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

How the body's biological clock works. For which they were given the Nobel Prize in Medicine in 2017

Jeffrey Hall, Michael Rosebash and Michael Young website

Three American Scientists Share the Highest Scientific Award for Researching the Mechanism of the 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 of biological clocks inside living organisms, including humans, that help to anticipate and adapt to the circadian rhythm. But how exactly does this clock work? American geneticists and chronobiologists were able to look inside this mechanism and shed light on its hidden work. Their discoveries explain how plants, animals and humans adapt their biological rhythms to synchronize with the daily rotation of the Earth.

Using fruit flies as test organisms, the 2017 Nobel Prize winners have 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, causing it to follow this rhythm. They subsequently identified additional protein components that drive the self-sustaining "clock" mechanism within the cell. And now we know that the biological clock functions according to the same principle both inside individual cells and inside multicellular organisms, for example, people.

With exceptional precision, our internal clocks adapt our physiology to these different phases of the day - morning, afternoon, evening and night. This clock regulates so important functions like behavior, hormone levels, sleep, body temperature and metabolism. Our well-being suffers when there is a desynchronization of the external environment and internal clocks. An example is the so-called jet lag that occurs among travelers who move from one time zone to another, and then cannot adapt to the shift of day and night for a long time. They sleep in the daytime and cannot fall asleep in 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 inner clock cannot be fooled

Experiment of Jean-Jacques d "Ortois de Mairana 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, the French astronomer Jean-Jacques d "Ortois de Mairan. He observed a mimosa bush and found that its leaves turn after the sun during the day and close at sunset. The scientist wondered what would what happened if the plant were in constant darkness? By 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 clocks.

Later studies have shown that not only plants, but also animals and humans obey the biological clock, which helps to adapt our physiology to daily changes. This adaptation is called circadian rhythm. The term comes from Latin words circa - "about" and dies - "day". But how exactly this biological clock works has long been a mystery.

Discovery of the "clock gene"

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

The 2017 Nobel Prize winners have also experimented with fruit flies. Their goal was to discover how the internal clock works. In 1984, Jeffrey Hall and Michael Rosebash, who worked closely with each other at Brandeis University in Boston, and Michael Young of Rockefeller University in New York, successfully isolated the period gene. Hall and Rosebash 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 during a 24-hour cycle in sync with the circadian rhythm. The "pendulum" of the internal cellular clock was discovered.

Self-adjusting clockwork

Simplified scheme of the work in the cell of proteins that regulate the circadian rhythm Nobel Committee

The next key goal was to understand how these circadian oscillations can arise and be maintained. Hall and Rosebash suggested that the PER protein blocks period gene activity during the diurnal cycle. They believed that using an inhibitory feedback loop, the PER protein could intermittently interfere with its own synthesis and thereby regulate its level in a continuous cyclic rhythm.

Only a few elements were missing to build this curious model. To block the activity of the period gene, the PER protein produced in the cytoplasm would have to reach the cell nucleus, which contains the genetic material. Hall and Rosebash's experiments showed that this protein actually accumulates in the nucleus at night. But how does it get there? This question was answered in 1994 by Michael Young, who discovered a second key "clock gene" that encodes a TIM protein that is essential for maintaining a normal circadian rhythm. In a simple and elegant work, he showed that when TIM is associated with PER, these two proteins are able to enter the cell nucleus, where they actually block the period gene to close the inhibitory feedback loop.

This regulatory mechanism explained how this fluctuation in levels came about. cellular protein, but did not close 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 - it delays the accumulation of the PER protein. Thus, it was possible to understand how this fluctuation is adjusted to match the 24-hour cycle as closely as possible.

These discoveries, made by today's laureates, underlie the key principles of the biological clock. Later, other molecular components of this mechanism were also discovered. They explain the stability of its work and the principle of operation. For example, Hall, Rosebash, and Young discovered additional proteins needed to activate the period gene, as well as the mechanism by which daylight synchronizes the biological 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 our biological clock, therefore, a carefully tuned circadian rhythm adapts our physiology to different phases of the day. Thanks to the fruitful work of today's three Nobelists, circadian biology has evolved into a vast and dynamic field of research exploring the effects of circadian rhythms on our health and well-being. And we received one more confirmation that it is still better to sleep at night, even if you are an inveterate "owl". It's healthier.

reference

Jeffrey Hall- was 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 cooperation with the University of Maine.

Michael Rosebash- was born in 1944 in Kansas City, USA. He defended his doctorate at the Massachusetts Institute of Technology (Cambridge, MA). 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- was born in 1949 in Miami, USA. Completed his doctorate at the University of Texas (Austin, TX) in 1975. Until 1977, he completed postdoctoral studies at Stanford University (Palo Alto, California). In 1978 he joined the faculty of 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 work 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 discovery of scientists - in the material RT.

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

The Nobel Committee of the Karolinska Institute in Stockholm on Monday, October 2, announced that the 2017 Nobel Prize in Physiology or Medicine was awarded to American scientists Michael Young, Jeffrey 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 said.

Circadian rhythms are the cyclic fluctuations of various physiological and biochemical processes in the body associated with the change of day and night. In almost every organ of the human body, there are cells with an individual molecular clock mechanism, and therefore, circadian rhythms are a biological chronometer.

According to the release of the Karolinska Institute, Young, Hall and Rosbash managed 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 work of this mechanism, and understand the work of the independent mechanics of this phenomenon inside each individual cell. We now know that the biological clock works the same way in the cells of other multicellular organisms, including humans, ”the award committee said in a release.

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

The presence of a biological clock 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 the level of illumination from receptors on the retina and sends a signal to other organs using nerve impulses and hormonal changes.

In addition, some cells of the nucleus, like cells of other organs, have their own biological clock, the work of which is provided by proteins, the activity of which varies depending on the time of day. The synthesis of other protein bonds depends on the activity of these proteins, which give rise to the circadian rhythms of the vital activity of individual cells and entire organs. For example, staying indoors with bright lighting at night can shift the circadian rhythm, activating the protein synthesis of PER genes, usually starting 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 is only available during the day, their liver circadian cycle shifts by 12 hours.

The rhythm of life

Circadian rhythms are diurnal 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 is not a discovery of yesterday or today. These studies have been carried out for many decades - from the 80s of the last century to the present - and have made it possible to discover one of the deepest mechanisms that regulate the nature of the human body and other living beings. The mechanism discovered by scientists is very important for influencing the body's circadian rhythm, ”Melnikov said.

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

“These factors are very important, but very often they are violated in people. These processes are regulated at the gene level, which was confirmed by the laureates of the award. Nowadays, people very often change time zones and are exposed to various stresses associated with abrupt changes in circadian rhythm. The tense rhythm of modern life can affect the correctness of regulation and the possibility of resting the body, "concluded Melnikov. He is confident that the study of Young, Hall and Rosbash provides an opportunity for the development of new mechanisms for influencing the rhythms of the human body.

Prize history

The founder of the Alfred Nobel Prize in his will entrusted the selection of the laureate in physiology and medicine to the Karolinska Institute in Stockholm, founded in 1810 and is one of the leading educational and scientific medical centers the world. The University's Nobel Committee consists of five permanent members, who, in turn, have the right to invite experts for consultations. The list of nominees for this year's award numbered 361 names.

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

In 2017, the amount of the award 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. The prizes in physiology and medicine, physics, chemistry and literature will be presented in Stockholm. The Peace Prize, according to Nobel's will, is awarded on the same day in Oslo.

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The Nobel Prize in Physiology or Medicine in 2017 was awarded for the discovery of genes that determine the work of the biological clock - an intracellular mechanism that controls the cyclical fluctuations of biological processes associated with the change of day and night. Daily subsistence 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. For the first time, the idea of ​​a biological clock arose in the 17th century, when the French astronomer Jean-Jacques de Meran discovered that the circadian rhythm of the movement of plant leaves does not disappear even in the dark: it is rigidly "programmed" and not caused by the action of the environment.

From that moment on, the study of the phenomenon of the biological clock began. It turned out that almost all living organisms are cyclical processes with a daily or circadian 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 the diurnal rhythm, although the period of this rhythm may be longer / less 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 gene (from period) was discovered in the fruit fly. The authors of this discovery, Seymour Benzer and his student Ronald Konopka of California Institute of Technology, conducted a large-scale experiment, working with hundreds of laboratory lines of flies obtained by chemical mutagenesis. Scientists noticed that with the same period of illumination in some flies, the period of the daily rhythm of sleep and wakefulness became either significantly less than the usual day (19 hours), or more (28 hours); in addition, "arrhythmias" with a completely asynchronous cycle were found. In an effort 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 laureates 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 encoded by it changes with a daily periodicity, reaching a peak at night and decreasing during the day.

This discovery gave a new impetus to research, the goal of which is to understand why mechanisms circadian rhythms work exactly this way, and not otherwise, why the daily period may differ for different individuals, but at the same time it turns out to be resistant to action external factors such as temperature (Pittendrich, 1960). Thus, the work carried out on cyanobacteria (blue-green algae) showed that with an increase in temperature by 10 ° C, 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 almost order! This fact has become a real challenge, since all biochemical reactions must obey the rules of chemical kinetics.

Now scientists have agreed 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 the PER protein level. With an increase in temperature, the production of not only proteins participating in the formation of the circadian cycle increases, but also other proteins that inhibit it, as a result, the work of the biological clock does not go astray.

The basic mechanisms of circadian rhythms are currently well understood, although many details remain unexplained. So, it is not clear how several "clocks" can coexist simultaneously in one organism: how the processes occurring 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. The 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 an organism under extreme conditions, for example, in the Arctic, where natural factors of synchronization of circadian rhythms do not work under conditions of polar day and night. There is convincing evidence that with a long stay in such conditions in humans, the daily rhythms of a number of functions significantly change (Moshkin, 1984). We now recognize that this factor can have a significant impact on human health, and knowledge of the molecular basis of circadian rhythms should help in identifying gene variants that will be "useful" 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 more. The effectiveness of some drugs and their side effects... In case of a forced discrepancy between internal and external "clocks" (for example, due to latitudinal flight or work in the night shift), various dysfunctions of the body can be observed, from disorder gastrointestinal tract and of cardio-vascular system to depression, while also increasing 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. Influence of the natural light regime on the biorhythms of polar explorers // Human Physiology. 1984,10 (1): 126-129.

Prepared by Tatiana Morozova

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

Each of us knows what an ordinary clock is, we measure time with a pendulum. But it turns out that almost all living things have their own internal clocks, and instead of a pendulum, a change of day and night "works" in us, which are a consequence of the rotation of the Earth around its axis, "Professor of the Skolkovo Institute of Science and Technology, professor of Rutgers University told the 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 the emergence of life, all living things had to adapt to such a change. Turn on these little clocks in every cell of every organism. And live by them. In accordance with their "indications" to change their physiology - to run, sleep, eat and so on.

The current laureates in the late 70s decided to look inside this watch and understand how it works. To do this, they studied fruit flies, selected insects with mutations, in which the sleep and wakefulness cycles were altered. For example, some people generally slept in a completely disorderly manner. So it was possible to identify genes that are responsible for the cycles to be correct and coordinated.

And then scientists figured out the molecular background of this watch, - 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 a fluctuation in concentration is 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 also in all living things. It was invented by nature to count the 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.

Evaluating the award of this prize, a number of experts already declare that this is a "quiet 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 has become a boom in recent years. “I don’t agree with this opinion,” says Severinov. “Editing the genome will have time to get its prize, and this is not really a discovery, but rather a genetic technique. And the cell clock is a real, deep fundamental science, it explains how the world works.

It should be noted that the forecast of the Thomson Reuters company, which has been predicting the winners since 2002 and most often in comparison with competitors guesses the winners, this time was wrong. They were betting on American cancer scientists.

The ceremony of awarding the laureates will take place according to tradition on December 10, the day of the death of the founder of the Nobel Prizes - Swedish entrepreneur and inventor Alfred Nobel (1833-1896). The amount of the Nobel Prize in 2017 is nine million Swedish kronor (million US dollars).

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