INSPIRATIONS FROM HISTORY
Year : 2018 | Volume
: 23 | Issue : 1 | Page : 69--71
Chronobiology: Discovery of the molecular mechanisms of circadian rhythm
Pooja Shakya, Shyama Nand Roy, Raman Deep
Department of Psychiatry, AIIMS, New Delhi, India
Associate Professor, Department of Psychiatry, AIIMS, New Delhi - 110 029
Advances in the field chronobiology have potential implications for physical as well as mental health and human behavior. Several paradigm-shifting discoveries established key mechanistic principles for the biological clock. We trace the origins and key discoveries that helped to advance the field of chronobiology and a ground-breaking work recently recognized by Nobel prize. The foundational work by Hall, Rosbash and Young led them to Nobel prize in physiology or medicine (2017) for discoveries pertaining to molecular basis of circadian rhythm.
|How to cite this article:|
Shakya P, Roy SN, Deep R. Chronobiology: Discovery of the molecular mechanisms of circadian rhythm.J Mental Health Hum Behav 2018;23:69-71
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Shakya P, Roy SN, Deep R. Chronobiology: Discovery of the molecular mechanisms of circadian rhythm. J Mental Health Hum Behav [serial online] 2018 [cited 2023 Jun 1 ];23:69-71
Available from: https://www.jmhhb.org/text.asp?2018/23/1/69/244912
The concept of time originated with the big bang, as per the theory of relativity. Since its inception, earth has been exposed to “light and dark cycles” and one such complete cycle is 24 h in a solar day (and 23 h and 56 min in a sidereal day). The 24-h rhythmicity of biological activities has been continuing alongside the human evolution. Just as the simple observations of natural phenomena have led to various discoveries, the observations of biological activities in relation to this 24-h rhythmicity have contributed toward the development of the field of chronobiology.
Various discoveries in this field have tried to unravel how plants, animals, and humans adapt their biological activities to synchronize with the Earth's revolutions.
We trace the origins and key discoveries that helped to advance the field of chronobiology and a ground-breaking work recently recognized as Nobel Prize in physiology or medicine (2017).
Circadian Rhythms: Evolution of the Concept
Interestingly, the earliest known account of the rhythmicity in biological activities dates back to 4th century BC, when Androsthenes, a ship captain serving under Alexander the Great, described diurnal leaf movements of the tamarind tree. In modern times, French scientist Jean-Jacques d'Ortous de Mairan first documented the 24-h patterns in the movement of plant leaves in the 18th century. Swedish botanist and naturalist Carl Linnaeus even designed a flower clock using certain species of flowering plants. While initially the movement was thought to be influenced by sunlight, however, the rhythmicity was seen to continue even after putting the plant in constant dark environs and at constant temperature. Over the next century, numerous researchers, including Charles Darwin, extended Marian's observations to sleep movements of plants. Toward late 19th century and early 20th century, researchers identified a variety of behaviors that exhibit daily oscillations in animals and humans (such as food-seeking behavior in bees or body temperature in humans).
Once it was established that the biological rhythmicity was universal across plant and animal kingdom, the question was whether these oscillations were endogenously controlled or are governed by environmental cues. Initially, most of botanical researchers, including Pfeffer, were in favor of an external factor. Darwin supported the endogenous nature of the sleep movements in the plants.
During the early 20th century, two notable researchers, Anthonia Kleinhoonte and Erwin Bünning, with their extensive experiments on various plants supported that the rhythmicity appears to be endogenous in nature. The same was supported by various animal researchers including Curt Richter, Pittendrigh, and Aschoff (the three musketeers of chronobiology) through their experiments in constant environments. Pittendrigh and Aschoff organized an International Symposium on Biological Clocks (June 5–14, 1960, Cold Spring Harbor, USA), with 150 researchers participating from across the world, which effectively settled the debate in favor of endogenous nature of circadian behaviors. One of the most compelling forms of evidence put forth to favor the endogenous origin was that when light and other cues are removed (producing a condition known as free-running), the oscillatory period typically varied slightly from 24 h. This had led Halberg, Barnum, and Bittner to coin the term circadian (circa means about). The recognition that endogenous rhythms vary slightly from 24 h raised a question of how various cues such as light (known as Zeitgebers) entrained the oscillations to the 24-h light and dark cycle found on Earth.
The quest began to understand the underlying mechanisms for circadian rhythms. Over the next two or three decades, it became clear that there is a localized circadian clock in suprachiasmatic nucleus region of brain also known as pacemaker. However, it was still not clear that how this clock was regulated at a molecular and genetic level. Many researchers were struggling with these questions. Charles Darwin in the previous century had commented in his book (titled Power of Movements of Plants) that “the periodicit is to a certain extent inherited.” Further analysis of the role of any genes in the circadian clock had to await till the discoveries of structure of DNA and genetic code in the 1950s and 1960s.
Molecular Mechanisms of Circadian Rhythms and the Nobel Prize (2017)
Two main milestones could be construed as landmark discoveries in chronobiology, which were (a) demonstration of the genetic basis for circadian rhythm and (b) isolation of its responsible gene and their respective products. Persistent hard work and intuitive mind of few researchers were able to solve these mysteries. The important names for deducing genetic basis for circadian rhythm are Seymour Benzer and his student Ronald Konopka.
Benzer, who was a physicist, molecular biologist and behavioral geneticist, was born in 1921 in Brooklyn. He completed PhD in physics but was immensely curious about life and mysterious nature of genes. He was influenced from early years by a short book (What is Life? by Erwin Schrodinger's), the same book that turned Watson from ornithology to his quest for DNA structure. This led him to shift his interest from physics to biology to being a behavioral geneticist. Contrary to his contemporaries, he was of the view that animal behaviors can be directed by single gene. It was accepted among scientific fraternity that circadian rhythmicity is inherited. In 1970s, Seymour Benzer (along with his student Ronald Konopka) demonstrated that mutations in an unknown gene disturbed the circadian clock of flies and named this gene as period gene. It laid the basis for the intense search for the molecular-genetic foundations of circadian rhythmicity that dominated rhythms research in the coming decade.
In 1984, Jeffrey Hall and Michael Rosbash (Brandeis University, Boston, USA) working in close collaboration with Michael Young (Rockefeller University, New York, USA), succeeded in isolating the period gene. This paradigm-shifting discovery by these three researchers was recently recognized by an award of Nobel Prize in physiology or medicine (2017).
The discovery of period gene also fuelled a series of other notable discoveries to understand the molecular mechanisms fully. Another research group at Brandeis University found that the PER protein was rhythmically produced in the fly brain with a peak at the early night, while the per RNA showed a similar expression pattern, about 6 h in advance of the protein. This led Paul Hardin, Jeff Hall, and Michael Rosbash to propose the idea of the transcription–translation feedback loop (1990). After transcription, the mRNA leaves the nucleus into the cytoplasm and after the translation to PER protein, it returns to the nucleus to suppress further transcription of the gene. This loop became the leading theory in the immense effort in unraveling the first simple and then ever more complex ideas on how circadian rhythms are generated at the molecular level.
A group of researchers led by Joe Takahashi discovered the mammalian clock gene in 1994. Since then, a dozen or so genes have been shown to be involved in the complex feedback loops currently held responsible for the molecular generation of circadian rhythmicity in the different organisms and their pacemakers.
Jeffrey Hall and Michael Rosbash then went on to discover that PER, the protein encoded by period gene, accumulated during the night and was degraded during the day. Thus, PER protein levels oscillate over a 24-h cycle, in synchrony with the circadian rhythm. Jeffrey Hall and Michael Rosbash hypothesized that the PER protein blocked the activity of the period gene, by an inhibitory feedback loop. Therefore, the PER protein could prevent its own synthesis and thereby regulate its own level in a continuous, cyclic rhythm. To block the activity of the period gene, PER protein (which is produced in the cytoplasm) would have to reach the cell nucleus. Rosbash had shown that PER protein builds up in the nucleus during night.
Micheal Young later went on to discover TIMESLESS and doubletime genes. In 1994, he discovered a 2nd clock gene, TIMELESS, encoding the TIM protein that was required for a normal circadian rhythm. He showed that when TIM gets bound to PER, both were able to enter the cell nucleus where they block period gene activity to close the inhibitory feedback loop. Such a regulatory feedback mechanism explained how this oscillation of cellular protein levels emerged, but few questions still lingered. What controlled the frequency of these oscillations? Michael Young identified yet another gene, doubletime, encoding the doubletime protein that delayed the accumulation of the PER protein. This provided insight into how an oscillation is adjusted to more closely match a 24-h cycle.
During the following years, other molecular components of the clockwork mechanism were elucidated in mammals, explaining its stability and function. For example, additional proteins required for the activation of the period gene as well as the mechanism by which light can synchronize the clock were discovered. The synchronizing effect of light happens by retinal detection of light, leading to inhibition of secretion of melatonin by pineal gland in the daytime.
These paradigm-shifting discoveries established key mechanistic principles for the biological clock.
The foundational work on molecular basis of circadian rhythm by Hall, Rosbash, and Young led them to Nobel Prize in physiology or medicine (2017). As a prelude to it, their story begins with a shared passion and expertise for understanding biological phenomena which led to an amazing collaboration.
Jeffrey Hall had left his medical school half-way to pursue his interest in biology and genetics. Rosbash completed his graduation in chemistry and later a PhD in genetics. Both met in Brandeis University, where they became friends over “common interests in game, politics and being single.” One fine day after a serious conversation, they agreed to take on molecular mysteries of rhythmicity in Drosophila (fruit fly) by pooling their talents. This would be a precursor to the current understanding of circadian rhythms. Jeffrey Hall faced many challenges when attempting to establish his genetic approach to biological clocks (which was not easily accepted by more traditional chronobiologists). When Hall faced skepticism trying to establish the importance of a sequence of amino acids he isolated, the only other researcher working on a similar project was Michael Young. Micheal Young was a biologist with interest in molecular genetics. His own inspiration began in his childhood reading Darwin's book gifted by his parents which described a strange plant that produced flowers that closed during the day and opened at night, perhaps due to a biological clock in plants. The location and composition of these clocks were, however, matter of speculation. Courtesy their work, as he aptly puts, “we now know that we are truly rhythmic organisms. It's hard to find a cell that does not oscillate in response to these clocks.”
Advances in chronobiology have potential implications for physical as well as mental health and human behavior.
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Conflicts of interest
There are no conflicts of interest.
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