How Mapping and Rewiring Circadian Circuits Converge in Exciting New Rhythms

           The human circadian rhythm, commonly dubbed the “body’s clock,” controls a wide range of physiological processes and overt behaviors, including sleep-wake cycles and environmental responses. Consequently, the body’s clock has an enormous impact on people’s health and how they function. Notably, it influences body temperature, hormone release, metabolism, and is linked to various disorders and diseases, such as insomnia, bipolar disorder, depression, seasonal affective disorder, diabetes, and obesity (nigms.nih.gov/CircadianRhythms). Circadian rhythms are not unique to humans; they have been discovered in most animals, plants, fungi, and cyanobacteria (esciencenews.com/circadian.clock, 2015), and regulate processes akin to those regulated by circadian rhythm in humans. Studying different organisms’ circadian processes allows multiple fields of biology to integrate their developments into current knowledge about human circadian processes, in turn, leading to innovative approaches for regulating physiological behaviors and treating relevant diseases. Consider the implications of the neuroanatomical research conducted by Loyola University Chicago professor, Dr. Daniel J. Cavanaugh, and colleagues (see Cavanaugh et al., 2014), in relation to recent work in genetic engineering led by Harvard University synthetic biologist, Dr. Pamela Silver (see esciencenews.com/circadian.clock, 2015).

            In brief, Cavanaugh et al. focused on mapping neural pathways within the circadian circuit of fruit flies that produce rhythms of physiological behaviors, chiefly the flies’ daily rest/activity cycles. These overt rhythms are produced by the activity of circadian clocks: a system of neurons containing input pathways, which coordinate clock neurons to external cues such as light, and output pathways, which relay time-of-day signals to downstream neurons, thereby modulating rhythmic behavior (2014). Through a random activation of neurons, Cavanaugh et al. screened for relevant circadian clocks and found neurons in the pars intercerebralis (PI) that constitute an important part of the circadian output pathway for fruit fly rest/activity cycles. In addition, they identified DH44, a protein expressed by PI clock neurons, which is necessary for keeping with the flies’ regular overt rhythms (2014). These findings bridge gaps in the current understanding of human circadian circuits inasmuch as the PI is homologous to the mammalian hypothalamus, and DH44 is analogous to the corticotrophin releasing factor (CRF) rhythmically secreted in mammals (2014).

            The work led by Silver (2015), on the other hand, yielded the first successful transplant of a circadian network using genetic engineering. Silver and colleagues engineered a circadian E. coli, a bacterial species that does not have a circadian rhythm in nature. They created the synthetic strain by removing the protein network responsible for regulating circadian rhythms in cyanobacteria, which is circadian in nature, and transplanting it into E. coli  (2015). Once transplanted, the protein network was connected to other factors involved in gene expression in order to manipulate physiological processes relative to the day-night cycle (2015). Silver et al. demonstrated the transplants success using fluorescence, where the circadian protein network was linked to fluorescent proteins, making the E. coli glow in rhythmic unison with its new circadian oscillations (2015). In sum, their work not only revealed the transplantability of a circadian network, but also the ability to manipulate it and its processes in an anticipated manner (2015). Indeed, this novel capability has many applications, especially in medicine. Silver’s ultimate goal is to be able to deliver the synthetic E. coli to patients in pills. Then, the transplanted circadian rhythm should link to other biological networks, and allow for the control of drugs’ release-time in order to get optimal efficiency, or be able to realize and alter a patient’s circadian rhythm (2015). 

           In the direction of furthering current knowledge, multiple fields of scientific study prove not only useful, but also necessary for understanding the multifaceted nature of circadian circuits. Cavanaugh et al.’s research aimed to determine how circadian circuits produce and control physiological behaviors, whereas Silver et al.’s research aimed to tap into circadian circuits for the sake of reprogramming and regulating physiological behaviors. Incidentally, these studies exemplify how advances in various disciplines, like the neural and genetic advances discussed, converge in treatment options for circadian-linked diseases and behaviors.

Setting the Circadian Clock (2015, June 12). In (e) Science News. Retrieved October 
          15, 2015.

Cavanaugh, D. J., Geratowski, J. D., Wooltorton, J. R., Spaethling, J. M., Hector, C. E., 
          Zheng, X., & Johnson, E. C. (2014, April 24). Identification of a circadian 
          output circuit for rest: Activity rhythms in drosophila. Cell, 689-701.