fact, shift-work was recently classified as a Class 2A carcinogen, in same class as UV light.

However, sleep and circadian rhythm disruption (SCRD) is inevitable in today’s 24/7 society. If we understood better how the clock was regulated, we may be able to suggest new routes by which these chronic and debilitating conditions may be treated, or even prevented.

[caption id="attachment_51922" align="alignnone" width="200"] The circadian rhythm[/caption]

My research is on how the body clock senses time. A circadian clock must be sensitive to time cues in the environment, in order to ensure we live in synchrony with the outside light-dark environment. I study how these cues are fed to the clock at the molecular level.

Light is probably the most important time cue for the clock and specialised cells within the retina feed this information to the master clock in the brain, known as the suprachiasmatic nuclei (SCN). Neuronal and hormonal signals from the SCN feed down to “peripheral” clocks across the body which then tick in synchrony.

When the SCN senses light at the wrong time, for example in the middle of the night, it takes into account this information and adjusts clock gene expression accordingly, causing a shift in the circadian rhythm.

One of our recent studies was on jet-lag. We’ve all experienced it, and it is a real biological phenomenon, which occurs when the circadian clock is misaligned with the outside light-dark cycle. The circadian clock does eventually re-align, but it takes about a day for each time-zone crossed.

Why does it take so long for the circadian clock to adjust to a new light-dark cycle?

We decided to look at what happened at the molecular level when the SCN saw light at night and used microarrays to profile gene expression changes in response to light.

Lots of genes changed, but among these, we found one known as Salt Inducible Kinase 1 or Sik1, which went up in response to light. We found that Sik1 was acting as a brake on the clock. Sik1 was switched on in response to light and prevented the light-signaling pathway from changing clock-gene expression beyond a certain point.

We then knocked down Sik1 in the SCN with RNA interference, with the idea that taking away this brake should allow the clock to shift a lot faster and further. We simulated an eastward flight in mice, to cause a 6 hour misalignment of their circadian rhythms with the outside light-dark environment and found indeed that it would normally take an animal about six days to entrain. However, without Sik1 they adjusted their clocks to the new cycle within a couple of days.

I’m now interested in taking this one step further. Can we build on our understanding of how time cues are fed to the clock to develop strategies to shift the clock? Could we therefore minimise the effects of circadian disruption? I will be using my L’Oreal fellowship to try and answer these questions.

Author:

Dr Aarti Jagannath is Hayward Lecturer and Junior Research Fellow in Medicine at the University of Oxford.

She received one of the five highly contested 2015 L’Oréal-UNESCO UK & Ireland For Women In Science Fellowships.