Nobel Prize: Medicine

Inner timekeeper

Print edition : November 10, 2017

Jeffrey C. Hall joined the faculty at Brandeis University in Waltham, Massachusetts, United States, in 1974. In 2002, he became associated with the University of Maine. Photo: Robert F. Bukaty/AP

Michael Rosbash has been on the faculty at Brandeis University since 1974. Photo: Scott Eisen/Getty Images/AFP

Michael W. Young has been with Rockfeller University in New York since 1978. Photo: SHANNON STAPLETON/REUTERS

The circadian clock anticipates the different phases of the day and adapts the body to them. The biological clock helps to regulate sleep patterns, feeding behaviour, hormone release, blood pressure and body temperature. Photo: Nobel Prize.Org

The 2017 Nobel Prize in Physiology or Medicine has been awarded to Jeffrey C. Hall, Michael Rosbash and Michael W. Young for their research that conclusively established that the biological clock is built into the body and that the circadian cycle is not just prompted by reactions to external stimuli.

GROUND-BREAKING research that unravelled molecular mechanisms governing biological clocks ticking inside living organisms has earned three United States scientists the coveted Nobel Prize in Physiology or Medicine in 2017.

Using fruit flies as the model, Jeffrey C. Hall, Michael Rosbash and Michael W. Young were able to elucidate the inner workings of the biological clock, which scientists knew for a while existed in living organisms, including humans.

All three scientists will equally share the prize money of nine million Swedish krona (~ U.S.$1.1 million).

Hall and Rosbash were colleagues at Brandeis University and Young was at Rockefeller University when the discoveries were made. Hall subsequently moved to University of Maine in 2002.

Life on earth is adapted to the rotation of the earth. All living organisms have to anticipate and adapt themselves to the regular rhythm of the day to enhance their survival. For example, an animal that is not up at daybreak may run the risk of being hunted down. Similarly, a predator has a greater chance of landing a prey if it is agile in the early hours of the day.

Almost every organism on earth displays circadian rhythms—periodic cycles of behaviour or gene expression that repeat roughly every 24 hours. These rhythms are produced by an internal timekeeping mechanism that is aligned with environmental cues such as temperature or light/dark cycles. These rhythms are vital because they regulate bodily functions such as food intake, body temperature, metabolic rate and sleep.

Observations that organisms adapt their physiology and behaviour to the time of the day in a circadian fashion were first documented in the early 18th century by a French astronomer, Jean-Jacques d’Ortuous de Mairan. He observed that the leaves of the mimosa plant (touch-me-not) opened and closed rhythmically at the appropriate times of the day even when the plant was kept in the dark.

About two centuries later, in the 1930s, the German plant physiologist Erwin Bunning, who is considered the pioneer of chronobiology—the science of circadian rhythm—recorded the movements of leaves of a bean plant during normal day/night cycles and under constant light conditions, using an instrument called the kymograph. It is capable of recording subtle variations of pressure exerted by the opening and folding of the leaves. But the question whether circadian behaviours in plants and animals were governed by an internal clock or were mere reactions to external stimuli had been hotly debated for decades.

In 1971, the American scientist Seymour Benzer at the California Institute of Technology and his student Ron Konopka discovered that the knocking of a gene could upset the functioning of the internal clock in fruit flies. Konopka subsequently named this gene “period”. Even then, much was not known about the complex genetic machinery behind the internal biological clock until the Nobel Prize-winning trio arrived on the scene in the early 1980s.

Hall, Rosbash and Young were “able to peek inside our biological clock and elucidate its inner workings. Their discoveries explain how plants, animals and humans adapt their biological rhythm so that it is synchronised with the Earth’s revolutions,” the Nobel Prize committee said.

The quest to unravel the molecular basis for circadian rhythm began in the early 1980s in the laboratory of Young at Rockefeller University and the laboratories of Hall and Rosbash at Brandeis. Their research in fruit flies showed that the fly’s circadian clocks are formed through the actions of a small group of genes, the crucial one being period.

Interestingly, it is said that Rosbash got interested in circadian rhythms thanks to his friendship with Hall, who had trained under Benzer. After Rosbash came to Brandeis in 1974 as an assistant professor, he became increasingly interested in a subject with far-reaching consequences: the influence of genes on behaviour. But, this interest may have remained dormant if he had not met Hall, who also joined the Brandeis faculty around the same time.



A crucial protein

While Young was successful in isolating the period gene, Hall and Rosbash almost simultaneously discovered that PER, the protein encoded by the period gene, accumulated during the night and degraded in the day.

But the puzzle was far from over. They had to understand how such circadian oscillations are generated and sustained by the cells. Hall and Rosbash hypothesised that the PER protein blocked the activity of the period gene. They reasoned that by an inhibitory feedback loop, the PER protein could prevent its own synthesis and thereby regulate its own level in a continuous, cyclic rhythm.

Though the model was tantalising, a few pieces of the jigsaw puzzle were still missing. To block the activity of the period gene, the PER protein, which is produced in the cytoplasm, would have to reach the cell nucleus, where the genetic material is located. The duo had shown that the PER protein builds up in the nucleus during night, but how did it get there? In 1994, Young discovered a second clock gene, timeless, encoding the TIM protein that was required for a normal circadian rhythm. In an elegant work, he showed that when TIM bound to PER, the two proteins were able to enter the cell nucleus where they blocked period gene activity to close the inhibitory feedback loop.

They also identified additional protein components of this machinery, deciphering the entire mechanism that makes clockwork self-sustaining inside the cell. It is now known that biological clocks in the cells of other multicellular organisms, including humans, are governed by the same principles.

Piali Sengupta, an India-born scientist at the Department of Biology in Brandeis, where Hall and Rosbash did their award-winning work, said: “Michael and Jeff are brilliant scientists and larger-than-life characters. Both have the amazing ability to ask exactly the right questions and to come up with creative and rigorous experiments to answer them. They are both iconoclasts in that they are unafraid to challenge the status quo or the current prevailing dogma in any scientific issue. I think that this in particular has allowed them to make the kind of breakthroughs that they have.”

The Nobel Prize committee said in a release: “With exquisite precision, our inner clock adapts our physiology to the dramatically different phases of the day. The clock regulates critical functions such as behaviour, hormone levels, sleep, body temperature and metabolism. Our well-being is affected when there is a temporary mismatch between our external environment and this internal biological clock.”

Jet lag, experienced by many people who travel across several time zones, is caused by one such temporary disruption in the circadian rhythm. Of late, medical scientists have understood that chronic misalignment between our lifestyle and the rhythm dictated by our inner timekeeper, as encountered by those who are on rotating shift work, is associated with increased risk for various diseases such as sleep disorders, heart attacks and cancers.

Significantly, Young’s lab recently identified a common mutation that slows the human biological clock. People with the “night owl” variant of this gene have a long circadian cycle, making it challenging for them to stay on the normal 24-hour cycle. What is more interesting is that this is the sixth Nobel Prize that fruit flies have won for scientists. In his post-announcement interview with Nobelprize.org, Hall jocularly said: “The key fourth awardee here is…. the little fly. The little flies deserve another tip of the hat, I think, in terms of what has happened today.”

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