Why Was the 2017 Nobel Prize in Medicine Awarded to Circadian Rhythm Again?

Circadian Rhythm and the Nobel Prize

We “inwardly” believe that life follows a rhythm and try to live accordingly, because our biological clock, called the circadian rhythm, makes us sleep at bedtime and wake when needed, governing blood pressure, body temperature, heart rate and the sleep-wake cycle. Let us explore how the foundations of the increasingly familiar “biological clock and circadian rhythm” were investigated at the molecular level. Then we will visit the life of someone who could not hold onto life’s rhythm, one of the 3 scientists who won this Nobel Prize.

- Related topic: One of Aziz Sancar and his team’s most remarkable discoveries: circadian rhythm, cancer and chemotherapy!

The 2017 Nobel Prize in Physiology or Medicine

The 2017 Nobel Prize in Physiology or Medicine was won by 3 American scientists: Jeffrey C. Hall, Michael Rosbash and Michael W. Young, for their studies of circadian rhythm at the molecular level. Humanity had long known about internal/biological rhythms. In the 18th century, astronomer Jean Jacques d’Ortous de Mairan observed this in mimosa plants using a practical method: their leaves opened toward the sun during the day and closed in the evening. Wondering how the plant would behave without sunlight, he kept it in darkness. It still continued its normal daily activity. This could only be possible through the plant’s own “internal clock.” Later studies showed that humans and other animals, not just plants, also have biological clocks. But research needed to go further: the clock had to be explained molecularly and the genes maintaining it discovered.

Left to right: Jeffrey C. Hall; Michael Rosbash; Michael W. Young

How Does Our Biological Clock Work?

In the 70s, Seymour Benzer and his student began studying, in fruit flies, the gene controlling the biological clock . They had induced a mutation in an unknown gene, disrupting the fruit fly’s biological clock. They called this gene period but could not isolate it or fully demonstrate its effect. In 90, Jeffrey C. Hall and Michael Rosbash, two of the Nobel laureates, would isolate it. A protein encoded by the gene, PER, was produced and stored in cells at night and broken down during the day, maintaining the clock’s cycle. However, questions remained: how was the need to stop producing proteins stored at night recognized, and how was production stopped? How did the clock delay itself until another round of production? Answers came from the other Nobel laureate, Michael W. Young.

Stopping and Delaying Protein Production

In his work in 94, Young isolated a gene whose name means “without time,” the timeless gene, which produces TIM protein, which takes PER from the cytoplasm, the cell region outside the nucleus, into the nucleus, where it binds PER and stops its production. By 98, Young had discovered another gene, “doubletime,” showing that its DBT protein delays PER production.

This important series of studies is valuable for explaining circadian rhythm. Our biological clock adjusts physiology to different phases of the day, affecting behavior, hormone release, maximum or minimum alertness, coordinated movements and various other activities.

Figure 1: Organisms’ biological clocks are controlled by oscillations in levels of PER, a protein produced by the period gene (1). TIM protein, produced by the TIMELESS gene, transports PER into the nucleus (2), where PER accumulates and inhibits period gene activity at that time.

Figure 2: Additional proteins are required for period gene oscillation. TIM protein, encoded by timeless, interacts with PER. This interaction is critical for PER accumulation in the nucleus and suppression of the period gene. DBT is encoded by doubletime and is a protein kinase that phosphorylates PER, causing its degradation. DBT-mediated PER degradation contributes to the delay between period mRNA and PER accumulation. CLK and CYK, encoded by clock and cycle genes, are two transcription factors activating the period gene.

Note: a transcription factor is a protein that can bind a specific DNA sequence to regulate gene transcription. Transcription is the process of copying the nucleotide sequence of DNA into an RNA sequence by RNA polymerase. In other words, it transfers genetic information from DNA to RNA.

The Circadian Clock Affects Our Physiology in Many Ways: It helps regulate sleep patterns, feeding behavior, hormone release, blood pressure and body temperature. A large proportion of our genes are regulated by the clock.

Behind the Scenes of Science – A Scientist’s Struggles

Success stories do not always have happy endings. Scientists’ lives contain more hardship than triumph and happiness. Jeffrey C. Hall, one of the 3 distinguished scientists illuminating our biological clock, left science approximately 10 years ago. He spent about half his career, which began in the 1980s, trying to solve the clock’s mysteries. He was unhappy when he left because he could not find sufficient support or obtain research funding. In a lengthy interview with Current Biology at his rural home, he discussed serious problems facing scientists. The world had lost a Nobel-worthy mind because his vision was not understood.

The lesson from Hall’s life should be precisely this: if we want to nurture people who shape the future, we must work together for generations striving for success and support science and progress under all circumstances.

What Do These Biological Clock Studies Mean for Us?

• Circadian rhythm plays an important role in hormone release, sleep regulation, repair of DNA damage and blood pressure regulation.
• As is known, the fundamental cause of cancer is the accumulation of DNA damage. Circadian rhythm contributes to DNA damage repair. Discovering proteins involved in circadian rhythm may open the way to next-generation cancer treatments. 
• Circadian rhythm has an important effect on disease treatment. Recent research has found that the effects of certain cancer drugs vary according to circadian rhythm. 
• Many factors in daily life—sleeplessness, excessive use of stimulants such as coffee (nicotine is also a stimulant), stress and night shifts—adversely affect circadian rhythm and predispose to certain diseases. Understanding its mechanism is therefore one of modern medicine’s most fundamental issues.

Related Topic:

- Aziz Sancar’s Nobel-winning work: mechanistic repair of DNA

- The 2016 Nobel Prize in Medicine was awarded to Yoshinori Ohsumi for autophagy research