Have you wondered how most of us wake up around a specific time every day without an alarm clock? Our body has an intrinsic ‘clock system’ that times every biological event and creates a rhythm. Amazing isn’t it!
Our daily cues for wakefulness, hunger and sleepiness repeat in about 24-hour cycles. This 24-h period reflects one orbital rotation of the earth around the sun. Since the beginning of times, our internal rhythms are synced with the sun. When the sun rises, we naturally feel alert and active and when the sun sets, we start feeling tired and drowsy. This is because of the ‘sleep hormone,’ melatonin which is secreted from the pineal gland and regulated by the circadian clock. Increase in melatonin secretion at night stimulates sleep signals in our body and helps maintain our daily rhythms and sleep-wake cycles [1].
Imagine that the sun does not rise one day, what will happen? Catastrophic events may ensue in the world, yet, we would still wake up around the same time because that’s how our body clocks are tuned. Not only us, but most living organisms have an integrated clock network that modulates their activities in response to light and dark cycles.
Plants, for example, photosynthesize only in the presence of sunlight. The light signals perceived by the circadian regulators signal molecular pathways on when to start or stop photosynthesis [2]. Interestingly, nectar collection by honeybees [3] and nocturnal activities of animals [4] are all dictated by their internal clocks which tell them when to do what. In mammals, daily oscillations in body temperature, hormone secretion, and motor activities are examples of circadian rhythms [5]. It makes sense that circadian rhythms evolved as a survival strategy in living organisms for energy conservation and protection.
Our circadian rhythms coordinate biological activities
such that they happen at the right cell and at the right time
In humans, circadian rhythmicity is generated in the anterior hypothalamus of the brain through the suprachiasmatic nucleus or the central master clock that governs all peripheral clocks in different tissues of the body [6]. Three scientists, Jeffrey C. Hall, Michael Rosbash, and Michael W. Young were awarded the Noble Prize in 2017 for unlocking the complex circadian machinery. Zooming in at the molecular level, the clock is driven by an integrated network of specialized core proteins that are auto-regulated by a transcription-translation feedback loop [7]. This results in the rhythmic expression of core clock proteins. These proteins, in turn, regulate the expression of several clock-controlled genes thereby propagating rhythmicity and maintaining the circadian cycle [8]. Thus, the internal clock regulates important biological processes such as the cell cycle, DNA replication and repair, post-translational modifications and metabolic pathways. Given the energy cost of executing any biological function, the primary survival strategy for every cell in the body is to perform tasks in a timely manner without wasting energy. Therefore, stable functioning of the clock is essential to regulate cellular pathways of synthesis and repair and to maintain homeostasis relative to changing environmental cues.
But what if the rhythms do not sync anymore?
Primarily, our circadian rhythms coordinate biological activities such that they happen at the right cell and at the right time. But what if the rhythms do not sync anymore? Disruption of circadian clocks occurs either genetically through inherent mutations or through environmental factors. In today’s modernized world, that functions around the clock, many professional sectors including medicine, technology, law enforcement, and air transport require people to work in rotating night shifts and across different time zones [9]. In addition, lifestyle choices of mobile and laptop overuse at night increase exposure to artificial light at night and therefore affect the secretion of melatonin, the biological marker for the time of the day. Disruption of nocturnal melatonin not only affects our sleep-wake cycle but also dysregulates our internal clocks [10]. Contrast to other organisms, humans have a flexible circadian system that adapts well to changing environmental conditions. However, complexity arises when individual clocks in different organs of the body shift gears at varying paces independent of the master clock.
Imagine an orchestra where musicians playing different instruments synchronize and tune in rhythmically. What happens when there is an unprompted shift or change in rhythm? Confusion among the players leading to wreck in harmony and unpleasant music. The same happens to our body when the internal clock is disturbed. Although not immediately, clock disruption undeniably leads to a state of confusion (or state of chaos) in our body causing cellular imbalance, metabolic chaos and possibly, weakened immunity [11, 12]. When the circadian deregulation persists over a prolonged period, it often leads to insomnia, gastrointestinal complications, cardiovascular dysfunction and metabolic disorders.
Imagine an orchestra where musicians playing
different instruments synchronize and tune in rhythmically.
What happens when there is an unprompted shift
or change in rhythm?
Given that the circadian clock manages key biological functions, it is not surprising that clock distortion may be a plausible cause for the development of chronic health issues including cancer, Alzheimer’s and diabetes [13]. Cancer is one of the most studied diseases with respect to circadian disruption [14, 15]. Growing scientific evidence confirms that the expression patterns of clock proteins are altered in different cancer types. Establishing circadian profiles of tumor cells remains a prodigious task due to their intrinsic heterogenicity and mutagenic nature. Several epidemiological evidences relate cancers of breast, endometrium, prostate, and skin to disruption in circadian rhythms due to night shift work. Therefore, the declaration made by the International Agency for Research on Cancer to include ‘shiftwork that involves circadian disruption as a positive carcinogenic factor in humans’ is well fitting [16].
A simple way to oil our biological clock
and to maintain its robustness even later in life
is to eat and sleep on time,
our clock will take care of the rest!
Understanding the circadian network has opened new avenues for effective treatment schedules of timed administration of therapeutics aimed at maximum response and minimum toxicity. Clinical studies on timed administration of chemotherapeutic drugs like cisplatin and oxaliplatin in ovarian and colorectal cancer patients revealed evening is to be the best time for treatment than morning [17, 18]. Dr.Gaddameedhi’s research group at the Department of Pharmaceutical Sciences, Washington State University has unveiled the mechanism behind these clinical observations. They showed that the circadian clock directly regulated tumor response and reduced cisplatin toxicity in mice and humans [19]. Such studies are building a solid foundation for circadian-based therapy (chronotherapy) as a promising treatment option for cancer.
In a nutshell, circadian rhythms are important. Being mindful of our circadian rhythms and taking logical steps to stay in rhythm will prevent complications arising from worn and torn biological clocks and live long healthy lives. It is advisable for shift workers to simulate night-like conditions to enable their bodies to naturally transition to sleep state. Avoiding untimely food intake and artificial light during sleep hours will tremendously benefit the overall health. A simple way to oil our biological clock and to maintain its robustness even later in life is to eat and sleep on time, our clock will take care of the rest.
References:
1. Brown, G.M., Light, melatonin and the sleep-wake cycle. J Psychiatry Neurosci, 1994. 19(5): p. 345-53.
2. Hennessey, T.L. and C.B. Field, Circadian Rhythms in Photosynthesis : Oscillations in Carbon Assimilation and Stomatal Conductance under Constant Conditions. Plant Physiol, 1991. 96(3): p. 831-6.
3. Bloch, G., et al., Time is honey: circadian clocks of bees and flowers and how their interactions may influence ecological communities. Philos Trans R Soc Lond B Biol Sci, 2017. 372(1734).
4. Kronfeld-Schor, N., G. Bloch, and W.J. Schwartz, Animal clocks: when science meets nature. Proc Biol Sci, 2013. 280(1765): p. 20131354.
5. Rivkees, S.A., The Development of Circadian Rhythms: From Animals To Humans. Sleep Med Clin, 2007. 2(3): p. 331-341.
6. Herzog, E.D., J.S. Takahashi, and G.D. Block, Clock controls circadian period in isolated suprachiasmatic nucleus neurons. Nat Neurosci, 1998. 1(8): p. 708-13.
7. Buhr, E.D. and J.S. Takahashi, Molecular components of the Mammalian circadian clock. Handb Exp Pharmacol, 2013(217): p. 3-27.
8. Ruben, M.D., et al., A database of tissue-specific rhythmically expressed human genes has potential applications in circadian medicine. Sci Transl Med, 2018. 10(458).
9. James, S.M., et al., Shift Work: Disrupted Circadian Rhythms and Sleep-Implications for Health and Well-Being. Curr Sleep Med Rep, 2017. 3(2): p. 104-112.
10. Dumont, M., et al., Melatonin production and light exposure of rotating night workers. Chronobiol Int, 2012. 29(2): p. 203-10.
11. Yu, E.A. and D.R. Weaver, Disrupting the circadian clock: gene-specific effects on aging, cancer, and other phenotypes. Aging (Albany NY), 2011. 3(5): p. 479-93.
12. Brainard, J., et al., Health implications of disrupted circadian rhythms and the potential for daylight as therapy. Anesthesiology, 2016. 122(5): p. 1170-1175.
13. Marcheva, B., et al., Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature, 2010. 466(7306): p. 627-31.
14. Masri, S. and P. Sassone-Corsi, The emerging link between cancer, metabolism, and circadian rhythms. Nat Med, 2018. 24(12): p. 1795-1803.
15. Sahar, S. and P. Sassone-Corsi, Metabolism and cancer: the circadian clock connection. Nat Rev Cancer, 2009. 9(12): p. 886-96.
16. Straif, K., et al., Carcinogenicity of shift-work, painting, and fire-fighting. Lancet Oncol, 2007. 8(12): p. 1065-6.
17. Boughattas, N.A., et al., Circadian rhythm in toxicities and tissue uptake of 1,2-diamminocyclohexane(trans-1)oxalatoplatinum(II) in mice. Cancer Res, 1989. 49(12): p. 3362-8.
18. Hrushesky, W.J., Circadian timing of cancer chemotherapy. Science, 1985. 228(4695): p. 73-5.
19. Dakup, P.P., et al., The circadian clock regulates cisplatin-induced toxicity and tumor regression in melanoma mouse and human models. Oncotarget, 2018. 9(18): p. 14524-14538.
Author: Prasanna Vadhana
Prasanna pursued her doctorate at Anna University, India specializing in the field of industrial biotechnology. After moving to the US, she ventured into cancer research during her post-doctoral term at the Washington State University. Following her passion in translational clinical research, she is now a Project Manager cum Clinical Intern at Vitalant, expanding her expertise in solid organ transplantation. She aims to become an effective science communicator and bring science closer to people. Besides research and writing, she loves ‘learning with fun’ activities with kids, cooking and connecting with people.
Editor and Blog Design: Rajamani Selvam
Rajamani Selvam received her Ph.D. in Neuroscience. She is currently pursuing a fellowship where she studies the blood-brain barrier. She is interested in a career in science policy or regulatory affairs. During her free time, she volunteers as a judge to Science Fairs to elementary and high schoolers, performs demonstrations and hands-on activities to provide insights on brain and Neuroscience. She also mentors students through 1000 girls’ 1000 futures program and Freedom English Academy where she provides career guidance. Away from science, she is an artist and enjoys leisure travel.
Illustrators:
Cover image: Disha Chauhan; Inline image: Saurabh Gayali
Disha Chauhan did her Ph.D. in IRBLLEIDA, University of Lleida, Spain in Molecular and Developmental Neurobiology. She has post-doctoral experience in Cell Biology of Neurodegenerative diseases and is actively seeking a challenging research position in academia/industry. Apart from Developmental Neurobiology, she is also interested in Oncology. She is passionate about visual art (Illustration, painting and photography) and storytelling through it. She enjoys reading, traveling, hiking and is also dedicated to raising scientific awareness about Cancer. Follow her on Instagram.
Saurabh Gayali recently completed his Ph.D. in Plant Molecular Biology from National Institute of Plant Genome Research (JNU), New Delhi. Currently he is DBT RA at IGIB (New Delhi) and his research focuses on finding binding associations of Indian plant metabolites with human pathogen proteins, creating a platform for future plant extract based drug discovery. He has keen interest in data analysis, visualization and database management. He is a skilled 2D/3D designer with a specific interest in scientific illustration. In leisure, Saurabh plays guitar and composes music, does photography or practices programming. Follow him on Instagram or Twitter.
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