By Sola Ogundipe
THE Nobel Prize in Physiology or Medicine 2017 has been jointly awarded by the Nobel Assembly at Karolinska Institute, to American scientists – Jeffrey Hall of the University of Maine, Michael Rosbash of Brandeis University in Massachusetts and Michael Young of Rockefeller University in New York.
They were awarded for their discoveries of molecular mechanisms controlling the circadian rhythm. They will share 9 million Swedish kronor ($1.1 million) for their discovery of important biological mechanisms that drive our ability to go to bed at night and be awake during the day.
In the 1980s, the three scientists isolated the “period gene,” which had been theorized to control the biological clock, or circadian rhythm, in fruit flies. Hall and Rosbash then discovered aprotein called PER that is encoded by the period gene and fluctuates over a 24-hour cycle; PER levels build up at night and drop during the day.
The prize came as a surprise to at least one of the winners.
But how could this gene influence the circadian rhythm?
This year’s Nobel Laureates, who were also studying fruit flies, aimed to discover how the clock actually works. In 1984, Jeffrey Hall and Michael Rosbash, working in close collaboration at Brandeis University in Boston, and Michael Young at the Rockefeller University in New York, succeeded in isolating the period gene. Jeffrey Hall and Michael Rosbash then went on to discover that PER, the protein encoded by period, accumulated during the night and was degraded during the day. Thus, PER protein levels oscillate over a 24-hour cycle, in synchrony with the circadian rhythm.
A self-regulating clockwork mechanism: The next key goal was to understand how such circadian oscillations could be generated and sustained. Jeffrey Hall and Michael Rosbash hypothesized that the PER protein blocked the activity of the period gene. They reasoned that by an inhibitory feedback loop, PER protein could prevent its own synthesis and thereby regulate its own level in a continuous, cyclic rhythm.
Simplified illustration of the feedback regulation of the period gene
Figure 2A. A simplified illustration of the feedback regulation of the period gene. The figure shows the sequence of events during a 24h oscillation. When the period gene is active, period mRNA is made.
The mRNA is transported to the cell’s cytoplasm and serves as template for the production of PER protein. The PER protein accumulates in the cell’s nucleus, where the period gene activity is blocked. This gives rise to the inhibitory feedback mechanism that underlies a circadian rhythm.
The model was tantalizing, but a few pieces of the puzzle were missing. To block the activity of the period gene, PER protein, which is produced in the cytoplasm, would have to reach the cell nucleus, where the genetic material is located. Jeffrey Hall and Michael Rosbash had shown that PER protein builds up in the nucleus during night, but how did it get there?
In 1994 Michael Young discovered a second clock gene, timeless, encoding the TIM protein that was required for a normal circadian rhythm. In 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 (Figure 2B).
The molecular components of the circadian clock.
Figure 2B. A simplified illustration of the molecular components of the circadian clock.
Such a regulatory feedback mechanism explained how this oscillation of cellular protein levels emerged, but questions lingered. What controlled the frequency of the oscillations? Michael Young identified yet another gene, doubletime, encoding the DBT protein that delayed the accumulation of the PER protein. This provided insight into how an oscillation is adjusted to more closely match a 24-hour cycle.
The paradigm-shifting discoveries by the laureates established key mechanistic principles for the biological clock. During the following years other molecular components of the clockwork mechanism were elucidated, explaining its stability and function. For example, this year’s laureates identified additional proteins required for the activation of the period gene, as well as for the mechanism by which light can synchronize the clock.
Keeping time on our human physiology
The biological clock is involved in many aspects of our complex physiology. We now know that all multicellular organisms, including humans, utilize a similar mechanism to control circadian rhythms.
A large proportion of our genes are regulated by the biological clock and, consequently, a carefully calibrated circadian rhythm adapts our physiology to the different phases of the day (Figure 3). Since the seminal discoveries by the three laureates, circadian biology has developed into a vast and highly dynamic research field, with implications for our health and wellbeing.