The 2017 Nobel Prize in Chemistry was awarded jointly to Jacques Dubochet, Joachim Frank and Richard Henderson for developing cryo-electron microscopy that can determine high-resolution structures of biomolecules in solution.
Mirsky: Welcome to Scientific American Science Talk, posted on October 4th, 2017. I'm Steve Mirsky.
Goran Hansson: The Royal Swedish Academy of Sciences has decided to award the 2017 Nobel Prize in Chemistry, jointly, to Jacques Dubochet, Joachim Frank, and Richard Henderson, for developing cryo-electron microscopy for the high-resolution structure determination of biomolecules in solution.
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Mirsky: Goran Hansson, secretary general of the Academy, at 5:53 this morning, Eastern time. What follows is an edited version of the announcement and explanation.
Hansson: Jacques Dubochet was born in 1942, in Switzerland. He studied in Basel and in Geneva, and he is currently honorary professor at the University of Lausanne in Switzerland. He's a Swiss citizen. Joachim Frank was born in 1940, in Germany. He got his Ph.D. at the Technical University in Munich, München, and he is currently a professor at Columbia University in New York. He is nowadays a US citizen. Last, but not least, Richard Henderson was born in 1945, in Scotland. He received his Ph.D. at the University of Cambridge in the United Kingdom, and he is, since many years, at the Laboratory of Molecular Biology in Cambridge – and I think he is the 15th Nobel Laureate from that laboratory. With that, I'll give the word to the chairman of the Nobel Committee, Sara Snogerup Linse. She will provide a brief summary of the research that's been awarded, today. Sara, please.
Sara Snogerup Linse: Thank you, Goran. We are made of more water than anything else. Biomolecules, the molecules of life, they do their job in water, to help us execute important functions like thinking and carrying around stuff.
Mirsky: She tossed a small vial full of protein into a glass of water.
Snogerup Linse: Cryo-EM is able to see each and every one of these protein molecules. It can see each and every atom inside each protein, to tell us how they are arranged to build up their intricate structures. It can show us how the different parts of the protein moves relative to one another when they execute their jobs. Richard Henderson showed the first protein structure at atomic resolution, using cryo-electron microscopy. Jacques Dubochet developed a method to take these samples of biomolecules in water, and freeze them so rapidly that they formed a thin film in which the water was preserved in a liquid state, just like in a glass window. Joachim Frank developed a method to combine the information, from multiple blurry images of those individual proteins, into one sharp image. Now, we can see the intricate details of the biomolecules in every corner of our cells, in every drop of our body fluids. We can understand how they are built, and how they act, and how they work together in large communities. We are facing a revolution in biochemistry.
Mirsky: Peter Brzezinski then explained further – he a professor of biochemistry at Stockholm University, and a member of the Nobel Committee for Chemistry.
Brzezinski: The techniques developed by the laureates have opened a completely new world to us, to be able to see all these molecules inside the cell, and how they interact. And not even that, we can even see the atoms that build up these molecules, and see the details of all these molecules. The electron microscope is not a new instrument. It was developed almost 100 years ago. The problem is that there is a great challenge in studying biological objects using electron microscopy, because there must be vacuum inside the electron microscope. And biological objects are composed primarily of water, and if you place an object containing water in a vacuum, it dries and the structure changes. If you switched on the electron beam, then, the object is burned, and the structure does not even remind us about the original object.
Richard Henderson studied protein from an organism that lives in salt ponds. This is a microorganism which carries patches of photosynthetic proteins on its surface, and these proteins, they are arranged in regular arrays that contain many, many of these molecules. And Richard Henderson placed these patches in the electron microscope, and by observing about 5 million of these bacteriorhodopsin molecules at the same time, he could distribute the electron radiation of a large number of molecules, so that each one of them did not receive enough electron radiation that would damage them, but he could then study the molecules. And in this way, he could obtain a high-resolution structure of the protein, of bacteriorhodopsin. But this is a special case; not all molecules are oriented like in this case, in this microorganism.
Most molecules are free in water, and Richard Henderson believed that the technique could be also used to study, essentially, any molecule that is found in a cell. When we study a picture of molecules that are in solution, all the molecules are randomly distributed in the solution. So the challenge is now to, using this very low, low electron radiation that would not damage the molecules, to actually see them and see where they are. Then we have to see how are they oriented relative to each other, because we must know in order to determine the three-dimensional structure to combine all these pictures into the whole structure.
Joachim Frank developed these methods – here are the molecules in solution; they have different orientation. When these molecules are illuminated by the electron beam, we see projections of these molecules, like shadows of these molecules. These shadows differ in shape depending on the orientation of the object that was illuminated. This can be, now, sorted – those that have the same shape or originate from molecules with the same orientation are sorted in groups. And then, an average of all these pictures can be taken in each of these groups, and in this way, one can obtain sharper pictures, one can increase the signal relative to the background noise. And this is the way, now, to obtain better resolution pictures. Then these pictures can be combined to build a three-dimensional structure. But in order, now, to obtain information about the details, about the atoms, what the molecule looks like inside, better sample preparation methods were needed.
And many people believed that the way to prepare samples would be to freeze them. The problem is that, if you place a biological object in ice, in water and freeze, then ice crystals are formed around the object. And the ice crystals diffract the electron beam, so when it's illuminated, all the information is lost, because the ice crystals diffract the electron beam. But people also believed that it would be possible, perhaps, to freeze the sample fast enough so that the water would not have time to arrange itself into crystals, to form ice, but would be structured that this, it's like a liquid: all the water molecules are randomly distributed and not forming the ice crystals. And if this is the case, then it would be possible to obtain a sharp picture, because all the electron beams would be evenly absorbed by the – this vitrified water, it is called. And in this way, Jacques Dubochet developed a technique that allowed to see biomolecules at good contrast.
And everyone who are working in this field traveled to his lab in order to learn the technique, and it was then rapidly used by many other in many other laboratories. The technique has transformed the electron microscopy from a technique that could be used to just see the shapes, the outer shapes, of molecules, into one that is now used to see the details, the atoms, inside the molecules. And the latest technical developments occurred very recently, so it's very recent developments that you can actually see the details of these molecules. The technique is also relatively rapid, so once one has samples that can be studied, the structure can be determined relatively rapidly. And this was exemplified last year, when the structure of the zika virus was determined in just a few months, and the structure shows the atomic details of the surface, which, of course, it's important when developing drugs against the virus.
But the technique is not only about seeing molecules, and I think this is a fantastic development that has already started but will be seen also in the future. And that is, because the molecules are frozen in solution, if a molecule does some work, then all these molecules are frozen exactly in the moment, in the different states, in different structures. And it's like frames of a movie, and they can be put together into a movie and we can see what the molecules do. So I think, in the future, this is not only about getting structures of molecules, which in itself is, of course, fantastic, but it's also, for the future, we'll be able to see processes, what is happening, what is going on inside the cells, how do the molecules interact, how do they move, what do they do.
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