Francisco J. Rojas, Ph.D.
The 2017 Nobel Prize in Medicine or Physiology was awarded to the scientists Jeffry Hall, Michael Rosbash and Michael Young for their discoveries of molecular mechanisms that control and drive circadian rhythms.
An essential feature of life on Earth is its capacity to adapt to profound changes in the environment. To adapt to daily changes in light and temperature, most organisms have evolved an internal biological clock that anticipates day/night cycles and helps them optimize their physiology and behavior. This internally generated cycle is known as circadian rhythms and exists in all forms of life, from unicellular bacteria to multicellular organisms, including plants, fungi, insects, rodents and humans.
That organisms adapt to the time of the day in a circadian fashion have been documented for a long time. But Hall, Rosbash and Young set out to determine just how our biological clocks function. They used as an experimental model the fruit fly (Drosophila melanogaster) to study the complicated process of circadian rhythms. This insect has a developmental process called eclosion, in which Drosophila emerges from its pupal case. Because pupae emerge only at a specific time of the day, the researchers can measure the timing between rounds of eclosion for different strains of flies and identify those that had a bad clock. By studying fly strains with timing problems they were able to zero in on the relevant gene that controlled this internal clock. The control gene, named Period was then isolated.
They found that Period gene encodes a protein called PER, whose oscillations in its levels inside the cells controls the organism’s biological clocks: the amount of PER protein accumulates in cells overnight before being broken down in the daytime. It means that levels of PER protein rose and fell over the 24-hour daily cycle.
One key discovery was that PER protein actually blocks the activity of the Period gene, creating a mechanism that allows PER to regulate its own levels throughout the day. This is called a negative feedback loop. As levels of PER protein build up over the course of the night, less and less PER protein is made; when dawn brakes, the protein levels eventually disappear and the process starts over again in a cycle manner. This series of steps repeats over and over each day with nearly exact timing. The discovery demonstrated that biological clocks use negative feedback loop from clock proteins like PER to turn themselves on and off again each 24 hours.
Later work by the researchers uncovered two other clock genes that are essential for the oscillation of the Period gene in the cycle. One is a gene that encodes a protein that allows PER protein to enter the cell nucleus to shut down the activity of the Period gene. The other is a gene that encodes a protein that degrades PER protein and thereby slows down its accumulation, helping synchronize the clock to the familiar 24-hour cycle.
How the cellular clockwork connects with the light-dark changes in the outside environment? This is largely the job of the photoreceptor called cryptochrome protein which contributes to accurate timing by phase-shifting the clock in response to light. The capture of photon by cryptochrome (a blue light-absorbing substance) in the morning when the lights come on, leads to conformational change in cryptochrome. This conformational change leads to an interaction with the protein that degrades PER protein, which accelerates its decline, allowing cells set the time by the light every day.
The pioneered studies of this year’s Nobel laureates launched a subgenre of molecular biology that focuses on circadian rhythm. Though the genes differ from species to species, the key mechanistic principles for the biological clocks discovered by them, has been ultimately found in all organisms, from plants to Homo sapiens.
In humans, the clock regulates critical functions such as hormone levels, sleep patterns, blood pressure, heart rate, alertness, body temperature, metabolism, and behavior. So these discoveries have had important implications for health research and helped establish what is now called chronobiology, a growing field of science. As recognized by the Nobel committee, the work of Hall, Rosbash and Young is pivotal because the misalignment between a person’s lifestyle and the rhythm dictated by an inner timekeeper could affect well-being and over time could contribute to the risks for various diseases.
c&en, 98: 6, 2017