Behind the Nobel win: uncovering circadian rhythm mechanisms

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Photo Credit: Courtesy of The Rockefeller University

Three American scientists, including UT alumnus Michael W. Young, received the Nobel Prize in Physiology or Medicine for their pioneering research on circadian rhythms on Monday.

Circadian rhythms control our sleep-wake cycles and feeding behaviors and are linked to everything from hormone release to blood pressure. The three laureates are the first researchers to discover the mechanisms underlying these rhythms.  

Specifically, they isolated the gene, called period, in fruit flies. Co-researchers and laureates Jeffrey C. Hall and Michael Rosbash found that the period gene produces a protein, PER. The concentration of PER fluctuates, increasing at night and decreasing during the day, thereby corresponding to sleep-wake cycles. The PER protein is involved in a negative feedback loop with period, and this loop serves as the basis for circadian rhythms.

According to Dell Medical School professor Molly Bray, the research revealed a physiological mechanism behind the long-observed rhythms. She added that these rhythms are connected to nearly every aspect of our metabolism. 

“So the greatest thing about … these discoveries (is) that there’s this molecular mechanism that drives rhythmicity of gene expression (that) very much controls metabolism,” Bray said. “(Circadian rhythms) regulate rhythmicity in fatty-acid metabolism, sleep-wakefulness, hunger (and) vagal tone.”

The laureates’ work continues to spur research in this field, as it was the first to show that there are genes and proteins directly involved with circadian rhythms, Bray added. 

“The discovery … led to (a lot) of downstream discoveries,” Bray said. “And that was really cool, it got a lot of people excited about what other components (were involved).”

In 1994, Young found a second gene, timeless, that produced TIM, a protein essential to nuclear localization of the PER protein. In other words, PER was not able to enter the nucleus, access the period gene, and exert its inhibitory effect in the absence of TIM. 

Young also discovered doubletime, a gene that codes for a protein that regulates PER accumulation in the cell and may affect our bodies’ 24-hour internal clocks. Flies with abnormal doubletime genes had periods that were either significantly shorter or longer than the 24 hours that comprise typical circadian rhythms. 

Young, Hall and Rosbash’s work has long-lasting implications for medicine as well as research, Bray said. 

“It already has (had an impact on medicine),” Bray said. “There are a lot of therapies now that are given in a specific timed manner because the systems they target are rhythmic.”

According to Bray, the laureates have paved the way for further discoveries. 

“Of course, the importance of the Nobel Prize is not only that you just discover something cool, but (that) there’s impact,” Bray said. “And the impact was all of this later knowledge that the clock itself is more complex than they had originally hypothesized … the link between the clock mechanism and what it controls is why it’s really impactful. They discovered this really central mechanism for rhythms.”