Who received the Nobel Prize in Medicine. Nobel in Medicine awarded for discovering the mechanisms of circadian rhythms

How the body's biological clock works. Why was the Nobel Prize in Medicine awarded in 2017?

Jeffrey Hall, Michael Rozbash and Michael Young website

Three American scientists shared the highest scientific award for research into the mechanism of internal clocks in living organisms

Life on Earth is adapted to the rotation of our planet around the Sun. For many years we have known about the existence inside living organisms, including humans, biological clock, which help to anticipate the circadian rhythm and adapt to it. But how exactly does this clock work? American geneticists and chronobiologists were able to look inside this mechanism and shed light on its hidden workings. Their discoveries explain how plants, animals and people adapt their biological rhythms to synchronize with the daily cycle of the Earth's rotation.

Using fruit flies as test organisms, the 2017 Nobel Prize winners isolated a gene that controls the normal circadian rhythm in living things. They also showed how this gene encodes a protein that accumulates in the cell at night and breaks down during the day, thereby forcing it to maintain this rhythm. They subsequently identified additional protein components that control the self-sustaining clock mechanism inside the cell. And now we know that the biological clock functions according to the same principle both inside individual cells and inside multicellular organisms, such as humans.

Thanks to exceptional precision, our internal clock adapts our physiology to such different phases of the day - morning, afternoon, evening and night. This clock regulates so much important functions, such as behavior, hormone levels, sleep, body temperature and metabolism. Our well-being suffers when the external environment and internal clock are out of sync. An example is the so-called jet lag, which occurs among travelers who move from one time zone to another, and then for a long time cannot adapt to the shift of day and night. They sleep during daylight hours and cannot sleep during the dark. Today there is also a lot of evidence that a chronic mismatch between lifestyle and natural biorhythms increases the risk of various diseases.

Our internal clock cannot be fooled

Experiment of Jean-Jacques d'Hortois de Mairan Nobel Committee

Most living organisms clearly adapt to daily changes environment. One of the first to prove the presence of this adaptation back in the 18th century was the French astronomer Jean-Jacques d'Ortois de Mairan. He observed a mimosa bush and discovered that its leaves turn to follow the sun during the day and close at sunset. The scientist wondered what would what would happen if the plant were in constant darkness? After performing a simple experiment, the researcher found that, regardless of the presence sunlight, the leaves of the experimental mimosa continue to make their usual daily movements. As it turns out, plants have their own internal clock.

More recent research has shown that not only plants, but also animals and humans are subject to a biological clock that helps adjust our physiology to daily changes. This adaptation is called the circadian rhythm. The term comes from Latin words circa – “about” and dies – “day”. But exactly how this biological clock works has long remained a mystery.

Discovery of the "clock gene"

In the 1970s, American physicist, biologist and psychogeneticist Seymour Benzer, together with his student Ronald Konopka, investigated whether it was possible to isolate genes that control the circadian rhythm in fruit flies. Scientists were able to show that mutations in a gene unknown to them disrupt this rhythm in experimental insects. They called it the period gene. But how did this gene influence the circadian rhythm?

The 2017 Nobel Prize winners also conducted experiments on fruit flies. Their goal was to discover the mechanism of the internal clock. In 1984, Jeffrey Hall and Michael Rozbash, who worked closely together at Brandeis University in Boston, and Michael Young at The Rockefeller University in New York, successfully isolated the period gene. Hall and Rozbash then discovered that the PER protein encoded by this gene accumulates in cells during the night and is destroyed during the day. Thus, the level of this protein fluctuates over a 24-hour cycle in synchrony with the circadian rhythm. The "pendulum" of the internal cellular clock was discovered.

Self-regulating clock mechanism

A simplified diagram of the work of proteins in the cell that regulate the circadian rhythm Nobel Committee

The next key goal was to understand how these circadian oscillations might arise and be maintained. Hall and Rozbash suggested that the PER protein blocks the activity of the period gene during the daily cycle. They believed that, through an inhibitory feedback loop, the PER protein could periodically inhibit its own synthesis and thereby regulate its levels in a continuous cyclical rhythm.

To build this curious model, only a few elements were missing. To block the activity of a period gene, the PER protein produced in the cytoplasm would have to reach the cell nucleus, where the genetic material is contained. Experiments by Hall and Rozbash showed that this protein actually accumulates in the nucleus at night. But how does he get there? This question was answered in 1994 by Michael Young, who discovered the second key “clock gene,” which encodes the TIM protein necessary for maintaining a normal circadian rhythm. In simple and elegant work, he showed that when TIM is bound to PER, the two proteins are able to enter the cell nucleus, where they actually block the period gene from working to close the inhibitory feedback loop.

This regulatory mechanism explained how this fluctuation in levels arose. cellular protein, but still did not answer all the questions. For example, it was necessary to establish what controls the frequency of daily fluctuations. To solve this problem, Michael Young isolated another gene encoding the DBT protein, which delays the accumulation of the PER protein. Thus, it was possible to understand how this oscillation is regulated in order to coincide as closely as possible with the 24-hour cycle.

These discoveries made by today's laureates underlie the key principles of the functioning of the biological clock. Subsequently, other molecular components of this mechanism were discovered. They explain the stability of its operation and the principle of operation. For example, Hall, Rozbash and Young discovered additional proteins needed to activate the period gene, as well as a mechanism by which daylight synchronizes the body clock.

The influence of circadian rhythms on human life

Human circadian rhythm Nobel Committee

The biological clock is involved in many aspects of our complex physiology. We now know that all multicellular organisms, including humans, use similar mechanisms to control circadian rhythms. Most of our genes are regulated by the biological clock, so a carefully tuned circadian rhythm adapts our physiology to the different phases of the day. Thanks to the seminal work of today's three Nobel Prize winners, circadian biology has grown into a broad and dynamic field of research examining the impact of circadian rhythms on our health and well-being. And we received yet another confirmation that it is still better to sleep at night, even if you are an inveterate night owl. It's healthier.

Reference

Geoffrey Hall– born in 1945 in New York, USA. He received his doctorate in 1971 from the University of Washington (Seattle, Washington). Until 1973, he served as a professor at the California Institute of Technology (Pasadena, California). Since 1974 he has been working at Brandeis University (Waltham, Massachusetts). In 2002, he began collaborating with the University of Maine.

Michael Rozbash– born in 1944 in Kansas City, USA. He completed his doctorate at the Massachusetts Institute of Technology (Cambridge, Massachusetts). For the next three years he was a doctoral student at the University of Edinburgh in Scotland. Since 1974 he has been working at Brandeis University (Waltham, Massachusetts).

Michael Young– born in 1949 in Miami, USA. He completed his doctoral studies at the University of Texas (Austin, Texas) in 1975. Until 1977, he completed postdoctoral studies at Stanford University (Palo Alto, California). In 1978 he joined the faculty of The Rockefeller University in New York.

Translation of materials from the Royal Swedish Academy of Sciences.

In 2017, the Nobel Prize in Medicine was awarded to three American scientists who discovered the molecular mechanisms responsible for the circadian rhythm - the human biological clock. These mechanisms regulate sleep and wakefulness, the functioning of the hormonal system, body temperature and other parameters of the human body, which change depending on the time of day. Read more about the scientists' discovery in the RT material.

Winners of the Nobel Prize in Physiology or Medicine Reuters Jonas Ekstromer

The Nobel Committee of the Karolinska Institutet in Stockholm on Monday, October 2, announced that the 2017 Nobel Prize in Physiology or Medicine was awarded to American scientists Michael Young, Geoffrey Hall and Michael Rosbash for their discoveries molecular mechanisms that control the circadian rhythm.

“They were able to get inside the body’s biological clock and explain how it works,” the committee noted.

Circadian rhythms are called cyclic fluctuations of various physiological and biochemical processes in the body associated with the change of day and night. Almost every organ of the human body contains cells that have an individual molecular clock mechanism, and therefore circadian rhythms represent a biological chronometer.

According to a release from the Karolinska Institutet, Young, Hall and Rosbash were able to isolate a gene in fruit flies that controls the release of a special protein depending on the time of day.

“Thus, scientists were able to identify the protein compounds that are involved in the operation of this mechanism and understand the independent mechanics of this phenomenon inside each individual cell. We now know that the biological clock works on the same principle in the cells of other multicellular organisms, including humans,” the committee that awarded the prize said in a release.

• Drosophila fly
• globallookpress.com
• imagebroker/Alfred Schauhuber

The presence of biological clocks in living organisms was established at the end of the last century. They are located in the so-called suprachiasmatic nucleus of the hypothalamus of the brain. The nucleus receives information about light levels from receptors on the retina and sends signals to other organs through nerve impulses and hormonal changes.

In addition, some nuclear cells, like the cells of other organs, have their own biological clock, the work of which is ensured by proteins whose activity changes depending on the time of day. The activity of these proteins determines the synthesis of other protein bonds, which generate circadian rhythms in the life of individual cells and entire organs. For example, being indoors with bright lighting at night can shift the circadian rhythm, activating protein synthesis of PER genes that usually begins in the morning.

The liver also plays a significant role in circadian rhythms in mammals. For example, rodents like mice or rats are nocturnal animals and eat in the dark. But if food becomes available only during the day, their liver circadian cycle shifts by 12 hours.

Rhythm of life

Circadian rhythms are daily changes in the body's activity. They include the regulation of sleep and wakefulness, the release of hormones, body temperature and other parameters that change in accordance with the circadian rhythm, explains somnologist Alexander Melnikov. He noted that researchers have been developing in this direction for several decades.

“First of all, it should be noted that this discovery is not yesterday or today. These studies were carried out for many decades - from the 80s of the last century to the present - and made it possible to discover one of the deep mechanisms that regulate the nature of the human body and other living beings. The mechanism that scientists discovered is very important for influencing the body’s circadian rhythm,” said Melnikov.

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According to the expert, these processes occur not only due to the change of day and night. Even in polar night conditions, circadian rhythms will continue to operate.

“These factors are very important, but very often they are impaired in people. These processes are regulated at the gene level, which was confirmed by the award winners. Nowadays, people very often change time zones and are exposed to various stresses associated with sudden changes in the circadian rhythm. The intense rhythm of modern life can affect the correct regulation and opportunities for rest of the body,” concluded Melnikov. He is confident that the research of Young, Hall and Rosbash provides an opportunity to develop new mechanisms for influencing the rhythms of the human body.

History of the award

The founder of the prize, Alfred Nobel, in his will entrusted the selection of the laureate in physiology and medicine to the Karolinska Institute in Stockholm, founded in 1810 and one of the leading educational and scientific medical centers peace. The university's Nobel Committee consists of five permanent members, who, in turn, have the right to invite experts for consultation. There were 361 names on the list of nominees for this year's award.

The Nobel Prize in Medicine has been awarded 107 times to 211 scientists. Its first laureate was in 1901 German doctor Emil Adolf von Behring, who developed a method of immunization against diphtheria. The Karolinska Institute Committee considers the most significant prize to be the 1945 prize awarded to British scientists Fleming, Cheyne and Florey for the discovery of penicillin. Some awards have become irrelevant over time, such as the award awarded in 1949 for the development of the lobotomy method.

In 2017, the bonus amount was increased from 8 million to 9 million Swedish kronor (about $1.12 million).

The award ceremony will traditionally take place on December 10, the day of the death of Alfred Nobel. Prizes in the fields of physiology and medicine, physics, chemistry and literature will be awarded in Stockholm. The Peace Prize, according to Nobel's will, is awarded on the same day in Oslo.

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The 2017 Nobel Prize in Physiology or Medicine was awarded for the discovery of genes that determine the functioning of the biological clock - an intracellular mechanism that controls the cyclic fluctuations of biological processes associated with the change of day and night. Daily life or inherent in all living organisms, from cyanobacteria to higher animals.

Of course, any scientific result that has received such worldwide recognition is based on the achievements of its predecessors. The idea of ​​a biological clock first appeared in the 17th century, when the French astronomer Jean Jacques de Meran discovered that the daily rhythm of the movement of plant leaves does not disappear even in the dark: it is strictly “programmed” and not determined by the action of the environment.

From this moment the study of the biological clock phenomenon began. It turned out that almost all living organisms undergo cyclic processes with a daily or near-daily period. And even in the absence of the main external factor of synchronization - the change of day and night, organisms continue to live according to a daily rhythm, although the period of this rhythm may be longer or shorter than the length of the day, depending on individual characteristics.

The genetic basis of the biological clock was first established in the 1970s, when the Per (for period) gene was discovered in the fruit fly. The authors of this discovery, Seymour Benzer and his student Ronald Konopka from the Californian Institute of Technology, conducted a large-scale experiment, working with hundreds of laboratory lines of flies obtained using chemical mutagenesis. Scientists noticed that with the same period of illumination, in some flies the period of the circadian rhythm of sleep and wakefulness became either significantly shorter than the usual day (19 hours) or longer (28 hours); in addition, “arrhythmics” with a completely asynchronous cycle were discovered. In an attempt to identify genes that control the circadian rhythm in fruit flies, scientists have demonstrated that disturbances in this rhythm are associated with mutations in an unknown gene or group of genes.

Thus, future Nobel Prize winners Hall, Rosbash and Young already had at their disposal lines of flies with genetically determined changes in the period of sleep and wakefulness. In 1984, these scientists isolated and sequenced the desired Per gene and found that the level of the protein it encodes varies daily, peaking at night and decreasing during the day.

This discovery has given new impetus to research aimed at understanding why the mechanisms circadian rhythms work exactly this way and not otherwise, why the daily period may vary among different individuals, but at the same time it turns out to be resistant to the action external factors such as temperature (Pittendrich, 1960). Thus, work carried out on cyanobacteria (blue-green algae) showed that with an increase in temperature by 10 ºС, the daily period of their cyclic metabolic processes changes by only 10–15%, while according to the laws of chemical kinetics this change should be greater by almost order! This fact became a real challenge, since all biochemical reactions must obey the rules of chemical kinetics.

Scientists now agree that the rhythm of cyclic processes remains quite stable because the daily cycle is determined by more than one gene. In 1994, Young discovered the Tim gene in Drosophila, which encodes a protein involved in the feedback regulation of PER protein levels. As the temperature rises, the production of not only the proteins involved in the formation of the circadian cycle increases, but also other proteins that inhibit it, as a result the functioning of the biological clock does not get disrupted.

The basic mechanisms of circadian rhythms have now been sufficiently studied, although many details remain unexplained. Thus, it is not clear how several “clocks” can simultaneously coexist in one organism: how are the processes that occur with different periods? For example, in experiments when people lived indoors or in a cave, without receiving information about the change of day and night, their body temperature, secretion steroid hormones and other physiological parameters were cycled with a period of about 25 hours. In this case, periods of sleep and wakefulness could vary from 15 to 60 hours (Wever, 1975).

The study of circadian rhythms is also important for understanding the functioning of the body in extreme conditions, for example, in the Arctic, where, under conditions of polar day and night, natural factors of synchronization of circadian rhythms do not operate. There is convincing evidence that during a long stay in such conditions, a person’s circadian rhythms of a number of functions change significantly (Moshkin, 1984). We now recognize that this factor can have marked effects on human health, and knowledge of the molecular basis of circadian rhythms should help identify gene variants that will be “beneficial” when working in polar conditions.

But knowledge about biorhythms is important not only for polar explorers. Circadian rhythms affect our metabolic processes, work immune system and the process of inflammation, on blood pressure, body temperature, brain function and much more. The effectiveness of some medications and their side effects. If there is a forced discrepancy between the internal and external “clocks” (for example, due to a long-distance flight or night shift work), various dysfunctions of the body can be observed, from the disorder gastrointestinal tract And of cardio-vascular system to depression, which also increases the risk of developing cancer.

Literature

PITTENDRIGH C.S. Circadian rhythms and the circadian organization of living systems. Cold Spring Harb Symp Quant Biol. 1960;25:159-84.

Wever, R. (1975). "The circadian multi-oscillator system of man." Int J Chronobiol. 3 (1): 19–55.

Moshkin M.P. The influence of the natural light regime on the biorhythms of polar explorers // Human Physiology. 1984, 10(1): 126-129.

Prepared by Tatyana Morozova

The 2017 Nobel Prize in Physiology or Medicine was awarded to American professors Geoffrey Hall, Michael Rosbash and Michael Young. They studied the mechanism that regulates the body's circadian rhythms, the so-called cellular clock. Introducing the laureates, the Nobel Committee expert emphasized that this problem itself is far from new. Back in the 18th century, a French scientist drew attention to some flowers that open in the morning and close at night. The biologist conducted an experiment by placing flowers in complete darkness for several days. And they behaved as if they were in natural conditions. A similar picture was observed in the study of other plants and animals. Then, for the first time, a hypothesis was put forward about the internal clock of living organisms. What is their essence?

Each of us knows what an ordinary clock is; we measure time using a pendulum. But it turns out that almost all living things have their own internal clock, and instead of a pendulum, the change of day and night “works” in us, which are a consequence of the rotation of the Earth around its axis,” a professor at the Skolkovo Institute of Science and Technology and a professor at Rutgers University told an RG correspondent. Head of laboratories at the Institute of Molecular Genetics of the Russian Academy of Sciences and the Institute of Gene Biology of the Russian Academy of Sciences Konstantin Severinov. - From the very beginning of life, all living things had to adapt to such a change. Turn on these little clocks in every cell of any organism. And live by them. In accordance with their “indications”, change your physiology - run, sleep, eat, and so on.

The current laureates decided in the late 70s to look inside these watches and understand how they work. To do this, they studied fruit flies and selected insects with mutations in which their sleep-wake cycles were altered. Let's say that some slept completely randomly. In this way, it was possible to identify genes that are responsible for ensuring that the cycles are correct and coordinated.

And then scientists figured out the molecular background of these watches,” says Severinov. - It turned out that the identified genes control the production of certain proteins in such a way that they accumulate at night and fall apart during the day. In fact, such fluctuations in concentration are a kind of pendulum in our body. And depending on this, various genes are activated in the cell, which ultimately controls many processes.

Then scientists found out that exactly the same mechanism works not only in flies, but in all living things. It was invented by nature to count time in the body. The practical significance of this discovery is obvious, say, many mental disorders associated with sleep disturbance due to disruptions in the circadian cycle system.

Assessing the award of this prize, a number of experts have already stated that this is a “calm prize”; it will not become an explosion in world science, if only because it was made several decades ago. Moreover, rewarding old works is becoming a trend. At the same time, the Nobel committee passed by the sensational work on genome editing, which became a boom recent years. “I don’t agree with this opinion,” says Severinov. “Genome editing will get its prize, and it’s not exactly a discovery, but rather a genetic technique. And the cellular clock is a real, deep fundamental science, it explains how the world works.

It should be noted that the forecast of Thomson Reuters, which has been predicting laureates since 2002 and guesses the laureates most often compared to its competitors, was wrong this time. They bet on American scientists who work on cancer problems.

The award ceremony will traditionally take place on December 10, the day of the death of the founder of the Nobel Prizes, Swedish entrepreneur and inventor Alfred Nobel (1833-1896). The 2017 Nobel Prize is worth nine million Swedish kronor (million US dollars).

Jeffrey Hall was born in 1945 in New York and has worked at Brandeis University since 1974. Michael Rosbash was born in Kansas City and also works at Brandeis University. Michael Young was born in 1945 in Miami and works at Rockefeller University in New York. York.