Professor Howard first described the basic principles of X-ray crstallography. When X-rays are passed through a crystal, diffraction patterns are produced; each diffraction pattern is unique to the specific arrangements of the atoms within a molecule, so examination of diffraction patterns enables the investigator to deduce the molecular structure of the material, and to study the forces which bind the particles together. Not knowing the properties in advance, one has to work empirically by proposing models and comparing them with the observations. The models will of course depend on the state of relevant knowledge at the time; for example, researchers in the nineteenth century assumed that a molecule must have a two-dimensional structure, and it was not until the 1930's that models for three-dimensional structure could be considered seriously, although Dorothy Hodgkin had in fact visualized 3-D solutions in her BSc thesis in 1932. Most molecular structures were then largely unknown, and to extract them from the diffraction patterns that the investigators were learning how to make involved an enormous labour of calculations by hand. The dynamic behaviour of molecular structure was also not appreciated for a long time. Today we use computer graphics to give full 3-dimensional structures and to identify the details of molecular interaction.
Dorothy Hodgkin began her X-ray crystallography work during an undergraduate project to determine the three-dimensional structure of thallium dialkyl halides. She was obviously very inspired by the subject, and went on to study increasingly complicated molecules with what was then a new technique of X-ray crystallography. Dorothy not only had the kind of patience and persistence that the hand-calculated modelling demanded, but was also blessed with gifts of pattern recognition and inspiration. It was said that she could spot the essentials of a molecule's structure just from a single X-ray diffraction pattern, even though such a pattern is only one section through a three-dimentional structure. Most researchers need the full set of pictures in order to visualize the structure - or to have a graphics package draw it out for them.
One of the molecules Dorothy Hodgkin worked on during her early career was cholesteryl iodide. There were two current models for its structure, and both were consistent with the chemical observations available to date. However Dorothy was able to perform calculations that confirmed which of the models was the correct one. She then went on to study the complex molecule penicillin: it was war-time, and there was an urgent need to understand the structure of this powerful antibiotic so that chemists could synthesize it in large quantities. The structure was eventually published by Dorothy and her colleagues in 1949 (though with the wrong chirality - at the time the X-ray techniques were unable to resolve the left-right ambiguity). In the late 1940's she began her studies on vitamin B12 - the work which was to gain her the Nobel Prize for Chemistry in 1964. Vitamin B12 had a much more complex structure than any other previously resolved, though certain of its chemical properties aided the investigations (it contained a heavy atom, cobalt, which showed up well in X-ray diffraction patterns). However, Dorothy Hodgkin's principal achivement was to understand the structure of insulin. She began work on this vital substance in 1934, taking the first X-ray photographs of the crystals, although it was not until 1969 that her group was able to publish the basic structure, and she continued to work on higher-resolution details of that structure until the late 1980s.
As X-ray crystallography techniques have steadily sharpened there have been many gradual improvements in the quality of the results, while fresh discoveries have also given rise to important developments in the techniques themselves. It was suspected, for instance, that much clearer diffraction patterns could be obtained at low temperatures when the blurring due to the natural movements of the atoms would be significantly reduced, but it was generally feared that below about 4 C the water in the crystal would freeze and thus destroy the crystalline structure. However, it was discovered that protein crystals do still preserve their molecular structure if cooled very quickly to low temperatures - a technique developed in Oxford, and now applied routinely worldwide. This was as significant as the discovery in the 1930's that X-ray diffraction patterns could be obtained for some biological crystals if they were maintained 'wet' in their mother liquors and not allowed to dry out. The resulting improvements in the resolution of all molecular structures has, for example, enabled chemists to investigate in much finer detail the bonding forces and weak links within and between molecules.
The improvements which the chemists have been able to achieve in understanding molecular structures and interactions have fed over into other sciences. In industrial chemistry, for instance, a knowledge of the molecular structure of natural crystalline products such as silk is at the heart of the artificial fibre and polythene industries; the wide spectrum of different properties induced by the inclusion of different metal atoms into a molecular structure promises an almost infinite variety of synthetic materials. Equally, at the interface with biology the development of molecular biosensors, which employ different molecules to identify the presence of small amounts of trace elements, depend critically upon a detailed knowledge of the molecular structures in question, while a knowledge of the trace elements is fundamental to understanding the physical properties of that substance.
Professor Howard's group in Durham is currently investigating the effects which low temperatures (25 - 300 K) and different pressure have upon the attainable resolution of X-ray diffraction patterns. When crystals are cooled to the lower of those limits the inter-molecular spaces and interatomic regions can then be studied. The ability to look in between molecules, as well as at their structural detail, has led to an increased understanding of the weak interactions that exist between the molecules in the crystal. The completed structures with which she illustrated these developments were as beautiful as they were complicated, each showing a different intricate maze of three-dimensional patterns.
World-wide developments in X-ray crystallography owe a great deal to Dorothy Hodgkin's demonstrations of how molecular structures could be solved with a slide-rule and a certain amount of vision, even though it took days or months to acquire the data. Today, diffraction patterns of considerably greater resolution can be obtained in a matter of hours and synthesized digitally in a matter of minutes. The potential of still higher resolution that might be obtained at temperatures below 10 K is extremely attractive, but remains elusive at present because single crystal diffraction data is technically difficult to obtain at such very low temperatures. The Durham group, in particular, is planning to develop a technique for reducing the temperature below 10 K in order to realize that potential. Who can foretell what applications - in chemistry, biophysics, surgery, architecture, art, telecommunications or space travel - may result when the innermost structure of everyday materials and compounds is understood to the full?
In thanking Professor Howard for a stimulating lecture, Elizabeth Griffin (Oxford AWiSE) remarked on the huge advances in technology since Dorothy Hodgkin's first work in X-ray crystallography: technological advances allow higher-resolution data to be collected quickly, and computational power enables data to be interpreted very rapidly. But she also cautioned that tools are only as good as those who use them, and that what Dorothy Hodgkin was able to achieve with the basic technology available to her at the time was due to her intelligence and hard work - skills which are just as vital today.
These lectures are sponsored by Somerville College, the University Museum of Natural History and Oxford AWiSE.
Dr Catherine Hobbs & Dr Elizabeth Griffin.