Dorothy Hodgkin was one of the outstanding scientists of the 20th century. In 1969 she determined the three-dimensional structure of insulin by the X-ray crystallographic method, thus making a fundamental contribution to our understanding of the hormone’s chemical and biological properties. Her achievements rested on extraordinary experimental skills in X-ray crystallography and a genius for applying and developing its methods. It should also be appreciated that Dorothy Hodgkin had also solved the structures of cholesterol (1937), penicillin (1945) and vitamin B12 (1954), accomplishments for which she was awarded the Nobel Prize in 1964. These achievements had an immense impact on chemistry, biochemistry and medical science, establishing the power of X-ray crystallography, and changing the practice of synthetic chemistry.
Dorothy became aware of the potential of X-ray crystallography during a period spent at Cambridge with J. D. Bernal from 1932 to 1934. She realised that this technique offered the possibility of determining the structure of protein molecules—then far from understood. When she moved back to Oxford in 1934 she was offered a sample of microcrystalline insulin by Robert Robinson, and this marked the beginning of a lifelong commitment to insulin research. The hormone attracted her because of its fundamental importance for chemistry and biology, and because of its direct relevance to disease. Her decision to undertake serious crystallographic study of insulin in 1934 still astonishes. There were huge technical and theoretical problems that no-one had as yet begun to address, and even the constitution of proteins was unknown! Yet Dorothy did not hesitate; she knew that the essential step was to begin, and that the necessary insight and techniques would develop as the research grew. This confidence, shared also by her friend and colleague Max Perutz, marks Dorothy out. She was to be proved right, and indeed played a key role in the crystallographic research that showed her to be so. It is important to realise that her research into insulin’s crystal structure rested on her crystallographic research into the structures of cholesterol, penicillin and vitamin B12, all of which broke new ground, and allowed her in each case to tackle molecules of increasing size and complexity. The size and complexity of the crystallographic problems presented both by insulin, and by haemoglobin, lysozyme and chymotrypsin—other large molecules under study at the time—were finally overcome by improved methods of modifying proteins in the crystal, by access to computers, and by automated measurement of the tens of thousands of X-ray reflections collected from the crystals. When the crystal structure of insulin was finally determined in August 1969, Dorothy was fully involved in interpreting the hormone’s three-dimensional structure. Like us all, she took total pleasure and satisfaction as the molecule’s full structure was revealed, allowing us to define the position and geometry of each of the individual amino acids in the sequence determined 15 years earlier by Sanger. When the structure was completed, the organisation of the hormone as a dimer coordinated by two central zinc ions into a hexamer was immediately understood and the chemical and structural basis for its behaviour in solution established. Further analysis explained the hormone’s chemical behaviour and the pattern of amino acid variation seen in the sequences of the other animal insulins then available. It then became possible to speculate where the surfaces responsible for insulin’s physiological action were located. Dorothy always thought that solving the structure of insulin was her greatest scientific achievement, even though this did not offer any real insight into the structural factors that determine its activity. This would require the structure of insulin complexed with its receptor partner, still not achieved but—one hopes—imminent.
Dorothy, very typically, remained in contact with laboratories active in insulin research all over the world. Even before the structure of insulin was solved, her exceptional scientific abilities and her generous and sympathetic nature allowed her to provide advice and to use her influence to great effect. She retained an active interest in insulin research, and followed with excitement the epic programme of chemical synthesis undertaken in China, Germany and USA, together with the seminal discovery of proinsulin in Chicago. The structure of insulin brought a molecular dimension to insulin chemistry and to its biology, stimulated research into its chemical modification and pharmacology, and provided the framework for understanding its biosynthesis, processing, secretion and circulation. In the years that followed, Dorothy travelled all over the world giving vivid but measured accounts of insulin structural research, accounts in which its relevance to diabetes was always a major concern.
Dorothy Hodgkin in the labShe received many honours and distinctions but was more interested in contact with other scientists and the opportunity her research gave her to advance understanding and treatment of disease. This reflected Dorothy’s remarkable personality. She had extraordinary scientific and intellectual gifts, yet was at the same time the most unassuming, thoughtful and considerate of individuals, who also employed her intelligence to think about other people’s problems. This underpinned her uncompromising position on social inequalities and her commitment to avoiding and stopping conflict. In 1975, inevitably perhaps, she became President of Pugwash, a post she filled with unique ability for 13 years. Scientific discovery was Dorothy’s passion but she offers a lesson to us all in her ability to see outside her science, to recognise the utter importance of human obligations and to act on them. Her contribution in this arena will be remembered as much as her science.