The science of sleep: for which they were awarded the Nobel Prize in Medicine. Tick-tock in Swedish. Nobel Prize for Circadian Rhythms

The 2017 Nobel Prize winners in Physiology or Medicine - Americans Michael Young, Jeffrey Hall and Michael Rosbash - received awards "for their discovery of the molecular mechanisms that control the circadian rhythm."

Together with the editors of the popular science portal "Attic" we figured out what these mechanisms are, how they work and why the cell needs to know what time it is.

What is circadian rhythm?

For more than four billion years that the Earth has existed, the conditions of life on it have constantly changed. But one thing almost always remained unchanged - a 24-hour day, a change of day and night, caused by the rotation of the planet around its axis. During this time earthly life adapted to sunsets and sunrises and acquired her own internal clock. These circadian (from Latin circa - "around, about" and dies - "day") rhythms are mercilessly subordinated to many processes in the body: in addition to sleep and wakefulness, these are, for example, metabolism, hormonal levels, body temperature, and even (indirectly) behavior.

Many studies show how important the natural “internal clock” is for us. For example, artificially prolonging daylight hours can cause obesity and related diseases (like diabetes). IN different time days, the body is susceptible to infections in different ways: the biological clock of animals affects the ability of viruses to replicate and spread. Even the perception of colors can be associated with circadian rhythms - this was shown in the example of the very dress, because of which the Internet almost quarreled in 2015.

Why was the award given in 2017?

Alexandra Puchkova, senior Researcher laboratory of neurobiology of sleep and wakefulness of the Institute of Higher nervous activity and Neurophysiology of the Russian Academy of Sciences, said that the laureates of 2017 discovered a "cellular clock" in fruit flies. Later, scientists found out that this clock mechanism is quite universal - in a similar way, the change of day and night is fixed on genetic level both in other animals and humans.

For the first time, a gene that affects the circadian rhythm was identified back in the 70s. Then the scientists called it period . Two of today's laureates, Geoffrey Hall and Michael Rosbash, were able to isolate this gene in 1984. They then showed that the PER protein encoding the gene accumulates at night and is destroyed during the day.

“[Laureates] found out on fruit flies that there is one gene. Then it turned out that there are actually many of these genes, they regulate each other, and if they are changed, then this period can become more or less than 24 hours, and if you break it, then it [ gene] will disappear altogether. And then they found out that a person has a very similar mechanism ... They showed how this whole machine works, ”explained Alexandra Puchkova.

Irina Kurbatova, a researcher at the Genetics Laboratory of the Institute of Biology of the Karelian Scientific Center of the Russian Academy of Sciences, is not surprised that the award was given precisely for these works - according to her, this is an extremely promising area scientific research directly related to both fundamental medicine and medical practice.

What's next?

Interestingly, the "clock" found by Hall, Rosbash and Young works in all cells that have a nucleus. This is how they intervene in all the biological processes that interest the new field of science, chronobiology.

Chronobiologists, along with somnologists (sleep specialists) and other scientists, are trying to figure out how to influence the resetting of the "internal clock", which, for example, occurs when you fly to a different time zone or work the night shift. As scientists explain, the chemical "clock" in our body is able to perceive external signals - primarily light. This means that with the help of light therapy it will be possible to treat depression or seasonal affective disorder caused by unnaturally short daylight hours.

Among other things, circadian rhythms regulate the rhythm blood pressure, and if their work is disrupted, a person has an increased risk of cardiovascular pathologies.

So research Nobel laureates summed up theoretical basis under the whole field of medicine.

MOSCOW, 2 Oct— RIA Novosti, Anna Urmantseva. The names of the Nobel Prize winners in Physiology or Medicine have been announced in Stockholm. They were scientists who discovered the mechanisms of regulation of biological intracellular clocks - these are Professor Jeffrey Hall from New York, Michael Rozbash from Kansas City and Michael Young from Miami.

The essence of their discovery is that an explanation was found for the rhythms that are present in the organisms of biological beings on Earth, regardless of the illumination (day and night). Since ancient times, volunteers have conducted experiments confirming that circadian rhythms exist. Researchers went into caves for a long time, closed in bunkers to test the hypothesis of the existence of wakefulness and sleep rhythms in those conditions where the body is deprived of information about daylight hours, as well as any sounds. It turned out that although the day stretches, according to various sources, from 25 to 27 hours, a person continues to live with his "daily-like" rhythms, which is why they talk about "circadianity" - the likeness of a day (the word comes from the Latin circa - "about" and dies - "day").

On plants, the first such experiments were carried out back in 1729: the French astronomer Jean-Jacques d "Ortois De Mairan placed a heliotrope in a dark room and noticed that its leaves rise and fall in the same way as in the light.

Since then, similar experiments have been repeated many times and completely convinced scientists that everyone has circadian rhythms, including unicellular organisms and cells in culture. It is clear that these rhythms are synchronized with the rotation of the Earth.

In their research, chronobiologists have gone very far, setting up experiments to extract a single cell and analyze its individual rhythms. It turned out that a small cell continues to live outside the body, correlating its activity with established biorhythms. Moreover, the activity of a cell from the body of a human "owl" will differ from the activity of a cell taken from a "lark".

professors American universities Geoffrey Hall, Michael Rozbash and Michael Young figured out the mechanism of circadian rhythms and identified the genes that regulate this process.

© AP Photo / The Chinese University of Hong Kong

© AP Photo / The Chinese University of Hong Kong

In 1990, Michael Rozbash and colleagues discovered the role of one of the genes in circadian rhythms in Drosophila (fruit fly). The gene, called period (per), regulated the production of the PER protein, the level of which in the body fluctuated in the light and dark hours of the day, and the fluctuations persisted when the fruit flies were kept in the dark.

Scheme of activation of "clock genes" Per and Cry in a cell. The protein complex activates genes that trigger the production of other protein molecules that block the activity of this complex.

Periodic decrease in protein concentration was carried out using the mechanism of negative feedback: the more the concentration increased, the less protein was synthesized. The scientists also deliberately altered these genes, producing two mutations. 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 rush or lag behind. Corresponding changes in PER protein concentration correlated with the level motor activity in Drosophila.

In the laboratory of Rosebash and Hall, two other Drosophila genes associated with circadian rhythms, cycle and clock, were also studied. In the future, the study of the genetic basis of circadian rhythms was continued. As a result, a model of transcriptional-translational oscillation was formed, that is, rhythmically changing gene expression.

If we talk about a person, it turned out that the causes of the syndrome of early falling asleep or late waking up can also be found in the genes. The "culprit" of early falling asleep may be a mutation in the hPer2 gene (h here from human - "human"), and late waking up is associated with a changed hPer3 gene.

© RIA Novosti illustration. A.Polyanina

© RIA Novosti illustration. A.Polyanina

How are healthy cells regulated? The process is started by the sun's rays. The central clock of the body begins to work, located in the brain and consisting of two main elements - the suprachiasmatic nuclei (SCN) of the hypothalamus and the pineal gland. The suprachiasmatic nuclei are able to maintain an autonomous circadian rhythm of electrical activity and impose it on the intracellular clock.

Life on Earth obeys the rhythm that sets the rotation of the planet around itself and around the Sun. Most living organisms have an internal "clock" - mechanisms that allow you to live in accordance with this rhythm. Hall, Rosbash and Young looked into the cell and saw how the biological clock works.

Drosophila flies served as model organisms. Geneticists managed to calculate the gene that controls the rhythm of life of insects. It turned out that it encodes a protein that accumulates in cells at night and is slowly utilized during the day. Later, several more proteins were discovered that are involved in the regulation of circadian rhythms. It is now clear to biologists that the mechanism that regulates the daily routine is the same for all living organisms, from plants to humans. This mechanism controls activity, hormone levels, body temperature, and metabolism, which change with the time of day. Since the discoveries of Hall, Rosbash, and Young, there has been much evidence of how sudden or persistent lifestyle deviations from the biological clock can be hazardous to health.

The first evidence that living beings have a "sense of time" appeared back in the 18th century: then the French naturalist Jean Jacques d "Ortou de Maran showed that mimosa continues to open flowers in the morning and close in the evening, even in the dark all day long. Further research showed that not only plants sense the time of day. but also animals, including people. The periodic change of physiological parameters and behavior during the day was called circadian rhythms - from lat. circa- circle and dies- day.

In the 70s of the last century, Seymour Benzer and his student Ronald Konopka found a gene that controls circadian rhythms in Drosophila, and overlaid its period. In 1984, Geoffrey Hall and Michael Rosbash of Brandelis University in Boston and Michael Young of Rockefeller University in New York isolated the gene period, and then Hall and Rosbash found out what the protein encoded in it, PER, does - and it accumulates in the cell at night and is spent all day, so its concentration can be used to judge the time of day.

This system, as Hall and Rosbash suggested, regulates itself: the PER protein blocks the activity of the period gene, so protein synthesis stops as soon as there is too much of it and resumes as the protein is consumed. It only remained to answer the question of how the protein enters the cell nucleus - after all, only there it can influence the activity of the gene.

In 1994, Young discovered the second gene important for circadian rhythms, timeless, which encodes the TIM protein, which helps the PER protein cross the nuclear membrane and block the period gene. Another gene double time, turned out to be responsible for the DBT protein, which slows down the accumulation of the PER protein - so that the cycle of its synthesis and pauses between them stretched for 24 hours. In subsequent years, many other genes and proteins were discovered - parts of the delicate mechanism of the "biological clock", including those that allow you to "draw arrows" - proteins whose activity depends on illumination.

Circadian rhythms regulate a variety of aspects of life in our body, including at the genetic level: some genes are more active at night, others during the day. Thanks to the discoveries of the 2017 laureates, the biology of circadian rhythms has become a vast scientific discipline; Dozens are written every year scientific works about how the "biological clock" works different types, including humans.

So, for those people who do science or talk and write about it, the most important week of the year has come. Traditionally, in the first week of October, the Nobel Committee announces Nobel Prize winners. And traditionally, we are the first to recognize the winners of the prize in physiology or medicine (yes, for some reason in Russian this union turned into “and”, but it’s correct - either one or the other).

In 2017, the Karolinska Institute, which awards these awards, surprised everyone. It is no secret that many experts and agencies come forward with prophecies and predictions of the laureates. This year, for the first time, the Clarivate Analytics agency, which spun off from the Thomson Reyters agency, made predictions. In the field of medicine, they predicted victory for Lewis Cantley for the discovery of a protein that is responsible for the development of cancer and diabetes, Karl Friston for neuroimaging techniques, and Yuan Chan and Patrick Moore for the discovery of the herpes virus that causes Kaposi's sarcoma.

However, unexpectedly for everyone, three Americans (which is not at all unexpected) received the award for the discovery of the molecular mechanisms of circadian rhythms - the internal molecular clock of humans, animals and plants. Yes, read, almost all living beings. The very thing that is called biorhythms.

What did Michael Young of the Rockefeller University in New York, Michael Rosbash of Brandeis University, and Geoffrey Hall of the University of Maine discover?

To begin with, let's say that they did NOT discover circadian rhythms (from the Latin circa - around and diem - day). The first hints of this appeared in antiquity (and it is not surprising, we are all awake during the day and sleep at night). The gene responsible for the operation of the internal clock is also not discovered by our heroes. Seymour Benzer and Ronald Konopka conducted this series of experiments on fruit flies. They were able to find mutant flies in which the duration of the circadian rhythm was not 24 hours, as in nature (or like humans), but 19 or 29 hours, or no circadian rhythms were observed at all. It was they who discovered the period gene, which “rules” the rhythms. But alas, Benzer died in 2007, Konopka - in 2015, without waiting for his Nobel Prize. This is often the case in science.

So, the period or PER gene itself encodes the PER protein, which conducts the orchestra of circadian rhythms. But how does he do it, and how is the cyclicality of all processes achieved? Hall and Rosbash proposed a hypothesis according to which the PER protein enters the cell nucleus and blocks the work of its own gene (as we remember, genes are just instructions for assembling a protein. One gene - one protein). But how does it happen? Jeffrey Hall and Michael Rosbash showed that the PER protein accumulates in the cell nucleus overnight and is consumed during the day, but did not understand how it managed to get there. And then the third laureate, Michael Young, came to the rescue. In 1994, he discovered another gene, timeless ("without time"), which also encodes a protein - TIM. It was Yang who showed that PER can enter the cell nucleus only by combining with the TIM protein.

So, to summarize the first discovery: When the period gene is active, the so-called messenger RNA of the PER protein is produced in the nucleus, according to which, as in the model, the protein will be produced in the ribosome. This messenger RNA exits the nucleus into the cytoplasm, becoming the template for the production of the PER protein. Then the loop closes: the PER protein accumulates in the cell nucleus when the activity of the period gene is blocked. Next, Young discovered another gene, doubletime - "double time", which encodes the DBT protein, which can "tune" the accumulation of the PER protein, shifting it in time. It is thanks to this that we can adjust to changes in the time zone and the length of day and night. But - if we change day to night very quickly, the squirrel does not keep up with the jet, and jet lag happens.

It should be noted that the 2017 award is the first award in 117 years, which somehow relates to the cycle of sleep and wakefulness. In addition to the discovery of Benzer and Konopka, other researchers of circadian rhythms and sleep processes did not wait for their prizes, such as one of the founders of chronobiology Patricia DeCorcy, the discoverer of the "rapid" phase of sleep Eugene Azerinsky, one of the fathers of somnology Nathaniel Kleitman ... So we can call the current The decision of the Nobel Committee is significant for everyone who works in this field.