In 1984 Jeffrey Hall and Michael Rosbash, two biologists at Brandeis University, west of Boston, pioneered the science of biorhythms by interrogating fruit flies about what makes them ‘tick’. For the next thirty-three years the pendulum of deliberation at the Carolinska institute swung to and fro, sweeping Nobel Laureates on and off the stage in Stockholm. This year, the time has come for Hall and Rosbash, now septuagenarians, to be joined on stage by their only slightly younger colleague, Michael Young, to receive the 2017 Nobel Prize in Physiology or Medicine.
“Time flies like an arrow. Fruit flies like a banana.”
—attributed to Groucho Marx
Living organisms exhibit patterned behavior. The shape-shifting of moon glow and menstrual‘periods’ are set to a monthly cycle. But more prevalent in a broad scope of life forms, from animals to plants to fungi and some bacteria cycles, is the 24 hour diurnal, or circadian, rhythm.
In the words of the Nobel Prize organization:
"Using fruit flies as a model organism, this year's Nobel laureates isolated a gene that controls the normal daily biological rhythm. They showed that this gene encodes a protein that accumulates in the cell during the night, and is then degraded during the day.”
“With exquisite precision, our inner clock adapts our physiology to the dramatically different phases of the day. The clock regulates critical functions such as behavior, hormone levels, sleep, body temperature and metabolism. Our wellbeing is affected when there is a temporary mismatch between our external environment and this internal biological clock…”
The mechanism is eloquently simple. The period gene produces a protein PER, the accumulation of which in the nucleus blocks its own gene. This is feedback regulation that promotes oscillation, just as can be done with an electronic circuit. Hall and Hosbash showed that the PER protein accumulates in the nucleus at night. Young showed that a second clock gene, timeless, encoded the protein TIM. TIM binds to PER and that’s how they get into the nucleus.
Such are the founding principles of the active field of circadian biology. Further research has shown the importance of external influences, such as light, temperature and redox states, that adjust (or entrain) this endogenous clock. These external influences are collectively known by a term both scientific and poetic—zietgebers, or ‘time givers’.
But, as with all of science, these discoveries relied on prior observations. As usual, the ancients had clues. One of Alexander the Great’s ship captains noted (4th century BC) the daily leaf movements by the tamarind tree. Chinese manuals in the 13th century instructed on the importance of time of day in acupuncture.
Eventually, experiments where conducted. The Mimosa plant showed a diurnal cycle even if kept artificially in the dark (1729), ditto some animals (1918). thus an endogenous mechanism was suggested.
"The earth's daily rotation affects just about every living creature. From dawn through to dusk, there are changes in light, temperature, humidity, and rainfall. However, these changes are regular, rhythmic and, therefore, predictable. Thus, the near 24 hour circadian rhythm is innate: a genetically programmed clock that essentially ticks of its own accord."
"Why can’t teenagers get out of bed in the morning? How do bees tell the time? Why do some plants open and close their flowers at the same time each day? Why do so many people suffer the misery of jet lag? In this fascinating book, Russell Foster and Leon Kreitzman explain the significance of the biological clock, showing ..."
The hard evidence came from one of the authors on the seminal paper by Hall and Rosbash, Ron Konopka:
“Ronald J. Konopka (1947-2015) was an American geneticist who studied chronobiology. He made his most notable contribution to the field while working with Drosophila in the lab of Seymour Benzer at the California Institute of Technology. During this work, Konopka discovered the period (per) gene, which controls the period of circadian rhythms.”
The Nobel Prize is not given posthumously, in case you were perplexed by the omission of Konopka, or that of Benzer (1921-2007), winner of the Thomas Hunt Morgan Medal.Timing is everything.
The circadian rhythm has become a subject of great practical interest. The European Space Agency is studying the effects of space station duty. And the pharmaceutical industry has, of course, come on board, particularly for blind people. It turns out they may have “Non-24, a circadian rhythm disorder” and should ask their doctor about Hetlioz.
The seminal paper by Konopka, Rosbash and Hall from 1984, P-Element Transformation with period Locus DNA Restores Rhythmicity to Mutant, Arrhythmic Drosophila melanogaster, is available online.
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