One can look at a piece of art or engineering and use the design filter to rule out chance or natural law. How much more is the design inference valid when seeing a sequence of events that work together for a purpose? If a sculpture appears designed, how much more a pendulum clock, or a symphony? Life is filled with dynamically changing, yet carefully regulated processes.

Hippos and Hedgehogs

Take the protein Sonic Hedgehog (SHH), whimsically named after a Japanese videogame character able to run at supersonic speeds, curl into a ball and attack enemies. Well known for its role in regulating embryonic development, SHH doesn’t just sit in the cell; it signals other proteins with the precision of a conductor. Patterns in the embryo, such as left-right symmetry and dorsal-ventral axis, are regulated by this important protein, coded for by the sonic hedgehog gene. Kim and Blackshaw, writing in Science, tell about a new function for this dynamic regulator that carries on throughout life.

Virtually all mammalian physiological functions fall under the control of an internal circadian rhythm, or body clock. This circadian rhythm is governed by master neural networks in the hypothalamus that synchronize the activity of peripheral clocks in cells throughout the body. Environmental perturbations that are a regular part of modern life, such as artificial light and international travel, can disrupt circadian rhythms, leading to adverse consequences for mental and physical health. On page 972 of this issue, Tu et al. report that primary cilia–mediated Sonic Hedgehog (SHH) signaling allows cells in the master circadian clock to maintain synchronization and control circadian rhythmicity in mice, identifying an unexpected functional role for this developmental regulator. [Emphasis added.]

How can a tiny protein within a cell have dramatic effects on the hypothalamus, and by extension on the entire body? 

The master circadian pacemaker responsible for regulating our daily rhythms is located in the suprachiasmatic nucleus (SCN) in the anterior hypothalamus. The cells that make up this pacemaker maintain intercellular coupling of molecular circadian rhythms, ensuring synchrony of SCN neurons. Robust clocks keep time using redundant mechanisms, and the SCN is no exception. Signals that promote cellular synchrony include paracrine signaling by fast neurotransmitters and multiple neuropeptides as well as gap junction–dependent electrical coupling. This cellular synchrony ensures the robust output of the central clock and renders it resistant to signals that reset peripheral clocks.

At this point in the story, one of the superheroes of irreducible complexity enters: the cilium, described by Michael Behe in his books. Neurons in the SCN synchronize their clocks via SHH signals sent and received through their primary cilia. Those non-motile cilia then transmit the timing signals inside via the molecular trucks inside the cilia: the intraflagellar transport (IFT) trains. 

The master circadian pacemaker in the suprachiasmatic nucleus (SCN) contains neuromedin S–expressing (NMS+) neurons that have primary cilia. The number and length of these cilia change throughout the day, which alters Sonic Hedgehog (SHH) signaling through Smoothened (SMO) co-receptors expressed on the cilia. When this signaling is disrupted, the cellular oscillators in the SCN become uncoupled, which affects circadian rhythmicity in mice. 

Kim and Blackshaw call the discovery “surprising” for a protein that had been almost exclusively studied for its role in development. The new study by Tu et al. shows that adult organisms rely on SHH every day to keep the body clock running on time. That’s why they call it a “Super sonic circadian synchronizer.” 

SHH is essential for the development and specification of many brain structures during embryogenesis, including the SCN, and it also regulates axonal targeting, dendrite formation, and synaptogenesis. An ongoing role for SHH signaling in the adult SCN raises several important questions. It is unclear what cells are the relevant source of SHH or how its synthesis and release are regulated. Primary cilia regulate many other classes of extracellular signaling—such as Notch, Wnt, Hippo, and mammalian target of rapamycin (mTOR) pathways—often through receptor-independent mechanisms. Thus, it is unclear whether other extrinsic factors might contribute to controlling SCN function. 

The Hippo pathway, which regulates body size, also transmits its signals about body size through the cilium. Look at this diagram to get a taste of the dynamic signals going on in the cell for that symphony of signals. The cilium looks more irreducibly complex than ever!

Encompassing a Body Compass

Understanding how SHH interacts with day-night cycles can help solve the problem of jet lag. It takes a while to resynchronize our body clock to the time of day in another location when we zoom off to another time zone and find the sun angle at odds with expectations. Time for a reset!

Just as the body clock can be reset by external cues, our internal compass can be reset by an external cue: namely, head direction. Results of experiments at McGill University, also done on mice, shows how whole-body actions interact with signals inside of cells.

This ability to accurately decode the animal’s internal head direction allowed the researchers to explore how the Head-Direction cells, which make up the brain’s internal compass, support the brain’s ability to re-orient itself in changing surroundings. Specifically, the research team identified a phenomenon they term ‘network gain’ that allowed the brain’s internal compass to reorient after the mice were disoriented. “It’s as if the brain has a mechanism to implement a ‘reset button’ allowing for rapid reorientation of its internal compass in confusing situations,” says Ajabi.

Fast Clocks, Slow Clocks

Speaking of development, we know that different animals have different gestation times: humans take nine months, mice around 20 days. Yet all of us live under the same day-night cycle. How do these “heterochronies” regulate themselves? It comes down to the dynamic activities going on inside cells as well, says a Focus article in Science Advances. The author’s one mention of evolution contributes nothing to the science:

In evolutionary developmental biology, differences in genetically controlled temporal programs are well recognized and referred to as heterochronies. These include differences in the time of initiation, duration, or rate of a process in comparison with an organisms’ ancestors or other species. Whereas shifts in the time of initiation or duration have been linked to genetic variation of regulatory sequences or differential expression dynamics, other heterochronies that emerge from changes in the rate of a process are distinct and usually involve the same genetic program operating at different speeds. This has been termed allochrony and does not seem to be explained by variations in regulatory sequences (Fig. 1, A to C). However, less is known about the mechanisms driving allochronies.

Nothing in Figure 1 owes anything to Darwinian evolution. Audiences know intuitively that any delicate dance is the work of a choreographer.

Developmental processes need to operate in harmony to synchronize cells, tissues, organs, and the whole organism. It is increasingly clear that a central element of this delicate dance is achieved by each cell using its own clock…. Cells offer the most basic model to expose timing control processes and to investigate the intrinsic genetic mechanisms that control timing.

Teresa Rayon’s article goes on to discuss the harmony between biochemical reactions, motor neurons, mitochondrial activity, metabolic rate and epigenetic mechanisms. The differences in scale between these players working toward a common goal—homeostasis—is astonishing.

Clocks that Must Not Reset

The body adjusts for day and night cycles, but some body clocks dare not change outside of tight limits: heart rate and breathing. We have a “resting heart rate” during sleep that was thought to be under the sole control of the parasympathetic nervous system, the nerve network that relaxes us. Scientists at Manchester University found, however, that the “fight-or-flight” sympathetic nervous system (SNS) works in concert with it to keep the heart ticking within its acceptable range. Listen to this orchestra play:

Importantly, transcription factors in the sinus node lost rhythmicity following the sustained β-adrenergic blockade. Thus, the team proposed that day-night rhythms in the sinus node are orchestrated by rhythmic β-adrenergic input from the SNS to regulate ion channel gene expression. “It’s a way of thinking about the involvement of the autonomic nervous system, not as commonly accepted, which is these very short range, immediate acute modulations of ion channel function, but through long range modulation by affecting gene expression in the heart or in the sinus node,” said D’Souza.

Here again is a case of tight coordination between cell signals and a body composed of trillions of cells. Talk about the tail wagging the dog: the goings on in specific ion channels in a cell membrane can influence the brain and the heart that are orders of magnitude larger. Sleep tight; your body knows what parts have to slow down and what parts must keep going.

No Real Hope for Evolution

One study on biological clocks attempted to “Darwinize” them, but only for the very simplest case: the KaiA/B/C oscillator in cyanobacteria (see this video for a quick presentation of this clock). “The central role of circadian rhythms in many biological processes, controlled by the day and night cycle on Earth, makes their evolution a fascinating topic,” say eight evolutionists in an open-access paper in Nature. They attempt to show a stepwise evolution “From primordial clocks to circadian oscillators.” Good luck.

Circadian rhythms play an essential part in many biological processes, and only three prokaryotic proteins are required to constitute a true post-translational circadian oscillator. The evolutionary history of the three Kai proteins indicates that KaiC is the oldest member and a central component of the clock. Subsequent additionsof KaiB and KaiA regulate the phosphorylation state of KaiC for time synchronization. The canonical KaiABC system in cyanobacteria is well understood, but little is known about more ancient systems that only possess KaiBC…. Here we investigate the primordial circadian clock in Rhodobacter sphaeroides, which contains only KaiBC, to elucidate its inner workings despite missing KaiA. Using a combination of X-ray crystallography and cryogenic electron microscopy, we find a new dodecameric fold for KaiC, in which two hexamers are held together by a coiled-coil bundle of 12 helices. This interaction is formed by the carboxy-terminal extension of KaiC and serves as an ancient regulatory moiety that is later superseded by KaiA. A coiled-coil register shift between daytime and night-time conformations is connected to phosphorylation sites through a long-range allosteric network that spans over 140 Å. Our kinetic data identify the difference in the ATP-to-ADP ratio between day and night as the environmental cue that drives the clock. They also unravel mechanistic details that shed light on the evolution of self-sustained oscillators.

The authors build phylogenetic trees to argue that KaiC is more ancient than KaiA and KaiB. While admittedly rigorous, their work does not explain the origin of KaiBC itself, the gene that codes it, or its functional connection to diurnal cycle. KaiC, as shown in the video, is the largest and most complex protein in the clock with 518 amino acids arranged in a geometrically-elegant pair of hexamers that can undergo conformational changes essential for its operation. Its function is intimately tied to specific serine and threonine residues at precise locations.

At best, their evolutionary hypothesis shows a division of labor when KaiA is present. Oddly, the authors say that the KaiBC clock in R. sphaeroides “can perform both autophosphorylation and nucleotide exchange on its own and does so faster than its more recently evolved counterparts.” The paper leaves many unasked and unanswered questions. They offer no stepwise evolution from the simple prokaryotic clock to the “complex and highly sophisticated” circadian clocks in eukaryotes. There is no mention of mutations or natural selection. And a chicken-and-egg conundrum arises when asking which came first: the gene or the protein. Why would a gene sequence 518 aa long emerge by mistake without a function being known for it? That’s too improbable. If the protein came first and ticked like a clock, how did the code for it become embedded in the genome, which has a different alphabet? In the concluding discussion, the authors give an essentially magical explanation, calling the simplest of clocks “an example of convergent evolution.” If one did not already believe in the creative power of natural selection, this paper would prove little and make less sense.

In the arts, design is evident in both static and dynamic works. If paintings and sculptures evince design, much more do finely crafted instruments performing in harmony in real time. That’s ID in the 4th dimension.