Prize in Physiology and Medicine. Nobel Prize Laureates in Medicine Named Nobel Prize Laureates in Medicine Named

Every year, on December 10, one of the most prestigious awards in the field of scientific achievements, the Nobel Prize, is awarded in Stockholm. On Monday, October 1, it became known names of the first Nobel laureates of 2018. 70-year-old University of Texas professor James Ellison and his 76-year-old colleague Tasuku Honjo from Kyoto University received the highest award for their significant contribution to cancer therapy.

"So simple!" will tell you the latest and explain what a fundamentally new approach to cancer treatment the scientists proposed and how it will change modern medicine.

Nobel Prize in Medicine

The concept of “cancer” is not just one disease, there are a lot of them, and they are all characterized by the uncontrolled growth of abnormal cells that can absorb completely healthy organs and tissues of the human body. Cancer takes the lives of hundreds of people every hour, and for modern healthcare this disease is the biggest problem and one of the most serious challenges.

The Nobel laureates put forward an extremely innovative approach to cancer therapy: James Ellison and Tasuku Honjo showed how to “take the brakes off the immune system” and use the body’s own powers to fight a terrible disease.

“This year’s laureates have shown how different strategies to curb the immune system can be used to treat cancer. Their joint discovery is a significant milestone in the fight against cancer.", said the Royal Swedish Academy of Sciences.

“Immune therapy does not have an independent antitumor effect - it forces immune cells to kill the tumor. True, releasing the brake in some cases leads to the immune system attacking its own cells.

This is somewhat similar to autoimmune diseases, and the problem is no small one. Frequent side effects are fatigue, cough, nausea, rash, itching, loss of appetite, diarrhea, inflammation of the intestines and lungs,” explains oncologist Mikhail Laskov.

The domestic oncologist has no doubt that such therapy will be a real breakthrough: “There are diseases that are difficult to treat. These are melanoma, lung cancer, pancreatic cancer, stomach cancer and so on. Immunotherapy has significantly improved outcomes for some of these diseases, namely melanoma and lung cancer. Some cancer patients, according to the results of the study, can live for several years without signs of the disease.".

And if previously such therapy was used mainly for metastatic cancer in almost hopeless cases, now such drugs are prescribed as postoperative therapy, for example, for melanoma.

Ellison and Honjo have inspired researchers around the world to combine different strategies to activate the immune system to combat cancer cells as effectively as possible. Currently, many tests and clinical trials are being carried out in the field of cancer immunotherapy and new control proteins discovered by Nobel laureates are being tested as targets.

Many immunotherapy drugs There are cancers in Russia, but they are all very expensive and accessible to a few. “These are, for example, pembrolizumab (Keytruda), nivolumab (Opdivo), ipilimumab (Yervoy) and atezolizumab (Tecentriq). Unfortunately, it cannot be said that such medicines are available to everyone.

According to one tariff, a state hospital can allocate 180 thousand rubles for it, although in real life the drug will cost 300 or more. That is, they simply won’t prescribe the medicine because there is nothing to buy it with,” explains Mikhail Laskov.

In an attempt to defeat the deadly disease, scientists have tried to involve the immune system in the fight against cancer for 100 years, but all attempts were in vain. Until the discoveries made by James Ellison and Tasuku Honjo, clinical progress in this area was very modest.

The 2018 Nobel Prize in Physiology or Medicine was awarded to James Ellison and Tasuku Honjo for their developments in cancer therapy by activating the immune response. The announcement of the winner is broadcast live on the Nobel Committee website. More information about the merits of scientists can be found in the press release of the Nobel Committee.

Scientists have developed a fundamentally new approach to cancer therapy, different from previously existing radiotherapy and chemotherapy, which is known as “inhibition of checkpoints” of immune cells (you can read a little about this mechanism in our article on immunotherapy). Their research focuses on how to reverse the suppression of immune system cells by cancer cells. Japanese immunologist Tasuku Honjo from Kyoto University discovered the PD-1 (Programmed Cell Death Protein-1) receptor on the surface of lymphocytes, the activation of which leads to the suppression of their activity. His American colleague James Allison from the Anderson Cancer Center at the University of Texas was the first to show that an antibody that blocks the CTLA-4 inhibitory complex on the surface of T-lymphocytes, introduced into the body of animals with a tumor, leads to the activation of an antitumor response and tumor reduction.

The research of these two immunologists led to the emergence of a new class of anticancer drugs based on antibodies that bind to proteins on the surface of lymphocytes or cancer cells. The first such drug, ipilimumab, a CTLA-4 blocking antibody, was approved in 2011 for the treatment of melanoma. The anti-PD-1 antibody, Nivolumab, was approved in 2014 against melanoma, lung cancer, kidney cancer and several other types of cancer.

“Cancer cells, on the one hand, are different from our own, but on the other hand, they are them. The cells of our immune system recognize this cancer cell, but do not kill it,” explained N+1 Professor of the Skolkovo Institute of Science and Technology and Rutgers University Konstantin Severinov. - The authors, among other things, discovered the PD-1 protein: if you remove this protein, immune cells begin to recognize cancer cells and can kill them. This is the basis for cancer therapy, which is now widely used even in Russia. Such PD-1 inhibitory drugs have become an essential component of the modern cancer-fighting arsenal. He is very important, without him it would be much worse. These people really gave us a new way to control cancer - people live because there are such therapies.”

Oncologist Mikhail Maschan, deputy director of the Dima Rogachev Center for Pediatric Hematology, Oncology and Immunology, says that immunotherapy has become a revolution in the field of cancer treatment.

“In clinical oncology, this is one of the largest events in history. We are now just beginning to reap the benefits that the development of this type of therapy has brought, but the fact that it turned the situation in oncology upside down became clear about ten years ago - when the first clinical results of the use of drugs created on the basis of these ideas appeared,” Maschan said in conversation with N+1.

With a combination of checkpoint inhibitors, he says, long-term survival, essentially a cure, can be achieved in 30 to 40 percent of patients with some types of tumors, particularly melanoma and lung cancer. He noted that new developments based on this approach will appear in the near future.

“This is the very beginning of the path, but there are already many types of tumors - lung cancer and melanoma, and a number of others, for which therapy has shown effectiveness, but even more - for which it is only being studied, its combinations with conventional types of therapy are being studied. This is the very beginning, and a very promising beginning. The number of people who have survived thanks to this therapy is already measured in tens of thousands,” Maschan said.

Every year, on the eve of the announcement of the winners, analysts try to guess who will receive the prize. This year, Clarivate Analytics, which traditionally makes predictions based on the citations of scientific papers, included in the Nobel List Napoleone Ferrara, who discovered a key factor in the formation of blood vessels, Minoru Kanehisa, who created the KEGG database, and Salomon Snyder, who worked on receptors for key regulatory molecules in the nervous system. Interestingly, the agency listed James Ellison as a possible Nobel Prize winner in 2016, which means that his prediction came true quite soon. You can find out who the agency is considering as laureates in the remaining Nobel disciplines - physics, chemistry and economics - from our blog. This year a prize will be awarded for literature.

Daria Spasskaya

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 wrote 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 adaptation to different conditions of day and night, organisms developed internal biological clocks - 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.

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 to Emil von Behring 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 a prize in medicine twice, although there were cases when an existing laureate was nominated (for example, our Ivan Pavlov). If you do not take into account the 2017 award, the average age of the laureate was 58 years. 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).

Anastasia Ksenofontova

The Nobel Committee has announced the winners of the 2018 Prize in Physiology or Medicine. This year's award will go to James Ellison from the Cancer Center. M.D. Anderson University of Texas and Tasuku Honjo of Kyoto University for "discoveries in inhibiting the immune system to more effectively attack cancer cells." Scientists have discovered how a cancer tumor “deceives” the immune system. This made it possible to create effective anticancer therapy. Read more about the discovery in RT's material.

2018 Nobel Laureates in Physiology or Medicine James Allison and Tasuku Honjo
TT News Agency/Fredrik Sandberg via REUTERS

The Nobel Committee of the Karolinska Institute in Stockholm announced the 2018 prize winners on Monday, October 1. The award will be presented to American James Ellison from the Cancer Center. M.D. Anderson University of Texas and Japan's Tasuku Honjo of Kyoto University for their "discovery of inhibiting the immune system to more effectively attack cancer cells." Scientists have discovered how a cancer tumor “deceives” the immune system. This made it possible to create effective anticancer therapy.

Cell Wars

Among traditional cancer treatments, chemotherapy and radiation therapy are the most common. However, there are also “natural” methods of treating malignant tumors, including immunotherapy. One of its promising areas is the use of inhibitors of “immune checkpoints” located on the surface of lymphocytes (cells of the immune system).

The fact is that activation of “immune checkpoints” suppresses the development of the immune response. Such a “control point” is, in particular, the CTLA4 protein, which Ellison has been studying for many years.

In the coming days, award winners in other categories will be announced. The committee will announce the physics laureate on Tuesday, October 2. On October 3, the name of the winner of the Nobel Prize in Chemistry will be announced. The Nobel Peace Prize will be awarded on October 5 in Oslo, and the winner in the field of economics will be announced on October 8.

The winner of the literature prize will not be named this year; it will be announced only in 2019. This decision was made by the Swedish Academy due to the fact that the number of its members had decreased and a scandal had erupted around the organization. 18 women have accused the husband of poet Katharina Frostenson, who was elected to the academy in 1992, of sexual harassment. As a result, seven people left the Swedish Academy, including Frostenson herself.

In 2016, the Nobel Committee awarded the Prize in Physiology or Medicine to the Japanese scientist Yoshinori Ohsumi for the discovery of autophagy and deciphering its molecular mechanism. Autophagy is the process of processing spent organelles and protein complexes; it is important not only for the economical management of cellular management, but also for the renewal of cellular structure. Deciphering the biochemistry of this process and its genetic basis presupposes the possibility of monitoring and managing the entire process and its individual stages. And this gives researchers obvious fundamental and applied prospects.

Science rushes forward at such an incredible pace that a non-specialist does not have time to realize the importance of the discovery, and the Nobel Prize is already awarded for it. In the 80s of the last century, in biology textbooks in the section on cell structure, one could learn, among other organelles, about lysosomes - membrane vesicles filled with enzymes inside. These enzymes are aimed at breaking down various large biological molecules into smaller blocks (it should be noted that at that time our biology teacher did not yet know why lysosomes were needed). They were discovered by Christian de Duve, for which he was awarded the Nobel Prize in Physiology or Medicine in 1974.

Christian de Duve and his colleagues separated lysosomes and peroxisomes from other cellular organelles using a then new method - centrifugation, which allows particles to be sorted by mass. Lysosomes are now widely used in medicine. For example, their properties are the basis for targeted delivery of drugs to damaged cells and tissues: a molecular drug is placed inside a lysosome due to the difference in acidity inside and outside it, and then the lysosome, equipped with specific labels, is sent to the affected tissue.

Lysosomes are indiscriminate by the nature of their activity - they break up any molecules and molecular complexes into their component parts. Narrower “specialists” are proteasomes, which are aimed only at the breakdown of proteins (see: “Elements”, 11/05/2010). Their role in cellular economy can hardly be overestimated: they monitor enzymes that have expired and destroy them as needed. This period, as we know, is defined very precisely - exactly as much time as the cell performs a specific task. If the enzymes were not destroyed after its completion, then the ongoing synthesis would be difficult to stop in time.

Proteasomes are present in all cells without exception, even in those without lysosomes. The role of proteasomes and the biochemical mechanism of their work was studied by Aaron Ciechanover, Avram Gershko and Irwin Rose in the late 1970s and early 1980s. They discovered that proteasomes recognize and destroy proteins that are tagged with the protein ubiquitin. The binding reaction with ubiquitin costs ATP. In 2004, these three scientists received the Nobel Prize in Chemistry for their research on ubiquitin-dependent protein degradation. In 2010, while looking through a school curriculum for gifted English children, I saw a series of black dots in a picture of a cell structure that were labeled as proteasomes. However, the schoolteacher at that school could not explain to the students what it was and what these mysterious proteasomes were for. There were no more questions with the lysosomes in that picture.

Even at the beginning of the study of lysosomes, it was noticed that some of them contained parts of cellular organelles. This means that in lysosomes not only large molecules are disassembled into parts, but also parts of the cell itself. The process of digesting one's own cellular structures is called autophagy - that is, “eating oneself.” How do parts of cellular organelles get into the lysosome containing hydrolases? This issue began to be studied back in the 80s, who studied the structure and functions of lysosomes and autophagosomes in mammalian cells. He and his colleagues showed that autophagosomes appear en masse in cells if they are grown in a low-nutrient medium. In this regard, a hypothesis arose that autophagosomes are formed when a backup source of nutrition is needed - proteins and fats that are part of the extra organelles. How are these autophagosomes formed, are they needed as a source of additional nutrition or for other cellular purposes, how do lysosomes find them for digestion? All these questions had no answers in the early 90s.

Taking up independent research, Ohsumi focused his efforts on studying yeast autophagosomes. He reasoned that autophagy must be a conserved cellular mechanism, therefore, it is more convenient to study it on simple (relatively) and convenient laboratory objects.

In yeast, autophagosomes are located inside vacuoles and then disintegrate there. Their utilization is carried out by various proteinase enzymes. If proteinases in a cell are defective, then autophagosomes accumulate inside vacuoles and do not dissolve. Osumi took advantage of this property to produce a yeast culture with an increased number of autophagosomes. He grew yeast cultures on poor media - in this case, autophagosomes appear in abundance, delivering a food reserve to the starving cell. But his cultures used mutant cells with non-functioning proteinases. So, as a result, the cells quickly accumulated a mass of autophagosomes in vacuoles.

Autophagosomes, as follows from his observations, are surrounded by single-layer membranes, inside of which there can be a wide variety of contents: ribosomes, mitochondria, lipid and glycogen granules. By adding or removing protease inhibitors to cultures of non-mutant cells, it is possible to increase or decrease the number of autophagosomes. So in these experiments it was demonstrated that these cell bodies are digested by proteinase enzymes.

Very quickly, in just a year, using the random mutation method, Ohsumi identified 13–15 genes (APG1–15) and corresponding protein products involved in the formation of autophagosomes (M. Tsukada, Y. Ohsumi, 1993. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae). Among colonies of cells with defective proteinase activity, he selected under a microscope those that did not contain autophagosomes. Then, by cultivating them separately, he found out which genes they had were damaged. It took his group another five years to decipher, to a first approximation, the molecular mechanism of how these genes work.

It was possible to find out how this cascade works, in what order and how these proteins bind to each other so that the result is an autophagosome. By 2000, the picture of membrane formation around damaged organelles that need to be recycled became clearer. The single lipid membrane begins to stretch around these organelles, gradually encircling them until the ends of the membrane come close to each other and merge to form the double membrane of the autophagosome. This vesicle is then transported to the lysosome and fuses with it.

The process of membrane formation involves APG proteins, analogues of which Yoshinori Ohsumi and his colleagues discovered in mammals.

Thanks to Ohsumi's work, we saw the entire process of autophagy in dynamics. The starting point of Osumi's research was the simple fact of the presence of mysterious small bodies in cells. Now researchers have the opportunity, albeit hypothetical, to control the entire process of autophagy.

Autophagy is necessary for the normal functioning of the cell, since the cell must be able not only to renew its biochemical and architectural economy, but also to utilize unnecessary things. In a cell there are thousands of worn-out ribosomes and mitochondria, membrane proteins, spent molecular complexes - all of them need to be economically processed and put back into circulation. This is a kind of cellular recycling. This process not only provides a certain saving, but also prevents rapid aging of the cell. Impaired cellular autophagy in humans leads to the development of Parkinson's disease, type II diabetes, cancer and some disorders characteristic of old age. Controlling the process of cellular autophagy obviously has enormous prospects, both fundamentally and in applications.