Going ever smaller
For millennia humans had to rely on what they could see with their eyes to explain the world around them. If you cut a piece of wood in half, you are left with two smaller pieces. Both still feel the same. Repeat the process several times and you have a much smaller piece, which still has all the same properties as the original piece; for example, it would burn at the same temperature. If you carry on until you have only sawdust left, you are still holding a piece of wood from the same tree, which still has the same density as the original. But now it looks quite different. How much further could you go?
Hypotheses
In ancient Greek philosophy we find the idea that all things are made up of a certain proportion of elements to make just the right final product. Once you disrupt this proportion, you no longer have the same material. While they were wrong about the elements they proposed (either fire, air, water and earth or hot, cold, wet and dry) the fundamental idea has proved correct.
Nowadays we know that water, rather than being an element itself, is composed of two elements: oxygen and hydrogen in a 1:2 ratio. In fact, we know the composition of many other substances as well; but how? Chemical formulae, like the one for sucrose, C6H12O6, have been known long before anyone succeeded at looking at an atom. And even if you had been able to see the sugar molecule, you would have been hard pushed to identify the composing elements, as atoms do not wear name tags. Rather, the question is resolved by taking the molecule apart. After applying an electric current to water, one is left with two gases. One of these is present in twice the abundance of the other, and produces a “pop” sound when held to a flame: long ago, a gas just like this was called hydrogen.
X-ray crystallography
While this is all well and good for working out what small molecules look like, and methods like atomic force microscopy (AFM, in which an atomic-scale tip scans across a surface to map its height profile) can be used to investigate surfaces on the atomic level, none of the methods so far can give us any idea what complex molecules like proteins look like. Mass spectrometry (in which the deflection of charged molecules by a magnetic field allows us to weigh them) might give us an idea of which atoms are involved, and how they are bonded to each other, but it can not tell us how the giant snaky protein is curled up in space. This is called the protein’s secondary, tertiary and quarternary structure (the primary, the sequence of amino acids, usually being known).
In 1912 Max von Laue wondered whether X-rays, discovered less than 20 years previously, would be diffracted by crystals, giving a diffraction pattern that could be used to learn something about the repeating units within the crystal. Within only a few years the new technology allowed the structure of table salt, diamonds and metals to be found.
In 1964 the Nobel prize in Chemistry was awarded to Dorothy Crowfoot Hodgkin for the development of protein x-ray crystallography. It took her 35 years to develop the methods far enough to solve the structure of the first protein: insulin. Today, the step from the refraction pattern to determining the structure is no longer the most time consuming. Many structures of similar proteins are available for comparison. Computer modelling of possible structures allows researchers to quickly narrow down to the right one. However it is often the work of several years to convince the protein in question to undergo the first step in the process: crystallization.
Since the invention of the microscope many centuries have passed. Humanity has developed numerous new methods to probe the invisibly small, and yet we are a long way from creating a full image of the world too small for our eyes.
Bibliography
Greek elements (this article is unfortunately behind a pay wall)
Lloyd, G. E. (1964). The hot and the cold, the dry and the wet in Greek philosophy. The Journal of Hellenic Studies, 84, 92-106.
AFM image:
By Mehrabanian – Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=45204019
History of x-ray crystallography