Nobel winners identified molecular ‘cogs’ in the biological clocks that control our circadian rhythms

 In Science
(The Conversation is an independent and nonprofit source of news, analysis and commentary from academic experts.)

Carrie L. Partch, University of California, Santa Cruz

(THE CONVERSATION) Circadian rhythms control when we’re at our peak performance physically and mentally each day, keeping our lives ticking in time with Earth’s day/night cycle. This year’s Nobel Prize in Physiology or Medicine was awarded to three American scientists, Jeffrey Hall and Michael Rosbash of Brandeis University and Michael Young of Rockefeller University, for shedding light on how time is measured each day in biological systems, including our own bodies.

From Darwin’s finches on the Galápagos Islands to modern city dwellers, organisms adapt to their environment. Regular 24-hour cycles of day and night on Earth led to the evolution of biological clocks that reside within our cells. These clocks help us unconsciously pick the best time to rest, search for food, or anticipate danger or predation.

The field of modern circadian biology got its start in the 1970s, when geneticist Seymour Benzer and his student Ron Konopka undertook a revolutionary study to track down the genes that encode biological timing in fruit flies. With that gene in their sights, the labs of Hall, Rosbash and Young ushered in the molecular era of circadian biology as they untangled the molecular mechanisms of biological timekeeping.

To get started, Benzer and Konopka performed a simple experiment: tracking when the fruit fly Drosophila melanogaster would emerge from its pupal case. This developmental process, called eclosion, served as a powerful tool to study the complicated biological process of circadian rhythms. Because Drosophila pupae only emerge at a specific time of the day, Konopka could measure the timing between rounds of eclosion for different strains of flies and identify those that had a bad clock. By isolating fly strains with timing problems, they hoped to be able to zero in on the relevant genes that controlled this internal clock.

In the end, Konopka found three mutant strains: one that had a short, 19-hour day, one with a long, 28-hour day, and one mutant that appeared to have no clock at all. Using genetic tools, he was able to show that each of the responsible mutations lay remarkably close on the same chromosome, suggesting that they were all located within a single gene, which Benzer and Konopka named period for its apparent control over clock timing.

Then the race was on and in 1984, two teams finally identified this so-called clock gene period in flies: the labs of Jeffrey Hall and Michael Rosbash working in close collaboration at Brandeis, and Michael Young’s lab at Rockefeller.

With the gene in hand, these groups then aimed to figure out how period fit into a biological clock. The first clue came when Jeffrey Hall and Michael Rosbash discovered that the protein encoded by this gene (called PER) increased during the night and decreased during the day, suggesting that levels of the protein might somehow communicate time information to the rest of the cell.

If you just imagine how a biological clock might best keep track of time over a day, you might jump to a mental picture of an hourglass timer. Sand gradually disappears over time; when all the sand is gone, it could signal the process to begin again. Was PER the substance that kept biological time by gradually changing throughout the day?

One key insight came when Hall and Rosbash reasoned that this PER protein might actually block the activity of the period gene, turning itself off each day. As levels of PER build up over the course of the night, less and less new PER protein would be made. Eventually the protein levels drop and the process starts over again. This is called a negative feedback loop. It’s the same type of biological balancing act that keeps everything from your blood sugar levels to your circadian rhythms in line throughout your body.

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