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Design on Time — Paley’s Watch Was Inside Him

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Photo credit: André Lage Freitas / CC BY-SA (

If young William Paley had today’s high-tech imaging tools, he wouldn’t need to build his argument for design from a watch on a heath. He would marvel at the clocks within his own body. Indeed, clocks are universal within biology, from bacteria to birds, from yeast to beast, from mammals to man. All the circadian rhythms in life are regulated by molecular clocks. Biology runs on time!

A Bacterial Timekeeper

Starting with a simple case, here is a new discovery about clocks in bacteria. The cyanobacterium Synechococcus elongatus, like many bacteria, has a timekeeping system consisting of three parts: KaiA, KaiB, and KaiC. This is one of the simplest biological oscillators in nature, and it has been studied in detail. Scientists know that the actions of these proteins regulate transcription of other proteins in feedback loops tied to day-night cycles. 

Researchers at Nagoya University in Japan found something new and interesting, which they published in PNAS on August 251: a particular amino acid in KaiC, at position 402, appears to be the central oscillator that controls the circadian period of the clock. KaiC proteins with mutations at 402 changed their period by a factor of 10: from 0.6 days to 6.6 days. 

Therefore, our results indicate that the circadian pacemaker of cyanobacteria, which functions without a transcription–translation feedback loop, can define the period of extra wide dynamic range, while keeping temperature compensation intact. These features are installed in the structure of KaiC protein, as ATPase activity of KaiC can determine both circadian period and temperature compensation. To establish both flexibility of period determination and persistence of temperature compensation within KaiC protein, it is possible that novel physical mechanism inside the KaiC structure links energy derived from the ATP hydrolysis with circadian pacemaker function. By maintaining such mechanism, cyanobacteria may have been able to adapt to the period of Earth’s rotation, which lengthened due to the tidal friction, and thus succeed among the organisms to inhabit this planet. [Emphasis added.]

They don’t say this ability evolved. Instead, they say that this amino acid allows the bacterium to tune its period to the rotation of the Earth.

The periods of KaiC mutants range from 16 to 60 h, showing the extremely wide-range tunability of periods by KaiC point mutations. In this point, circadian clock system of cyanobacteria would be an ideal model for the study of tuning mechanism of the 24-h period. However, the tuning mechanism of the 24-h period installed in KaiC protein remains unclear, as the mutation sites are distributed in an apparently random fashion throughout the protein, and the effects of mutation on circadian period are not consistent.

Clearly, there is still more to learn about the biological clock in one of the simplest of life-forms. The tunability of these clocks was further suggested by another paper in Nature Scientific Reports2. Two kinds of mat-forming microbes in coastal communities were examined by a team in the Netherlands. They both have the Kai-A-B-C system but respond differently depending on the consistency of the light.

Although functionally similar, both species of cyanobacteria displayed different 24-h transcriptional patterns in response to the experimental treatments, suggesting that their circadian clocks have adapted to different life strategies adopted by these mat-forming cyanobacteria.

Paley’s Internal Watch

In higher organisms including humans, biological clocks are much more sophisticated and less well understood. Researchers know that the suprachiasmatic nucleus (SCN) in the hypothalamus is involved. As recorded in Nature3, a team from Harvard Medical School found some VIPs in the clock: “vasoactive intestinal polypeptide-expressing” neurons that are required for normal rhythmicity. These SCNVIP neurons are heterogeneous, “comprised of molecularly distinct populations.” The complexity of this advanced biological clock quickly becomes overwhelming, but slow progress is being made:

Current understanding holds that circadian rhythms are generated within individual cells of the suprachiasmatic nucleus (SCN) and that cell–cell interactions within the SCN network are required to sustain them. One of the emergent properties of these cell–cell circuit interactions is the circadian period, a fundamental property of the SCN circadian clock. While the SCN contains a variety of neuropeptides, as well as the fast transmitter GABA, that might variably contribute to SCN network function and hence the ensemble period, previous work has suggested an especially important role for SCNVIP cells as “master pacemakers” of circadian rhythms.

The team tried disrupting these neurons in mice to watch what happened to their sleep-wake cycles, locomotor activity, body temperature and wheel-running exercise. They learned a few things, but much more study will be required to understand how the clock works.

Altogether, our work establishes necessity of SCNVIP neurons for the LMA [mammalian locomotor activity] circadian rhythm, elucidates organization of circadian outflow from and modulatory input to SCNVIP cells, and demonstrates a subpopulation-level molecular heterogeneity that suggests distinct functions for specific SCNVIP subtypes.

Biological Clocks Are Vital

Among the many things that biological clocks control beside the obvious sleep-wake cycle are processes vital for health. For instance, scientists at the University of Rochester found that circadian rhythms help guide waste from the brain. This has implications for night owls and students burning the midnight oil while studying for finals.

New research details how the complex set of molecular and fluid dynamics that comprise the glymphatic system — the brain’s unique process of waste removal — are synchronized with the master internal clock that regulates the sleep-wake cycle.  These findings suggest that people who rely on sleeping during daytime hours are at greater risk for developing neurological disorders.

In a related study from the University of Illinois in Chicago, scientists found that poor sleep leads to problems with the gut microbiome and high blood pressure. By putting rats on a 28-hour sleep-wake cycle, disruptions to digestion and circulation became evident.

“When rats had an abnormal sleep schedule, an increase in blood pressure developed — the blood pressure remained elevated even when they could return to normal sleep. This suggests that dysfunctional sleep impairs the body for a sustained period,” Maki said.  

Undesirable changes also were found in the gut microbiome — the genetic material of all bacteria living in the colon.

The gut problems took a week to manifest themselves. When the rats got back on the regular clock, the problems did not return to normal right away. 

Human Rats

College students substituted for lab rats in another study from Brazil. A team publishing in PLOS One4 concluded that “Quality of sleep and anxiety are related to circadian preference in university students.” The affects depended on the “chronotypes” of the students (night owls versus early birds, for instance). 

The high occurrence of anxiety levels and poor sleep quality in evening students may be a consequence of high academic demand in a shift incompatible with the phase delay of the circadian timing system of these individuals.

Organisms depend on the regular day/night cycle of sunlight to time their activities. The biological clock switches on the right things at the right time.

Living organisms experience several functional changes throughout one day. Examples of such changes are variations in hormone secretion, body temperature, and cognitive performance, among others. Most biological systems present some endogenous circadian timing system that are synchronized by exogenous photic and nonphotic cycles.

Scientists know the clocks are there. We know, too; we can tell by the effects when our normal routines are disrupted, like in jet lag or long work hours. Biologists can peer into the ticking gears in the simplest organisms and see some inputs and outputs of individual players involved. But still, after years of research, biological clocks are black boxes. They are nested like Russian dolls inside other black boxes in hierarchical systems. Darwin would best refrain from trying to explain such highly tuned wonders by unguided processes like natural selection.


  1. Ito-Miwa et al., “Tuning the circadian period of cyanobacteria up to 6.6 days by the single amino acid substitutions in KaiC.” PNAS August 25, 2020 117 (34) 20926-20931.
  2. Hörnlein et al., “Circadian clock-controlled gene expression in co-cultured, mat-forming cyanobacteria.” Scientific Reports volume 10, Article number: 14095 (2020).
  3. Todd et al., “Suprachiasmatic VIP neurons are required for normal circadian rhythmicity and comprised of molecularly distinct subpopulations.” Nature Communications volume 11, Article number: 4410 (2020).
  4. Silva et al., “Quality of sleep and anxiety are related to circadian preference in university students.” PLOS One, September 2, 2020.