By Helen Albert, Editor

We all have an inner clock that allows us to respond appropriately to our immediate environment according to the time of day or night. The existence of such biological clocks has been known about for some time, but the specific mechanism of action was unclear.  In the 1980s, three American scientists – Jeffrey Hall, Michael Rosbash (Brandeis University, Boston) and Michael Young (Rockefeller University, New York) – succeeded in isolating a gene called period that had previously been linked with disruption of the biological clock in fruit flies (Drosophila melanogaster). They went on to show that levels of the protein produced by this gene went up during the night and down during the day over a 24-hour cycle. The importance of this discovery has been recognised today, as these scientists have been jointly awarded the 2017 Nobel Prize in Physiology or Medicine.

Clockwork mechanism

The study of biological clocks, known as chronobiology, has increased exponentially in recent years. In the 1950s, one of the founders of this area of science, Franz Halberg, coined the term ‘circadian’ –from the Latin for ‘about’ (circa) and ‘day’ (diem). Since then the term circadian has been used to describe both the biological clocks that every organism has and also the rhythmic 24-hour cycle they are subject to.

In the 1970s, US-based researcher Seymour Benzer and his then student Ronald Konopka discovered that mutations in an unknown gene were causing disruptions in the circadian rhythms of Drosophila flies. They called this gene period.

In 1984, Hall, Rosbash and Young were able to isolate this gene and also show that levels of the protein it encoded – PER –  increased at night and went down during the day. Hall and Rosbash suggested that PER was self-regulating and could prevent its own production by blocking the activity of the period gene. This model seemed to work reasonably well, but there were still some missing pieces. For example, how did the PER protein get into the nucleus to block period activity from the cytoplasm where it is produced?

In 1994, Young discovered that another Drosophila gene called timeless produces a protein called TIM that binds to the PER protein and allows it to travel into the nucleus, answering this question. But, the researchers also wanted to know how the timing of the oscillations in the levels of PER are controlled? Young’s research also answered this with the discovery of a gene called doubletime. The protein DBT, encoded by doubletime, can delay accumulation of the PER protein thus allowing adjustments to match a 24-hour cycle.

Let sleeping dogs lie

Since the ground breaking discoveries of Hall, Rosbash and Young in the 1980s, research into the genetics of circadian rhythms has developed rapidly. Humans are also influenced by circadian rhythms and one key area of our physiology that is strongly influenced by our circadian clocks is sleep.

Although the average human has an internal clock set to approximately 24 hours, research has shown that mutations in genes involved with circadian rhythms can influence a person’s sleep patterns.

We all know someone who is either a ‘night owl’ and likes to get up and go to bed late or a ‘lark’ who likes to get up and go to bed early. There is evidence to suggest that if your circadian clock runs faster than 24 hours you may be more likely to be a lark, whereas if it runs slower than 24 hours you are more likely to be a night owl.

There is also evidence to suggest these tendencies are linked to mutations in circadian clock genes. For example, earlier this year, mutations in the gene CRY1 were linked to night owl tendencies. A study published in 2016, also found a number of genetic variants associated with being a morning-person or a lark.

A sleep a day keeps the doctor away

In addition to influencing normal sleep patterns, circadian genes also play an important role in keeping us healthy. Research shows alterations in circadian rhythms, whether through genetic or environmental disruption, can lead to abnormal immune responses. For example, sleep deprivation in shift workers has been linked to reduced immune response and increased susceptibility to infection.

Circadian genes also impact how we respond to stress. Recent research showed that people with a specific variant in the CLOCK gene were more likely to get migraines when exposed to stress than those without this variant.

Interestingly, circadian rhythms may also influence how effective a given medication is. For instance, research in this area has shown that giving the flu vaccine in the morning leads to higher production of antibodies by the body than giving it later in the day. It has also demonstrated that some drugs are more effective when taken at certain times – antihistamines work best when taken early in the morning or late at night, and cardiovascular drugs such as angiotensin receptor blockers and some statins work best when taken at night.

Back to the future

These are only a few examples of the many ways we are influenced by our circadian clocks. There are many more and it seems likely that researchers will continue to add to the discoveries of Hall, Rosbash and Young and uncover interesting findings about how humans and other organisms are impacted by mutations in circadian genes. One key message seems to be that modern society and technological advances, such as the rise of smartphones and tablets, is resulting in an increasingly sleep-deprived population. While there is always more to be discovered, the research to date suggests that if we do nothing else, making sure we get regular, sufficient sleep (no less than 6 hours) will at least help us to keep the doctor away for another day!

Further reading from Portland Press

By Jeffrey Hall, Michael Rosbash et al:

Circadian oscillations in protein and mRNA levels of the period gene of Drosophila melanogaster. Laurence J. Zwiebel, Paul E. Hardin, Jeffrey C. Hall and Michael Rosbash. Biochemical Society Transactions 1990. http://www.biochemsoctrans.org/content/19/2/533.full-text.pdf.

Other articles on circadian rhythms:

• Running on time: the role of circadian clocks in the musculoskeletal system. Michal Dudek, Qing-Jun Meng. Biochemical Journal http://www.biochemj.org/content/463/1/1
• The circadian clock and metabolism. Oren Froy. Clinical Science http://www.clinsci.org/content/120/2/65#
• HSG cells, a model in the submandibular clock. Yoshiaki Onishi. Bioscience Reports http://www.bioscirep.org/content/31/1/57 (Open Access paper)
• The sweet tooth of the circadian clock. Minnie Fu, Xiaoyong Yang. Biochemical Society Transactions http://www.biochemsoctrans.org/content/45/4/871
• Rethinking the clockwork: redox cycles and non-transcriptional control of circadian rhythms. Lisa Wu, Akhilesh B. Reddy. Biochemical Society Transactions. http://www.biochemsoctrans.org/content/42/1/1
• Essays in Biochemistry – issue 49, 2011. Chronobiology. http://essays.biochemistry.org/content/49