{'fraction_non_alphanumeric': 0.031148134733792104, 'fraction_numerical': 0.010865628395508874, 'mean_word_length': 5.07032967032967, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Origins of Circadian Rhythmicity

When I (CPK) was asked by our venerable editor to contribute a piece to follow on from Roenneberg and Merrow’s (2002 [this issue]) model, my immediate reaction on learning that it was to include some mathematics, was to say “no, thank you” (or words to that effect). However, the editor convinced me that it was not heavy going, and besides, he said that if I did not understand the article, I could just ignore it (nice!) and simply add some molecular/biochemical flesh to the mathematical bones. However, just in case I was left flailing about like a helpless infant, I requisitioned my colleague in Leicester, Ezio Rosato (who can do sums in Italian), to help me understand the math. Anyway, I was pleasantly surprised that I more or less understood the Roenneberg-Merrow model, which must be a testament to its clarity. To reiterate briefly Roenneberg and Merrow’s main points, their model reveals that a prototype organism with five metabolic negative feedback loops that converge on two state variables can, under conditions in which the input oscillates (thereby providing a “time giver”), and when at least two of the loops are coupled strongly together, stabilize the emergent clockworks and provide entrainment plus free-running capacity. Strengthening of the coupling between the feedback loops is the final evolutionary step necessary to achieve self-sustained rhythmicity and the genesis of a real circadian clock in the model. Their reasonable starting point is that before any circadian mechanism, even the most simple organism must have had a complex network of metabolism that made it difficult to respond to environmental variables in an ordered, predictable, and synchronized way. In a periodic world, the ability to properly respond to zeitgebers must have been of selective advantage favoring the evolution of mechanisms able to counteract chaotic responses of a complex intracellular network. This ‘fitness’ view of clocks appears obvious but, until relatively recently, represented an article of faith among chronobiologists used to help justify grant support. In fact, experimental evidence does show the impact of the circadian (24 h) clock on fitness in Cyanobacteria (Ouyang et al., 1998) and in flies, both at the DNAlevel of clock genes (Rosato et al., 1996, 1997) and at the functional level with natural clock gene variants (Sawyer et al 1997; Peixoto et al., 1998). In addition, negative feedback is a general regulatory mechanism found at every level of biological organization (Roenneberg and Merrow, 1998). Thus, the need for an oscillator is apparent, and the negative feedback loops in metabolic processes were undoubtedly present and ready to be abducted into a new circadian organization.