The title of this post is a quote from Dr. Steve Kay from the University of California, from a fascinating seminar he gave here at the University of Bristol this month. Dr. Kay’s subject is circadian rhythms – the 24-hour cycles that affect not only our conscious world, but also the functioning of organisms on a molecular level.
The Earth rotates on its axis every 24 hours, giving us a period of time in the dark and a period of time in the light. Multi-cellular life, including plants and mammals, has evolved accordingly such that our bodies don’t just respond to these conditions, but actually anticipate environmental changes and adjust our metabolism and cellular function to suit.
If you need convincing of this, watch this video. Notice how the sunflower plant tracks the sun across the sky and then wilts a little at night. But here’s the thing – notice how the plant then “resets” itself i.e. it then points towards where the sun will come up, before the sun has actually risen. You can imagine how this gives the plant an adaptive advantage, as it is then ready to bask in the maximum amount of sunlight possible in order to make food through photosynthesis. Our bodies have also evolved to regulate certain processes on a 24 hour cycle, such as brain activity, hormone production and metabolic rate.
How are circadian rhythms generated?
Individual cells in our bodies have circadian rhythms. If you take cells out of an organism and put them into cell culture (just a way of saying how we grow cells in the laboratory), they continue to exhibit these rhythms, but they are out of sync i.e. the rhythms don’t oscillate at the same time.
In our bodies, different tissues and cell types have circadian rhythms that allow them to switch on relevant genes at relevant times. These are referred to as “peripheral” clocks. Our brains can then control these rhythms and synchronise them, in an area called the suprachiasmatic nuclei (SCN). The SCN can be “reset” by light over time, which is how it can tie in with our sleep/wake cycles. The SCN is also referred to as our “central clock” due to its role in synchronizing our peripheral clocks.
So what exactly is it that generates these rhythms in the cells themselves? We’ve known for a while that a set of core proteins in the cell generates the rhythm, but a few years ago Dr. Kay and his laboratory group suspected it was more complicated than this.
They carried out experiments to identify the genes responsible, using what we call a siRNA (small interfering RNA) approach. A siRNA is a small molecule we can put into cells that temporarily switches off a specific gene. We can then look at the effect this has on the cell. Dr Kay’s laboratory obtained siRNAs for every gene in the human genome, and tried them all out on human cells. They then looked for effects on the cell circadian rhythm. If it is affected, you can predict that this gene is involved somehow.
How was the circadian rhythm detected, you might ask? The cells had been modified such that they glow with a different intensity at different stages of the circadian rhythm. Computers can then detect this intensity and measure how it has been changed, if at all. Dr Kay’s group found that over 200 genes, when switched off, affected the rhythm. Upon further investigation, they found that these were mainly genes that interacted in some way with the core cycle of proteins I mentioned earlier. So clearly the generation of circadian rhythms is more complicated than we originally thought.
Why do we care?
Because a lot of biological processes are regulated by the circadian rhythm, but also because a lot of disorders have been linked to disruption of circadian rhythms. Mutations in clock genes are unsurprisingly linked to sleep and mood disorders, such as Delayed Sleep Phase Syndrome (DSPS), or Familial Advanced Sleep Phase Syndrome (FASPS). People with bipolar disorder are also likely to have a mutation in a particular protein that is crucial to circadian clock function.
But there are other, less obvious afflictions that are linked to our circadian rhythms.
For example, there is a strong association between vascular diseases and the time of day. The risk of heart attack is mostly determined by a myriad of factors such as exercise, diet and smoking, but the circadian rhythm also plays a role. Susceptible patients are at the highest risk of suffering a heart attack in the morning.
There are theories as to why this might be. Fluctuations in blood pressure follow a circadian rhythm. It is naturally at its lowest just before waking up, and quickly rises when you wake up due to a change in the level of the hormone cortisol. In addition, platelets, the cells that cause blood clotting, have shown a peak in their activation when you wake.
Normally, these changes are not harmful to healthy individuals, but for a person with already partially blocked blood vessels due to other factors such as diet, these can be the tipping point that causes a heart attack.
Circadian rhythms and obesity
One of the problems with the Western lifestyle is that we are often awake at odd hours with the help of artificial light sources and technology. In addition, many of us do not have regular working patterns, particularly those on shift work who can end up working through the night. This can wreak havoc with our internal body clocks.
One of the things our bodies anticipate with circadian rhythms is food intake. It makes sense be poised to produce the enzymes and hormones required to break down sugar in the bloodstream during the day when we are more likely to take in food. Being ready to break down glucose makes the process more efficient.
For example, the hormone insulin has a daily cycle. Studies on animals have shown that they are more sensitive to the effects of insulin at certain times of day. Disrupting their circadian rhythms by changing the amount of time they spend in the light interferes with the daily cycle of insulin and makes rodents more prone to obesity and diabetes. Therefore, the timing of food intake might be a significant factor in weight gain – certainly an interesting concept, though it has yet to be proven and there are obviously a lot of other factors at play. But it may also explain why shift workers are more prone to obesity.
In 2012, Dr. Kay’s laboratory also carried out a screen for 120,000 drugs on the same type of cells I described for the siRNA screen earlier, to see if the drugs altered circadian rhythms by lengthening or shortening cycles. They identified a compound they rather imaginatively called “longdaysin”, that slows the circadian clock in human cells and also in zebrafish. Since then, Dr Kay’s laboratory have identified a number of compounds that can target the key machinery that generates circadian rhythms, including one that interferes with glucose metabolism. This could form the basis of clock-based medicines for diabetes.
In summary then, many body systems follow a daily clock that help us anticipate changes in the environment such as temperature and food intake, providing us with the ability to respond rapidly and effectively. Messing with this internal body clock can have detrimental effects, though it is not entirely clear yet how big the influence is, and whether we can do anything about it. Exciting progress in this research area has been made however, which may allow us to deal with many physical and mental disorders that have been attributed to a modified internal clock. The identification of more genes that are involved in regulating circadian rhythms allows us to build up a clearer picture of how things go wrong in disease.
Sources and Further Reading
Mainly the fascinating seminar from Dr. Kay, but here are some of the publications:
Paper from Dr. Kay’s laboratory about the siRNA screen.
As above for the drug screen.
A review on the subject, also from the Kay laboratory.