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Module 0 · Foundations

Biological Clocks

Every cell in a complex organism carries an endogenous, self-sustaining ~24-hour oscillator. These circadian clocks(from Latin circa diem, “about a day”) were demonstrated long before their molecular basis was known. This introductory module traces the founding behavioural experiments that established their existence, the emergence of the molecular clockwork whose elucidation won the 2017 Nobel Prize, and the distinction between central and peripheral clocks that the rest of the course will explore.

1. The Founding Observations

In 1729, the French astronomer Jean-Jacques d’Ortous de Mairan showed that the heliotrope plant Mimosa pudica continued to open and close its leaves on a ~24-hour cycle when kept in constant darkness — the first evidence that biological rhythms are endogenous, not merely responses to sunrise. Two centuries later, animal physiologist Colin Pittendrigh(Princeton) and Jürgen Aschoff (Max Planck) systematically demonstrated in the 1950s–60s that rhythms in flies, mice, and humans:

  • Persist in constant conditions:free-running rhythms continue with a species-specific intrinsic period, τ, usually 23.5–24.6 h in mammals.
  • Are temperature-compensated: unlike most biochemical reactions, clock period changes little (Q10 ≈ 1) across physiological temperature. This is their most surprising biophysical feature.
  • Can be entrained to environmental Zeitgebers (light being dominant, also feeding and temperature cycles), synchronising to a precise 24-hour day.

The Aschoff rule, the Pittendrigh phase-response curves, and the concept of “limit-cycle oscillator” all emerged from this era. The field was a quantitative discipline decades before molecular mechanism.

2. The 1971 Discovery & the 2017 Nobel

Ronald Konopka and Seymour Benzer at Caltech (1971) carried out chemical-mutagenesis screens in Drosophila and identified three mutants with altered eclosion and locomotor rhythms: short-period (~19 h), long-period (~29 h), and arrhythmic. All mapped to a single gene on the X chromosome they called period. This was the first demonstration that a single locus controls a complex behavioural phenotype.

Two decades later, Jeffrey Hall and Michael Rosbash at Brandeis and Michael Young at Rockefeller cloned period, then timeless, then additional clock genes, and worked out the transcription-translation feedback loop (TTFL) that produces ~24 h oscillation. For this mechanistic architecture, Hall, Rosbash, and Young shared the 2017 Nobel Prize in Physiology or Medicine.

Mammalian homologues were identified in the late 1990s by Takahashi, Bradfield, and Reppert: Clock, Bmal1, Per1/2/3, Cry1/2, Rev-erbα/β, Rorα/β/γ. The logic, with species-specific flourishes, is conserved from flies to humans. We cover it in Module 1.

3. Clocks Across the Tree of Life

Circadian clocks evolved independently multiple times:

  • Cyanobacteria: three proteins — KaiA, KaiB, KaiC — form a phospho-oscillator whose period is reconstituted in vitro (Kondo 2005). Cyanobacteria were the first organism in which a circadian system was fully reduced to its biochemistry, in a test tube.
  • Fungi (Neurospora): FRQ/WCC negative-feedback loop.
  • Plants: CCA1/LHY morning loop + TOC1/PRR evening loop. Light is the dominant input; clocks regulate ~80% ofArabidopsis transcripts.
  • Insects: Drosophila PER/TIM plus CLK/CYC activators.
  • Mammals: our focus for Modules 1–7.

Even red blood cells, which lack nuclei and transcription, display ~24 h oscillations in peroxiredoxin oxidation state (O’Neill & Reddy 2011) — a post-translational clock that apparently operates beneath the TTFL.

4. Chronotypes

Humans display large individual variation in preferred timing, captured by the chronotype (morningness-eveningness continuum). Measurements: Munich ChronoType Questionnaire (MCTQ), Horne-Östberg scale, midpoint of sleep on free days (MSFsc). Chronotype is ~40–50% heritable, with PER3 VNTR polymorphisms contributing. Extreme chronotypes correspond to clinical syndromes: advanced sleep phase (“early birds” with PER2/CK1δ mutations), delayed sleep phase (“night owls” with CRY1 variants). Shift work and adolescent biology often impose chronotype misalignment — a clinical problem we return to in Module 7.

5. Why Circadian Medicine Matters

~20% of working adults in industrialised societies are shift workers, routinely desynchronising their clocks. Another ~15% suffer chronic delayed or advanced sleep phase. Night work has been classified by the IARC as Group 2A “probably carcinogenic to humans” (WHO 2019), with elevated risks of breast, prostate, and colorectal cancers. Cardiovascular events peak in the morning; chemotherapy tolerability varies by time of day; drug pharmacokinetics vary over the 24 h cycle. Taking circadian time seriously is the subject of chronomedicine — and the subject of this course.

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