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Nobel Prize in Medicine 2017 - Deciphering the internal clock

On December 10, 2017, three American researchers were honored with the Nobel Prize for Medicine in Stockholm for their work on discovering the mechanism of the internal clock (3). As early as 1984, Jeffrey Hall, Michael Rosbash and Michael Young were able to isolate a gene that controls the internal rhythm of the flies through their research on the fruit fly Drosophila. The PER protein produced by this gene, which is aptly named period, accumulates in the cell nuclei of the cells at night, while it is broken down during the day, as Hall and Rosbash were able to show (4). The level of the PER protein oscillates synchronously with the internal clock during a 24-hour cycle.

After discovering the period gene, the next question the researchers wondered about was exactly how these circadian oscillations are created and maintained. Hall and Rosbash hypothesized that the PER protein inhibits the activity of the period gene. Using a so-called inhibitory feedback loop, the PER protein could prevent its own synthesis and thereby regulate its own level in a cyclical rhythm. If the period gene is active, period mRNA is formed and transported into the cytoplasm of the cell, where it ensures the production of the PER protein, which in turn accumulates in the cell nucleus and blocks the period gene activity there. This enabled them to prove their hypothesis.

But how does the PER protein get into the cell nucleus in order to be able to work there at all? This is where the second gene called timeless comes into play, which is part of the internal clockwork. Young discovered this gene in 1994, which produces the protein TIM4. He showed that when TIM bound to PER, both proteins were able to get into the cell nucleus, where they blocked the gene activity of period. The next question was what and how the frequency of the vibrations is controlled. With the discovery of the gene doubletime, which codes for the protein DBT, which in turn delays the accumulation of PER, Young was able to answer this question. Because he provided knowledge about the adaptation of the vibrations to the 24-hour cycle.

These paradigm-shifting discoveries by the Nobel Prize winners laid the foundation for the key principles of the biological clock and other molecular components of the internal clockwork. The scientists, who were awarded the Nobel Prize for Medicine, also discovered other proteins that activate the period gene and the mechanism by which light can synchronize the internal clock.

This year's Nobel Prize in Chemistry also recognizes a major contribution to the characterization of biomolecules with the discovery of cryo-electron microscopy (5). The prize goes to the Swiss Jacques Dubochet, the native German Joachim Frank (USA) and Richard Henderson from Great Britain.

The Nobel Prize for Medicine was traditionally awarded by the King of Sweden in Stockholm together with the prizes in the categories of physics, chemistry and literature on December 10, the anniversary of the death of the founder Alfred Nobel, while the Nobel Peace Prize was presented in Oslo on the same day.