Science is an ongoing dance between techniques and discoveries. For example, if the telescope had never been invented, would we know about nebulae, galaxies, double stars, and black holes? If the microscope hadn't been developed, would we understand bacteria, viruses, and the components of cells?
We need to be able to see further and deeper into the world around us in order to better understand how the world works. This is particularly true in the world of chemistry, microbiology and biochemistry.
We think of objects around us as being continuous. If you look at a table, a wall, or even the newspaper in front of you (or computer screen if you are reading this online), they look like a single solid object. But we know they are not. They are composed of vast arrays of atoms strung out in molecular chains or arranged with metallic lattices. This is the world as chemistry has revealed it over the past century.
Yet atoms and molecules are generally far too tiny to see with the naked eye or even the best optical microscopes. For chemists, the structure of molecules was revealed by two powerful and complementary techniques.
The first is X-ray diffraction crystallography. There are whole books written on the subject so please forgive my shortened version of how it works. In essence, a crystal - any crystal - is made of repeating units. Atoms lined up in millions and millions of repeating rows, columns and levels.
Think of office cubicles ad nauseam in three dimensions.
What crystallography does is take a picture of all of the cubicles and by blending them all together, we get a single image of what the average cubicle looks like.
It is a lot more complicated than that in practice.
It involves diffracting X-rays off planes of electron density and using the resulting reflection intensity to match a calculated profile based on the relative position of the atoms. But X-ray diffraction crystallography is the best way we have to image the world at the molecular level.
It does suffer from a fundamental problem - you have to be able to crystallize the material. The other powerful technique chemists employ is NMR spectroscopy. Again, whole books have been written on the subject but the short version is that the nuclei of atoms respond to their environment in subtly different ways. Distinctive atoms within a structure generate unique signals.
NMR allows us to look at and determine the structure of small molecules in solution. It can even be used to learn some things about big molecules in an aqueous environment. But it is limited in the complexity of molecules it can work with.
For microbiologists and biochemists, the limitation in size and the requirement that molecules can be crystallized represent stumbling blocks to the development of an understanding of the molecular machinery in cells.
How do you understand the workings of a cell if you can't see it?
In the 1930s, the electron microscope was invented. It allowed scientists a much deeper view of the world down to the level of millionth of a centimeter. Most of us have seen electron microscope images as they often show up in advertisements with something like an ant holding a computer chip.
The world of the truly microscopic was still not accessible until the mid-1970s. Richard Henderson had received his Ph.D. in X-ray crystallography but found it held too many setbacks for studying proteins.
One of the major problems with using electron microscopy to image molecules is the electron beam is so strong it destroys the molecule being imaged. What Henderson realized is he could use a much weaker beam which wouldn't destroy the molecules and use the crystalline packing to allow him to take lots and lots of pictures of individual molecules. He could then use the same approach as used in crystallography to develop an average picture of the molecules.
In 1975, he was able to publish the first rough 3D images of a protein's (bacteriorhodopsin) structure. By 2013, the technique had been refined to the point where it is now routine to get atomic level images of biologically interesting molecules.
This enhanced resolution is due to the work of Joachim Frank and the development of modern computer techniques. In 1982, Jacques Dubochet was able to cool cellular material fast enough that he could capture molecules in the act. He was able to see the inner workings and molecular machinery of cells in action.
For developing an effective method for generating three-dimensional images of the molecules and processes of life, Jacques Dubochet, Joachim Frank, and Richard Henderson were awarded the 2017 Nobel Prize in Chemistry. With these new techniques for electron microscopy, scientists can watch the inner workings of cells at a level unprecedented.
The technique will lead to all sorts of new discoveries.
