How Do Circadian Rhythms Work?-A Final Answer
Can you recall the last time you felt sleepy on a plane when it was bright outside the window? What is it that is making you feel sleepy. Now most people would say that it is jet lag. Even though that answer is correct, a more scientific answer of saying that is that your circadian rhythms haven't been synced with the new timezone that you are in. So in essence, circadian rhythms are natural biological clocks that are set at a time of roughly 24 hours. A disturbance to these natural rhythms is what causes jet lag
when you are in a different time zone. Let's consider the example depicted in the image below. The definitive sign that shows us that we are dealing with a circadian rhythm is the fact that there is an oscillation in the graph and the period between the troughs,which is where the leaves are almost full expanded, is roughly 24 hours. From this, we can deduce that the plant operates in a circadian rhythm where its leaves expand during the day and close during the night. Some important questions that you should be asking yourself are how do these oscillations occur, how are these oscillations sustained, and why is the period between the troughs kept to roughly 24 hours? In this article, you will be getting answers to all these questions.
(Courtesy To biologydiscussion.com)
Circadian rhythms are present on almost all living organisms and so far we have only been able to learn the pattern of them. For years, scientists have been trying to figure out the biochemical processes that result in the oscillation of them and finally the answer has been revealed by three scientists who won the Nobel prize for Physiology and Medicine this year for this discovery.
One of the most important steps to understand how Circadian rhythms work is to understand how they oscillate over the day. In the 1970s Seymour Bender and his student,Ronald Konopka, tried to identify a gene that may influence the function of circadian rhythms in the body. They identified a gene called the "period gene". However, they never got to know how it influences circadian rhythms. This research gap was one of the primary drivers for today's Nobel laureates to research about this topic. Michael Robash, Jeffrey Hall, and Michael Young all worked in close collaboration to effectively isolate the period gene. This helped them discover the "PER" protein. The PER protein is what the Period gene is converted into after the process of transcription and translation. In simpler words, it is this protein that the gene "codes" for. As a result of this discovery, they also recognized a very important pattern that answered how the rhythms oscillate over a time period of roughly 24 hours. They realized that as the day went on PER protein kept degrading and during the night the PER protein started accumulating as shown below.
(Courtesy to nobelprize.org)
Even though Robash, Hall, and Young discovered how these rhythms oscillate in a 24 hour cycle, that was not all that was required to truly crack the question. Now, they had to answer how these rhythms can be sustained or in other words how are these rhythms regulated. In the pursuit of this question, they reached an answer which stated that an inhibitory feedback loop is the primary way how the oscillations of these rhythms are maintained.
Before we jump into how this loop maintains the oscillations, we need to understand the how an inhibitory feedback loop works. Imagine that the blood sugar level in your body is very high. Receptors in the body sense that and,as a result, insulin is secreted by the beta cells of the pancreas into the bloodstream. As the insulin levels in your blood increases, the insulin reattaches to an early "step" in its production system to slow its rate of production. This occurs until the blood sugar levels are back to
normal. What an inhibitory feedback loop achieves is to stop the overproduction of a protein in the body which helps save energy and resources for other bodily functions. In fundamental terms, this is basically why the PER protein oscillates in quantity. As PER protein keeps accumulating throughout the day, these proteins attach to a certain early "step" in their production system to reduce the production rate. As a result, levels of PER protein and its production rate reduce throughout the day. Once the quantity of PER proteins in the body is very low, during night time for example, there aren't enough PER proteins to provide inhibitory feedback to the production system. As a result, PER protein levels increase.
However, before they could be happy with their result they faced a significant hurdle. They discovered that during the night PER protein accumulated inside the nucleus. They wondered how this could happen because the period gene is transcribed in the nucleus and then sent outside the nucleus via mRNA for translation into the PER protein. Eventually, they discovered the gene which encodes for a protein that allows the PER protein to effectively enter the nucleus and initiate an inhibitory feedback loop. In 1994, Young discovered another clock gene called Timeless which codes for the protein TIM. TIM basically attaches with the PER protein and helps it enter the nucleus to help perform its function.
Even though they answered most of the essential questions, there was still one last question left and that was how do our circadian rhythms set themselves to oscillate in a period of 24 hours? In order to answer this Michael Young and his team researched heavily on the causes for this and eventually discovered another gene called double-time which codes for a protein called DBT. This protein basically delays the accumulation of the PER protein to maintain a cycle that is roughly 24 hours in length.
Circadian rhythms is a topic that I studied in AP Biology last year and I was led to believe that circadian rhythms are a 24 hour cycle and "just work". There were no explanations as to why they were set to a 24 hour cycle, how the rhythms oscillate, and why they "just work". However, now there are detailed explanations for all these important questions. As a result, I am quite happy about how fast scientific research is progressing today to help us explain concepts that we previously thought were impossible to explain.
Works Cited
https://www.nobelprize.org/nobel_prizes/medicine/laureates/2017/press.html
Zehring, W.A., Wheeler, D.A., Reddy, P., Konopka, R.J., Kyriacou, C.P., Rosbash, M., and Hall, J.C. (1984). P-element transformation with period locus DNA restores rhythmicity to mutant, arrhythmic Drosophila melanogaster. Cell 39, 369–376.
Price, J.L., Blau, J., Rothenfluh, A., Abodeely, M., Kloss, B., and Young, M.W. (1998). double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell 94, 83–95.
Hardin, P.E., Hall, J.C., and Rosbash, M. (1990). Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels. Nature 343, 536–540.
