Creator of fertilizers and chemical weapons
One of the most controversial Nobel Prize winners is Fritz Haber. The Prize in Chemistry was awarded to him in 1918 for the invention of a method for the synthesis of ammonia - a discovery of decisive importance for the production of fertilizers. However, he is also known as the "father of chemical weapons" because of his work on the poison gas chlorine used during the First World War.
Deadly discovery
Another German scientist, Otto Han (pictured in the center) was awarded the Nobel Prize in 1945 for his discovery of the fission of the atomic nucleus. Although he never worked on the military application of this discovery, it led directly to the development of nuclear weapons. Gan received the award a few months after the nuclear bombs were dropped on Hiroshima and Nagasaki.
From Friedman to Obama: the most controversial Nobel laureates
Breakthrough banned
Swiss chemist Paul Müller received the Medicine Prize in 1948 for his discovery that DDT could effectively kill insects that spread diseases such as malaria. The use of the pesticide has saved millions of lives in its time. However, later environmentalists began to argue that DDT poses a threat to human health and harms nature. Today, its use is banned worldwide.
From Friedman to Obama: the most controversial Nobel laureates
An inconvenient reward
Because of its overt and indirect political overtones, the Peace Prize is perhaps the most controversial of all the Nobel Prizes. In 1935, the German pacifist Carl von Ossietzky received it for exposing German secret rearmament. Ossietzky himself was in prison on charges of treason, and an outraged Hitler accused the committee of interfering in German internal affairs.
From Friedman to Obama: the most controversial Nobel laureates
(Possible) Peace Award
The decision of the Norwegian Committee to award the Peace Prize to US Secretary of State Henry Kissinger and North Vietnamese leader Le Duc Tho in 1973 faced harsh criticism. The Nobel Prize was supposed to be a symbol of recognition of merit in achieving a ceasefire during the Vietnam War, but Le Duc Tho refused to receive it. The Vietnam War continued for two more years.
From Friedman to Obama: the most controversial Nobel laureates
Libertarian and dictator
Free market advocate Milton Friedman is one of the most controversial recipients of the Nobel Peace Prize in economics. The committee's decision in 1976 sparked international protests over Friedman's ties to Chilean dictator Augusto Pinochet. Friedman did visit Chile a year earlier, and critics say his ideas inspired a regime where thousands of people were tortured and killed.
From Friedman to Obama: the most controversial Nobel laureates
vain hopes
The Peace Prize, which was shared in 1994 by Palestinian leader Yasser Arafat, Israeli Prime Minister Yitzhak Rabin and Israeli Foreign Minister Shimon Peres, was supposed to provide additional impetus for a peaceful settlement of the conflict in the Middle East. Instead, further negotiations failed, and Rabin was assassinated by an Israeli nationalist a year later.
From Friedman to Obama: the most controversial Nobel laureates
Creepy memoir
Mayan human rights activist Rigoberta Menchu received the Peace Prize in 1992 "for her struggle for social justice". Subsequently, this decision caused a lot of controversy, as falsifications were allegedly discovered in her memoirs. The atrocities she described about the genocide of the indigenous peoples of Guatemala made her famous. However, many are convinced that she deserved the award anyway.
From Friedman to Obama: the most controversial Nobel laureates
Premature Reward
When the Peace Prize was awarded to Barack Obama in 2009, many were surprised, including himself. Less than a year in office by then, he received the award for "tremendous efforts to strengthen international diplomacy." Obama's critics and some supporters felt the award was premature, and he received it before he even had a chance to make a real move.
From Friedman to Obama: the most controversial Nobel laureates
Posthumous award
In 2011, the Nobel Committee named Jules Hoffmann, Bruce Butler, and Ralph Steinman as winners of the Medicine Prize for their discoveries in the field of the immune system. The problem was that a few days earlier, Steinman had died of cancer. According to the rules, the award is not awarded posthumously. But the committee nevertheless awarded it to Steinman, arguing that his death was not yet known at that time.
From Friedman to Obama: the most controversial Nobel laureates
"Greatest Omission"
The Nobel Prize is controversial not only because of who it was awarded to, but also because someone never received it. In 2006, Nobel Committee member Geir Lundestad stated that "undoubtedly the greatest omission in our entire 106-year history was that Mahatma Gandhi never received the Nobel Peace Prize."
The 2017 Nobel Prize in Chemistry has been awarded to Jacques Dubochet, Joachim Frank and Richard Henderson for their development of cryoelectron microscopy, which has made it possible to view the molecules of living organisms in detail - at very high resolution.
Jacques Dubuch is a Swiss, works at the University of Lausanne (University of Lausanne, Switzerland), Joachim Frank is an American from Columbia University (Columbia University, New York, USA), Richard Henderson is a British scientist from Cambridge (MRC Laboratory of Molecular Biology, Cambridge, UK).
It is emphasized that the research of the laureates, which continued in the 70s - 90s of the last century, provided a revolutionary breakthrough in biology, since it made it possible for the first time to look at what was previously completely invisible - at individual biological molecules and even at their constituent atoms.
In fact, scientists have modernized electron microscopy. Previously, inanimate matter was observed with an electron microscope. The laureates adapted it to observe wildlife. They learned how to freeze them in an aqueous solution so that the biomolecules retain their shape and properties, and at the same time "fixed" in a form convenient for observing them.
As a result, with the help of an electron microscope, it became possible to obtain three-dimensional images of the considered living objects. By 2013, the resolution of the method was phenomenal. Images of all sorts of molecular proteins have surfaced, such as those that make bacteria resistant to antibiotics. It was possible to "photograph" even viruses - for example, the Zika virus. What promises the nearest victory over him.
Researchers who have penetrated the microworld note that a detailed picture of an object is the shortest way to understanding its essence. That is, to knowledge. It is simply obvious that the Royal Swedish Academy of Sciences, which awards the Nobel Prizes, shares this opinion.
REFERENCE KP
The current Nobel Prize in Chemistry is the 109th in a row. Among the laureates who have been awarded this most honorable scientific award in the world since 1901, there are 4 women.
British scientist Frederick Sandger, included in the list of "100 geniuses of our time", received the Nobel Prize in Chemistry twice - in 1958 and in 1980. The first time - for determining the exact sequence of amino acids in the insulin molecule. The second - for the development of a method for deciphering the primary structure of DNA.
Last year, the prize went to scientists from France, the US and Holland. Frenchman Jean-Pierre Sauvage, American Sir James Fraser Stoddart and Dutchman Bernard L. Feringa were awarded "for the development and synthesis of molecular machines". The Loureates actually laid the material foundation for nanotechnology.
The 2017 Nobel Prize in Chemistry was awarded for the development of high-resolution cryoelectron microscopy for determining the structures of biomolecules in solutions. The laureates were from the University of Lausanne, Joachim Frank from Columbia University and from the University of Cambridge.
Cryoelectron microscopy is a form of transmission electron microscopy in which a sample is examined at cryogenic temperatures.
The method is popular in structural biology as it allows specimens that have not been stained or otherwise fixed to be observed, showing them in their native environment.
Electron cryomicroscopy slows down the movement of the atoms entering the molecule, which makes it possible to obtain very clear images of its structure. The information obtained about the structure of molecules is extremely important, including for a deeper understanding of chemistry and the development of pharmaceuticals.
Many breakthroughs in science are associated with the successful visualization of objects invisible to the human eye. Optical microscopy has made it possible to prove the existence of microorganisms, look at sperm and eggs, partially study the cellular structure, and even make out chromosomes. The physical limitations of optical telescopes were overcome by electron microscopy, where an electron beam was used instead of a light flux.
However, she also had her flaws. First, a powerful beam of electrons destroyed the biological material. Secondly, in order to accelerate the electrons, a vacuum is needed - accordingly, the drug should also be in the vacuum.
Therefore, it was impossible to study “live” samples with its help.
The contribution of Joachim Frank contributed to the wide dissemination of the method. Back in 1975-1986, he developed an image processing method that consisted in analyzing two-dimensional images obtained using an electron microscope and constructing three-dimensional structures of the objects under study on their basis.
Jacques Dubochet suggested using rapidly chilled water to preserve samples. Cooling samples as a way to preserve them has been considered by scientists for a long time. However, upon freezing of water and the formation of a crystal lattice, the structure of the samples was destroyed. And in liquid form, it evaporated in the vacuum chamber of an electron microscope, again leading to the destruction of the studied molecules.
Finally, a way was found to bypass the crystallization phase and make the water go into a glassy state. The method was called vitrification.
During vitrification, water was able to protect molecules from destruction even in a vacuum.
These discoveries gave a powerful impetus to the development of electron microscopy. In 2013, scientists were able to see even individual atoms of a substance. Such a high resolution allows us to consider ribosomes and mitochondria of cells, ion channels and enzyme complexes.
In 2015, the journal Nature Methods named single-particle cryoelectron microscopy the Breakthrough Method of the Year.
Recent technical advances in this area have allowed scientists to move away from the method of X-ray crystallography, the main drawback of which is the need for protein crystallization, which can be difficult for proteins with a complex structure. Scientific journals in recent years have been full of detailed images of the surface of the Zika virus and the proteins that cause antibiotic resistance. In particular, they succeeded in how Staphylococcus aureus bacteria resist the action of antibiotics and a snapshot of the structure by which coronaviruses penetrate cells.
Despite rapid progress in this area, the cost of equipment and standardized methods have somewhat slowed down the widespread adoption of cryoelectron microscopy technology.
Among the contenders for the Nobel Prize in Chemistry was a Russian - a leading researcher at the Institute of Chemical Physics (ICP) them. N. N. Semenov, together with colleagues from the United States, and he made a significant contribution to the field of carbon-hydrogen functionalization, an industry that develops new methods for the synthesis of organic compounds. Also on the list of possible winners were Dane Jens Norskov for fundamental achievements in the field of heterogeneous catalysis on solid surfaces and a team of chemists Tsutomu Miyasaki, Nam-Gyu Park and Henry Sneith for the discovery of the mineral perovskite and developments based on it.
In 2016, the prize went to Jean-Pierre Sauvage, Stoddart and Bernard Feringe for the invention of molecular machines.
Last week, it was announced that the 2017 Nobel Prize in Chemistry will go to Jacques Dubochet of Switzerland, Joachim Frank of German American origin and Richard Henderson of Scotland for "the development of high-resolution cryoelectron microscopy techniques for determining the three-dimensional structures of biomolecules in solution." Their work has made it possible, since the 1980s, to test and gradually improve this type of microscopy to such an extent that in recent years scientists can examine complex biological molecules in great detail. The Nobel Committee noted that the method of cryoelectron microscopy brought biochemistry into a new era, filling many gaps in knowledge about the molecules of life and living systems.
We note right away that it is hardly possible to call cryogenic electron microscopy a fundamentally new and self-sufficient method for the physical study of matter. Rather, it is a type of transmission electron microscopy (one of the authors of this method, Ernst Ruska, received the Nobel Prize in 1986), which has been specially adapted for the study of microbiological objects.
In a transmission electron microscope, a beam of electrons is passed through a sample thin enough to be transparent to electrons (usually tenths and hundredths of a micron), which, passing through the sample, are absorbed and scattered, changing the direction of motion. These changes can be registered (now the CCD matrix is most often used as a detector, the creators of which, Willard Boyle and George Smith, became laureates) and, after analysis, an image of the object under study can be obtained in a plane perpendicular to the beam. Since the intrinsic wavelength of electrons (tens of picometers at energies typical of electron microscopes) is much smaller than the wavelengths of light in the visible region (hundreds of nanometers), electron microscopy can "see" much finer details than optical microscopy, including including high-resolution fluorescence microscopy (HRFM), developed by laureates Erik Betzig, Stefan Hell and William Merner.
The limiting resolution of electron microscopes - a few angstroms (tenths of a nanometer) - has almost been reached. This makes it possible to obtain images in which, for example, individual atoms are distinguishable. For comparison: the limit of FMVR capabilities is 10–20 nm. But just like that, comparing different methods in terms of maximum resolution is rather pointless. Electron microscopes have high resolution, but it is not always possible to use it. The fact is that, in addition to grinding during preparation, during the study itself, the sample is subjected to quite serious irradiation with an electron beam (roughly speaking, the more intense the beam, the fewer errors and the better the result), while being in a vacuum (a vacuum is needed to the medium did not scatter electrons outside the sample, thereby introducing unnecessary distortions). Such conditions are completely unsuitable if you need to study complex biological molecules and objects - they are damaged in a rarefied environment and they have a lot of rather weak bonds that will simply be destroyed during the study.
The understanding that without additional improvements the electron microscope could not be adapted to the study of biomolecules and living systems appeared almost immediately after its invention. For example, three years after the demonstration of the principle of the electron microscope by Ernst Ruska in 1931, the Hungarian physicist Ladislav Marton (L. Marton, 1934. Electron Microscopy of Biological Objects) wrote about this. In the same article, Marton also suggested ways to solve this problem. In particular, he also pointed out that freezing samples can reduce the damage from electron beam irradiation. It is important to note that although not mentioned in Marton's article, freezing the sample also helps by reducing the thermal vibration of the molecules, which also improves the resulting image.
In the 1970s and 1980s, science and technology reached a sufficient level of development to overcome all difficulties. And this happened largely thanks to the efforts of this year's award winners.
Richard Henderson was the first to image an unsymmetrical protein at atomic resolution using transmission electron microscopy (with sample cooling). He began his research in the mid-1970s. Moreover, at first Henderson tried to obtain the structure of several proteins from the cell membrane using the method of X-ray diffraction analysis, which even then could give a resolution of several angstroms. However, it quickly became clear that a good result could not be achieved by this method: the substance under study must be in a crystalline form, while membrane proteins extracted from their environment either crystallize poorly or lose their shape altogether. Then he switched to electron microscopy.
A specific protein was chosen - bacteriorhodopsin - and it was decided not to extract it from the membrane, but to study it directly in it. The scientists additionally covered the samples with a glucose solution to protect it from drying out in a vacuum. This helped to solve the problem with saving the structure. Then Henderson and colleagues faced the already described problem of destruction of samples under the action of an electron beam. It was helped by a combination of several factors.
First, bacteriorhodopsin is located in the membrane regularly, so careful consideration of this regularity, combined with shooting from different angles, greatly helps in building the picture. This helped to reduce the beam intensity and shorten the exposure time, but to win in quality. Already in 1975, it was possible to obtain an image of this protein with a resolution of 7 angstroms (Fig. 3, see R. Henderson, P. N. T. Unwin, 1975. Three-dimensional model of purple membrane obtained by electron microscopy).
Secondly, Henderson had the opportunity to travel to different scientific centers and try different electron microscopes. Since there was no unification in those years, different microscopes had their own advantages and disadvantages: different degrees of chamber evacuation, different degrees of sample cooling (this reduces damage from electron irradiation), different energies of electron beams, different sensitivity of detectors. Therefore, the possibility of studying the same object on different microscopes made it possible to first select the “least unfavorable” conditions for obtaining an image, and then gradually improve them. So Henderson accumulated data and got more and more accurate structure of bacteriorhodopsin. In 1990, his article was published, in which an atomic resolution model of this protein was presented (R. Henderson et al., 1990. Model for the structure of bacteriorhodopsin based on high-resolution electron cryo-microscopy).
In this pioneering study, Henderson showed that cryoelectron microscopy could produce images with a resolution that was as good as X-ray diffraction, a breakthrough at the time. True, this result made significant use of the fact that bacteriorhodopsin is regularly located in the cell membrane, and it was not clear whether it would be possible to achieve such resolution for other, "irregular" molecules.
The problem of processing weak signals from randomly located biologically active molecules was solved by another Nobel Prize winner in 2017 - Joachim Frank. His main contribution to cryoelectron microscopy is the development of algorithms for the analysis of two-dimensional images obtained using cryoelectron microscopy, which allow the construction of a high-quality three-dimensional model. Similar algorithms have already been developed for other microscopy techniques. Frank optimized and greatly refined the methods of mathematical analysis, allowing to separate useful information obtained during electron microscopy from signals due to noise. Noise occurs in precision electronic devices for various reasons: random fluctuations in current and voltage may be due to uneven emission of electrons in electrovacuum blocks, uneven processes of formation and recombination of charge carriers (conduction electrons and holes) in semiconductor blocks, thermal motion of current carriers in conductors (thermal noise), or external interference (despite the fact that everything is usually well insulated).
The task becomes even more difficult. If objects, even if they are the same or approximately the same, as it should be in such studies, are disordered, then they give slightly different signals in structure, which can blur each other. Moreover, it is not easy to determine the reason for such blurring - whether it is noise or algorithm errors. Schematically, the principle of data processing is shown in fig. 5: Numerous flat images of the studied molecule are denoised and typed according to “angles”, then a better profile is built from images with close angles, and, finally, a three-dimensional model is built from these profiles.
In 1981, Frank generalized mathematical models in the first version of the computer program SPIDER (System for Processing Image Data from Electron microscopy and Related fields, first publication: J. Frank et al., 1981. Spider - A modular software system for electron image processing). This software package exists and is still being updated, moreover, these programs are free to distribute, which, of course, facilitates the work of scientists around the world. Frank used his own algorithms to obtain an image of the surface of the ribosome, a cell organelle consisting of RNA strands and associated proteins that serves to synthesize protein from amino acids based on genetic information.
Prefix "cryo-" appeared in electron microscopy thanks to the third laureate - Jacques Dubochet. He developed a method for rapid cooling of aqueous solutions with samples (J. Dubochet, A. W. McDowall, 1981. Vitrification of pure water for electron microscopy). Moreover, the water must freeze so quickly that the molecules do not have time to line up in a crystal lattice, freezing at random (see amorphous ice). This is achieved by quickly immersing a thin film of the solution with the sample into a container with liquid ethane cooled to –160°C (Fig. 6). The correct method of freezing can be called the key to the success of the whole method, since ordered ice crystals can cause electron diffraction, distorting information about the molecules under study. Due to the large molecular weight of proteins and nucleic acids, these molecules are clumsy, so that during instant freezing they do not have time to either change their position or change shape. That is, the structure of biologically active molecules during rapid freezing by this method does not change. Using it, Dubochet was the first to use cryoelectron microscopy to study the structure of viruses (Fig. 7, see M. Adrian et al., 1984. Cryo-electron microscopy of viruses).
During the 1990s and 2000s, cryoelectron microscopy has gradually developed and improved with advances in computing power and instrument accuracy. But the real heyday of cryoelectron microscopy begins in 2012. It is associated with the advent of CMOS-based direct electron detectors (CMOS), which can directly capture electrons that have passed through the sample. This made it possible to simplify the design of electron microscopes by removing complex focusing and signal conversion systems and reducing the number of nodes that can introduce random noise. As a result, the resolution of the cryoelectron microscopy method increased to 2–3 angstroms (Fig. 8).
One example of the practical application of cryoelectron microscopy in this area can be considered the study of the Zika virus (Fig. 10). During the outbreak of the Zika epidemic in Brazil in 2016, it took researchers several months to obtain information about the structure of the virus using cryoelectron microscopy (D. Sirohi et al., 2016. The 3.8 Å resolution cryo-EM structure of Zika virus).
Another example - this year, cryoelectron microscopy made it possible to obtain the capsid structure of the largest representative of the herpes virus family - human cytomegalovirus (X. Yu et al., 2017. Atomic structure of the human cytomegalovirus capsid with its securing tegument layer of pp150). The results of the study became the basis for the search for possible regions of the capsid of viruses that can become molecular targets for antiviral drugs.
Arkady Kuramshin