Nobel Rhythms: details

The molecular mechanism of the biological clock

Maxim Rousseau, Polit.roo

The 2017 Nobel Prize in Physiology or Medicine was awarded to three American scientists: Jeffrey C. Hall, Michael Rosbash and Michael W. Young for "discovering the molecular mechanisms of circadian rhythms." Four years earlier, these scientists received the Shao Prize for their work in this field.

Circadian rhythms are the same "biological clock" that almost all living beings have, that is, fluctuations in the intensity of processes in the body with a period close to 24 hours. The oldest observation of circadian rhythms was made by an associate of Alexander the Great Androsphenes, one of the chiefs of the fleet, who was returning to Hellas through the Persian Gulf and the Arabian Sea. His essay on this voyage has been preserved in fragments, one of which is quoted in Theophrastus' History of Plants.

Androsphen describes a tree on one of the islands, whose leaves "fold at night, begin to open at sunrise and finally unfold at noon; with the onset of evening, they gradually shrink again and fold at night. Locals say that the tree falls asleep" (per. M. E. Sergeenko). Most likely, Androsphen meant the Indian tamarind (Tamarindus indica).

In 1729, French astronomer and physicist Jean Jacques de Meran became interested in the ability of Mimosa pudica to open its leaves in the morning and fold them at night. He conducted an experiment in which the plants were kept in the dark around the clock, but still continued to open and fold the leaves once a day, that is, the change in the plant was not caused directly by sunlight, but depended on some internal mechanism, the "clock". However, de Meran was inclined to a different explanation, believing that plants are able to "feel the Sun without seeing it." Nevertheless, his little article on mimosa was the first study in chronobiology.

Later, similar rhythms were found not only in plants, but also in animals, not excluding humans. Body temperature, brain activity, hormone production, cell regeneration and other body processes are subject to these rhythms. The adjective "circadian", proposed for them in the 1950s by the American chronobiologist Franz Haldberg, is formed from the Latin words circa "about" and dies "day", that is, rhythms with a period of about a day.

In the XX century, scientists managed to learn a lot of details about the work of circadian rhythms. For example, they discovered that rhythmic processes not only persist in the absence of external factors (as in the experiment with mimosa in the dark), but are also able to adjust, shifting when external conditions change. We encounter this phenomenon when traveling by plane through several time zones. At first, a person experiences a "jet lag" while his circadian rhythms are going the same way, and then they are modified, adjusting to the local daytime and night hours. But the molecular genetic nature of circadian rhythms became known only in the last third of the XX century.

In the 1970s, Seymour Benzer and Ronald Konopka from the California Institute of Technology discovered fruit flies with altered circadian rhythms that were either longer or shorter than the “standard”, and there were also fruit flies whose rest and activity time had a random duration, that is, there was no circadian rhythm at all. All these deviations were transmitted to the offspring, which means that they were genetically implanted in mutant variants of an as yet unknown gene.

Jeffrey Hall and Michael Rosbash, who worked at Brandeis University in Boston and Michael Young from New York University, were able to identify this gene in 1984. It was named period (per). Hall and Rosbash then identified the protein (PER) encoded by this gene. They suggested that the nature of rhythms lies in the mechanism of negative feedback: the higher the concentration of protein in the cell increases, the less it is synthesized. Protein accumulated in the body at night and was destroyed during the day. The decrease in concentration triggered the mechanism of its synthesis again, and the process was repeated day after day.

The scientists also examined two mutations of this gene, which received the designations pers and perl. With the first mutation, the period of changes in protein concentration became shorter, with the second longer. That is, the "biological clock" of fruit flies with these mutations began to hurry or lag behind. The corresponding changes in the PER protein concentration correlated with the level of motor activity in drosophila.

An important point remained unclear: the protein PER, as befits a protein, is synthesized on ribosomes, and in order to influence the activity of its own gene and slow it down, the protein had to somehow penetrate the cell nucleus. In 1994, Michael Young found another drosophila gene, which he gave the name timeless. This gene encodes the TIM protein. Yang and his colleagues managed to prove that the TIM protein binds to the PER protein, forming a complex that biochemists call a heterodimer, and together they become able to get into the cell nucleus to suspend the activity of the period gene.

In the future, studies of the genetic basis of circadian rhythms were continued, and scientists were able to find out exactly how the period gene is inhibited.  In the laboratory of Rosbash and Hall, two more drosophila genes associated with circadian rhythms, called cycle and clock, were studied. The proteins encoded by these genes serve as transcription factors for the period and timeless genes, that is, they affect the synthesis of the matrix RNA of these genes. As it turned out, the heterodimer of the PER and TIM proteins, penetrating into the cell nucleus, affects the cycle and clock genes, suspending the synthesis of their matrix RNA, and indirectly – its own synthesis. The concentrations of PER and TIM proteins then decrease, their heterodimer is produced less, it no longer turns off the cycle and clock genes, their proteins again spur the work of the period and timeless genes – the process repeats in a circle.

The cryptochrome gene, discovered by Rosbash and his colleagues, and the protein of this gene (CRY) are responsible for the timely destruction of the PER and TIM proteins. The concentration of PER and TIM drops in the light and increases in the evening and at night. This is due to the fact that the CRY protein is sensitive to light waves in the blue part of the spectrum and reacts more actively with the TIM protein during the day, causing its decay. This also accelerates the breakdown of the PER protein, since without the TIM protein it is much less stable. Another gene discovered by Yang, doubletime, encoded the DBT protein, which accelerated the breakdown of the PER protein by attaching a phosphate group to its molecule. The cryptochrome and doubletime genes and their proteins affect the frequency of rhythm fluctuations, making it close to 24 hours.

Then similar genes were discovered in mammals. As a result of all these studies, a model of transcriptional-translational oscillation, that is, rhythmically changing gene expression, underlying the "biological clock" was formed.

Portal "Eternal youth" http://vechnayamolodost.ru  02.10.2017