The annual Nobel Week began in Stockholm on Monday with the announcement of the winners of the Prize in Physiology or Medicine. The Nobel Committee announced that the 2017 prize was awarded to researchers Geoffrey Hall, Michael Rosbash and Michael Young for
discovery of molecular mechanisms that control circadian rhythms - cyclical fluctuations in the intensity of various biological processes associated with the change of day and night.
Life on Earth is adapted to the rotation of the planet. It has long been established that all living organisms, from plants to humans, have a biological clock that allows the body to adapt to changes that occur during the day in the environment. The first observations in this area were made at the beginning of our era, and more thorough research began in the 18th century.
By the 20th century, the circadian rhythms of plants and animals had been studied quite fully, but exactly how the “internal clock” worked remained a secret. This secret was discovered by American geneticists and chronobiologists Hall, Rosbash and Young.
Fruit flies became a model organism for research. A team of researchers managed to discover a gene in them that controls biological rhythms.
Scientists have found that this gene encodes a protein that accumulates in cells during the night and is destroyed during the day.
Subsequently, they identified other elements responsible for the self-regulation of the “cellular clock” and proved that the biological clock works in a similar way in other multicellular organisms, including humans.
Our internal clocks adapt our physiology to completely different times of day. Our behavior, sleep, metabolism, body temperature, and hormone levels depend on them. Our well-being worsens when there is a discrepancy between the functioning of the internal clock and the environment. Thus, the body reacts to a sudden change in time zone with insomnia, fatigue, and headaches. Jet lag has been included in the International Classification of Diseases for several decades. The discrepancy between lifestyle and the rhythms dictated by the body leads to an increased risk of developing many diseases.
The first documented experiments with internal clocks were carried out in the 18th century by French astronomer Jean-Jacques de Meran. He discovered that mimosa leaves droop at nightfall and spread out again in the morning. When de Meran decided to test how the plant would behave without access to light, it turned out that the leaves of the mimosa fell and rose regardless of the lighting - these phenomena were associated with changes in the time of day.
Subsequently, scientists found that other living organisms also have similar phenomena that adapt the body to changes in conditions during the day.
They were called circadian rhythms, from the words circa - "around" and dies - "day". In the 1970s, physicist and molecular biologist Seymour Benzer wondered whether a gene that controlled circadian rhythms could be identified. He managed to do this, the gene was named period, but the control mechanism remained unknown.
In 1984, Hall, Roybash and Young managed to recognize him.
They isolated the necessary gene and found that it is responsible for the process of accumulation and destruction of the protein associated with it (PER) in cells, depending on the time of day.
The next task for the researchers was to understand how circadian fluctuations arise and are maintained. Hall and Rosbash suggested that the accumulation of the protein blocks the gene from working, thereby regulating the protein content in cells.
However, in order to block the operation of a gene, the protein produced in the cytoplasm must reach the cell nucleus, where the genetic material is located. It turns out that PER does indeed integrate into the nucleus at night, but how does it get there?
In 1994, Young discovered another gene, timeless, which encodes the protein TIM, which is essential for normal circadian rhythms.
He found that when TIM binds to PER, they are able to enter the cell nucleus, where they block the period gene through feedback inhibition.
But some questions still remained unanswered. For example, what controlled the frequency of circadian oscillations? Young subsequently discovered another gene, doubletime, responsible for the formation of the DBT protein, which delayed the accumulation of the PER protein. All these discoveries helped to understand how the oscillations are adapted to the 24-hour daily cycle.
Subsequently, Hall, Roybash and Young made several more discoveries that complemented and refined the previous ones.
For example, they identified a number of proteins necessary for the activation of the period gene, and also revealed the mechanism by which the internal clock is synchronized with light.
The most likely candidates for Nobel Prize in this area were named virologist Yuan Chang and her husband, oncologist Patrick Moore, who discovered Kaposi's sarcoma-associated herpes virus type eight; Professor Lewis Cantley, who discovered the signaling pathways of phosphoinositide 3-kinase enzymes and studied their role in tumor growth; and Professor Karl Friston, who made major contributions to the analysis of data obtained by brain imaging methods.
In 2016, the Japanese Yoshinori Ohsumi won the prize for his discovery of the mechanism of autophagy - the process of degradation and recycling of intracellular waste.
Nobel Prize in Physiology or Medicine. A group of scientists from the USA became its owners. Michael Young, Jeffrey Hall and Michael Rosbash received the award for their discovery of the molecular mechanisms that control circadian rhythm.
According to Alfred Nobel's will, the prize is awarded to "whoever makes an important discovery" in this field. The editors of TASS-DOSSIER have prepared material about the procedure for awarding this prize and its laureates.
Awarding the Prize and Nominating Candidates
The Nobel Assembly of the Karolinska Institute, located in Stockholm, is responsible for awarding the prize. The Assembly consists of 50 professors of the institute. Its working body is the Nobel Committee. It consists of five people elected by the assembly from among its members for three years. The Assembly meets several times a year to discuss candidates selected by the committee, and on the first Monday in October, it elects the laureate by majority vote.
Scientists have the right to nominate for the prize different countries, including members of the Nobel Assembly of the Karolinska Institute and winners of the Nobel Prizes in Physiology and Medicine and in Chemistry, who received special invitations from the Nobel Committee. Candidates can be proposed from September until January 31 of the following year. There are 361 people vying for the award in 2017.
Laureates
The prize has been awarded since 1901. The first laureate was the German physician, microbiologist and immunologist Emil Adolf von Behring, who developed a method of immunization against diphtheria. In 1902, the award was given to Ronald Ross (Great Britain), who studied malaria; in 1905 - Robert Koch (Germany), who studied the causative agents of tuberculosis; in 1923 - Frederick Banting (Canada) and John MacLeod (Great Britain) who discovered insulin; in 1924 - the founder of electrocardiography, Willem Einthoven (Holland); in 2003, Paul Lauterbur (USA) and Peter Mansfield (UK) developed the method of magnetic resonance imaging.
According to the Nobel Committee of the Karolinska Institutet, the most famous prize is still the 1945 prize awarded to Alexander Fleming, Ernest Chain and Howard Florey (Great Britain), who discovered penicillin. Some discoveries have lost their significance over time. Among them is the lobotomy method used in the treatment mental illness. The Portuguese António Egas-Moniz received the prize for its development in 1949.
In 2016, the prize was awarded to Japanese biologist Yoshinori Ohsumi “for the discovery of the mechanism of autophagy” (the process of a cell processing unnecessary contents in it).
According to the Nobel website, today there are 211 people on the list of prize winners, including 12 women. Among the laureates are two of our compatriots: physiologist Ivan Pavlov (1904; for work in the field of digestive physiology) and biologist and pathologist Ilya Mechnikov (1908; for research on immunity).
Statistics
In 1901-2016, the Prize in Physiology or Medicine was awarded 107 times (in 1915-1918, 1921, 1925, 1940-1942, the Nobel Assembly of the Karolinska Institutet was unable to choose a laureate). 32 times the prize was divided between two laureates and 36 times between three. The average age of the laureates is 58 years. The youngest is Canadian Frederick Banting, who received the prize in 1923 at the age of 32, the oldest is 87-year-old American Francis Peyton Rose (1966).
The Nobel Committee today announced the winners of the 2017 Prize in Physiology or Medicine. This year the prize will travel to the United States again, with Michael Young of The Rockefeller University in New York, Michael Rosbash of Brandeis University and Jeffrey Hall of the University of Maine sharing the award. According to the decision of the Nobel Committee, these researchers were awarded “for their discoveries of the molecular mechanisms that control circadian rhythms.”
It must be said that in the entire 117-year history of the Nobel Prize, this is perhaps the first prize for studying the sleep-wake cycle, or for anything related to sleep in general. The famous somnologist Nathaniel Kleitman did not receive the award, and Eugene Azerinsky, who made the most outstanding discovery in this field, who discovered REM sleep (REM - rapid eye movement, rapid eye movement phase), generally received only a PhD degree for his achievement. It is not surprising that in numerous forecasts (we talk about them in our article) any names and any research topics were mentioned, but not those that attracted the attention of the Nobel Committee.
Why was the award given?
So, what are circadian rhythms and what exactly did the laureates discover, who, according to the secretary of the Nobel Committee, greeted the news of the award with the words “Are you kidding me?”
Jeffrey Hall, Michael Rosbash, Michael Young
Circa diem translated from Latin as “around the day.” It just so happens that we live on planet Earth, where day gives way to night. And in the course of adapting to different conditions day and night in organisms, internal biological clocks appeared - the rhythms of the biochemical and physiological activity of the body. It was possible to show that these rhythms have an exclusively internal nature only in the 1980s, by sending mushrooms into orbit Neurospora crassa. Then it became clear that circadian rhythms do not depend on external light or other geophysical signals.
The genetic mechanism of circadian rhythms was discovered in the 1960s and 1970s by Seymour Benzer and Ronald Konopka, who studied mutant lines of Drosophila with different circadian rhythms: in wild-type flies the circadian rhythm oscillations had a period of 24 hours, in some mutants - 19 hours, in others - 29 hours, and for others there was no rhythm at all. It turned out that the rhythms are regulated by the gene PER - period. The next step, which helped to understand how such fluctuations in the circadian rhythm appear and are maintained, was taken by the current laureates.
Self-regulating clock mechanism
Geoffrey Hall and Michael Rosbash proposed that the gene encoded period The PER protein blocks the operation of its own gene, and this feedback loop allows the protein to prevent its own synthesis and cyclically, continuously regulate its level in cells.
The picture shows the sequence of events over a 24 hour oscillation. When the gene is active, the PER mRNA is produced. It exits the nucleus into the cytoplasm, becoming a template for the production of the PER protein. The PER protein accumulates in the cell nucleus when the activity of the period gene is blocked. This closes the feedback loop.
The model was very attractive, but a few pieces of the puzzle were missing to complete the picture. To block gene activity, the protein needs to get into the cell nucleus, where the genetic material is stored. Jeffrey Hall and Michael Rosbash showed that the PER protein accumulates in the nucleus overnight, but they did not understand how it managed to get there. In 1994, Michael Young discovered a second circadian rhythm gene, timeless(English: “timeless”). It encodes the TIM protein, which is needed for the normal functioning of our internal clock. In his elegant experiment, Young demonstrated that only by binding to each other can TIM and PER pair up to enter the cell nucleus, where they block the gene period.
Simplified illustration of the molecular components of circadian rhythms
This feedback mechanism explained the reason for the oscillations, but it was not clear what controlled their frequency. Michael Young found another gene doubletime. It contains the DBT protein, which can delay the accumulation of the PER protein. This is how the oscillations are “debugged” so that they coincide with the daily cycle. These discoveries revolutionized our understanding of the key mechanisms of the human biological clock. Over the following years, other proteins were found that influence this mechanism and maintain its stable operation.
For example, this year's laureates discovered additional proteins that cause the gene period work, and proteins with the help of which light synchronizes the biological clock (or, with a sharp change in time zones, causes jet lag).
About the award
Let us recall that the Nobel Prize in Physiology or Medicine (it is worth noting that in the original title the preposition “or” sounds in place of “and”) is one of the five prizes defined by Alfred Nobel’s will in 1895 and, if we follow the letter of the document, should be awarded annually "for a discovery or invention in the field of physiology or medicine" made in the previous year and bringing maximum benefit to humanity. However, it seems that the “principle of last year” was almost never followed.
Now the Prize in Physiology or Medicine is traditionally awarded at the very beginning of the Nobel week, on the first Monday in October. It was first awarded in 1901 for the creation of serum therapy for diphtheria. In total, throughout history, the prize was awarded 108 times, in nine cases: in 1915, 1916, 1917, 1918, 1921, 1925, 1940, 1941 and 1942 - the prize was not awarded.
From 1901 to 2017, the prize was awarded to 214 scientists, a dozen of whom were women. So far there has not been a case where someone received the prize in medicine twice, although there have been cases when an existing laureate was nominated (for example, ours). If you do not take into account the 2017 award, then average age The laureate was 58 years old. The youngest Nobel laureate in the field of physiology and medicine was the 1923 laureate Frederick Banting (award for the discovery of insulin, age 32 years), the oldest was the 1966 laureate Peyton Rose (award for the discovery of oncogenic viruses, age 87 years).
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 within living organisms, including humans, of biological clocks 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 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 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 found itself in constant darkness? After performing a simple experiment, the researcher discovered that, regardless of the presence of sunlight, the leaves of the experimental mimosa continued to make their usual daily movements. As it turned 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 the 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
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 cellular protein levels occurred, but it 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 teaching staff Rockefeller University in New York.
Translation of materials from the Royal Swedish Academy of Sciences.
On October 2, 2017, the Nobel Committee announced the names of the 2017 Nobel Prize laureates in physiology or medicine. 9 million Swedish kronor will be divided equally by American biologists Jeffrey C. Hall, Michael Rosbash and Michael W. Young for their discovery of the molecular mechanism of the biological clock, that is, the endlessly looped circadian rhythm of the life of organisms, including humans.
Over millions of years, life has adapted to the rotation of the planet. It has long been known that we have an internal biological clock that anticipates and adapts to the time of day. In the evening I want to fall asleep, and in the morning I want to wake up. Hormones are released into the blood strictly according to a schedule, and a person’s abilities/behavior - coordination, reaction speed - also depend on the time of day. But how does this internal clock work?
The discovery of the biological clock is attributed to the French astronomer Jean-Jacques de Meran, who in the 18th century noticed that mimosa leaves open towards the Sun during the day and close at night. He wondered how the plant would behave if placed in pitch darkness. It turned out that even in the dark, the mimosa followed the plan - it was as if it had an internal clock.
Later, such biorhythms were found in other plants, animals and humans. Almost all living organisms on the planet react to the Sun: the circadian rhythm is tightly built into earthly life, into the metabolism of all life on the planet. But how this mechanism works remained a mystery.
The Nobel laureates isolated a gene that controls the daily biological rhythm in fruit flies (humans and flies have many common genes due to the presence of common ancestors). They made their first discovery in 1984. The discovered gene was named period.
Gene period encodes the PER protein, which accumulates in cells at night and is destroyed during the day. PER protein concentration varies on a 24-hour schedule in accordance with the circadian rhythm.
They then identified additional components of the protein and fully uncovered the self-sustaining intracellular mechanism of circadian rhythm - in this unique response, the PER protein blocks gene activity period, that is, PER blocks synthesis of itself, but gradually breaks down over the course of the day (see diagram above). This is a self-sufficient endlessly looping mechanism. It works on the same principle in other multicellular organisms.
After the discovery of the gene, the corresponding protein, and the overall mechanism of the internal clock, a few more pieces of the puzzle were missing. Scientists knew that the PER protein accumulates in the cell nucleus at night. They also knew that the corresponding mRNA is produced in the cytoplasm. It was not clear how the protein gets from the cytoplasm into the cell nucleus. In 1994, Michael Young discovered another gene timeless, which encodes the TIM protein, also necessary for the normal functioning of the internal clock. He proved that if TIM attaches to PER, then a pair of proteins can penetrate into the cell nucleus, where they block gene activity period, thus closing the endless cycle of PER protein production.
It turns out that this mechanism adapts our internal clock to the time of day with exquisite precision. It regulates different critical functions body, including human behavior, hormone levels, sleep, body temperature and metabolism. A person feels unwell if there is a temporary discrepancy between external conditions and its internal biological clock, for example, when traveling long distances in different time zones. There is also evidence that chronic mismatch between lifestyle and body clock is associated with an increased risk of various diseases, including diabetes, obesity, cancer and cardiovascular disease.
Later, Michael Young identified another gene doubletime, encoding the DBT protein, which slows down the accumulation of the PER protein in the cell and allows the body to more accurately adjust to the 24-hour day.
In subsequent years the current Nobel laureates looked in more detail at the involvement of other molecular components in the circadian rhythm, they found additional proteins that are involved in gene activation period, and also found out the mechanisms of how light helps synchronize the biological clock with external environmental conditions.
From left to right: Michael Rozbash, Michael Young, Geoffrey Hall
Research into the internal clock mechanism is far from complete. We only know the main parts of the mechanism. Circadian biology - the study of the internal clock and circadian rhythm - has emerged as a separate rapidly developing area of research. And all this happened thanks to the three current Nobel Prize winners.
Experts have been discussing for several years that the molecular mechanism of circadian rhythms would be awarded the Nobel Prize - and now this event has finally happened.