who solved the structures of cholesterol (1937), penicillin (1946) and vitamin B12 (1956), for which she was awarded the Nobel Prize in Chemistry in 1964. In 1969, she succeeded in solving the structure of insulin, on which she worked for over thirty years. Biological macromolecular crystallography Crystal structures of proteins (which are irregular and hundreds of times larger than cholesterol) began to be solved in the late 1950s, beginning with the structure of sperm whale myoglobin by Sir John Cowdery Kendrew, for which he shared the Nobel Prize in Chemistry with Max Perutz in 1962. Since that success, over 130,000 X-ray crystal structures of proteins, nucleic acids and other biological molecules have been determined. The nearest competing method in number of structures analyzed is nuclear magnetic resonance (NMR) spectroscopy, which has resolved less than one tenth as many. Crystallography can solve structures of arbitrarily large molecules, whereas solution-state NMR is restricted to relatively small ones (less than 70 kDa). X-ray crystallography is used routinely to determine how a pharmaceutical drug interacts with its protein target and what changes might improve it. However, intrinsic membrane proteins remain challenging to crystallize because they require detergents or other denaturants to solubilize them in isolation, and such detergents often interfere with crystallization. Membrane proteins are a large component of the genome, and include many proteins of great physiological importance, such as ion channels and receptors. Helium cryogenics are used to prevent radiation damage in protein crystals. On the other end of the size scale, even relatively small molecules may pose challenges for the resolving power of X-ray crystallography. The structure assigned in 1991 to the antibiotic isolated from a marine organism, diazonamide A (C40H34Cl2N6O6, molar mass 765.65 g/mol), proved to be incorrect by the classical proof of structure: a synthetic sample was not identical to the natural product. The mistake was attributed to the inability of X-ray crystallography to distinguish between the correct -OH / -NH and the interchanged -NH2 / -O- groups in the incorrect structure. With advances in instrumentation, however, similar groups can be distinguished using modern single-crystal X-ray diffractometers. Despite being an invaluable tool in structural biology, protein crystallography carries some inherent problems in its methodology that hinder data interpretation. The crystal lattice, which is formed during the crystallization process, contains numerous units of the purified protein, which are densely and symmetrically packed in the crystal. When looking for a previously