Circadian rhythm based on DNA
We are creatures of pattern. We engage in certain activities at the same time each year. We have rhythms that run through the weeks and months of our lives. But perhaps most importantly, we have a daily cycle which controls much of what we do. Our inner clock helps us to negotiate our daily lives. It tells us when to get up, when to sleep, when to eat, and when to be most active. This circadian rhythm provides the background to our lives. Indeed, every creature – from the smallest microbe to mighty redwoods and blue whales – has some form of internal clock following a circadian rhythm.
With modern travel, we can even see how much we depend on our internal clock versus our surroundings. Travelling from Prince George to London results in an eight hour time shift, but despite the sunlight, your body will be telling you it is time to sleep. It takes days for our rhythm to shift to the new pattern.
We each have our own internal patterns, too. Some people are able to set their rhythms so they sleep in, but can last well into the night.
Others are early birds who are up with the dawn but are in bed by 9 p.m. every night. Some people are even true night owls and can comfortably stay up all night while sleeping during the day. But how does this internal clock work? What makes it tick? Jeffrey C. Hall, Michael Rosbash, and Michael W. Young were awarded this year’s Nobel Prize in Physiology or Medicine for “their discoveries of the molecular mechanisms controlling the circadian rhythm.”
To be clear, while the award was given to these three distinguished and deserving scientists, studying circadian rhythms in all creatures great and small has been a scientific pursuit which dates back centuries and involves many scientists.
But it has only been in the last 50 years or so, with the discovery of DNA, our understanding of genes, the elucidation of the mechanisms for gene transcription and protein production, and an overall understanding of life at the molecular level that biochemists have finally been able to tease out some of the fundamental details.
In particular, identification of a clock gene involved work on fruit flies. These annoying little creatures are probably some of the most well studied organisms on the planet. In the 1970s, Seymour Benzer and his student Ronald Konopka were attempting to isolate the fruit fly genes relevant to circadian rhythms.
They isolated three mutant strains of fruit flies. One with a 19 hour day, one with a 28 hour day, and one with a random cycle.
The respective length of each fly’s day had profound impacts upon its bodily functions and daily life. They were able to show these changes were the result of disruption in a single gene which they named “PERIOD.”
In 1984, Hall, Rosbash, and Young were successful in isolating the PERIOD gene.
Hall and Rosbash went on to discover the protein produced by the gene, which they called “PER,” accumulated at night and was degraded during the day. This oscillation in the level of PER in our cells over a 24 hour cycle leads to the synchrony of our circadian rhythm.
Like all good research, answers always lead to more questions. In this case, how did this protein produced in the cytoplasm exert its control in the nucleus? Their hypothesis was a feedback loop in which the PER protein could prevent its own synthesis by regulating the activity of the PERIOD. That is, once enough PER has been generated, the gene is shut off until the level drops to a point where it is no longer inhibiting activity. At this point, the gene turns on again generating more PER and around and around it goes.
While tantalizing, the model was missing pieces. In particular, while PER is constructed in the cytoplasm it builds up in the nucleus during the night. As the nucleus is protected from the rest of the cell by a membrane, how was this protein getting through the barrier?
In 1994, Young discovered a second clock gene which he named “TIMELESS” capable of encoding a protein called “TIM.” In an elegant use of biochemical techniques, he was able to show TIM binds to PER and it is the two proteins together which enter the cell membrane to control PERIOD.
Of course, this explains the mechanism of control, but not the frequency. That is controlled by another gene identified by Young called “DOUBLETIME” which encodes for another protein known as “DBT” which delays the accumulation of PER.
It is these three genes and their proteins working in synchrony which give rise to our circadian rhythms.
The upshot of this is if you are someone who really likes to sleep late, you can blame it on your genes.
Jeffrey C. Hall, Michael Rosbash and Michael W. Young give a lecture in Hong Kong on Sept. 24, 2013. The three Americans won the Nobel Prize in Physiology or Medicine on Oct. 2 for their discovery of the genetic basis of the circadian rhythm.