Professor Dorothy Hodgkin, OM, FRS

Home , 1965 in science, Dorothy Hodgkin, Guy Dodson, John Kendrew, Tom Blundell

Professor Dorothy Hodgkin worried that she may have lost the died at her home in Ilmington, real insulin in the course of her op Warwickshire, on Friday the 29th erations. She carried out the checks July, 1994. She was an outstanding herself to confirm that the crystals scientist and a remarkable person. In were in fact protein. She also sent 1964 she was awarded the Nobel the crystals to Henry Dale who mea prize for Chemistry for her work on sured their biological activity and the structures of natural products, found it to be 24 international units 1 notably penicillin and vitamin B12, mg- ; not very good, but good and during her life she received many enough to establish the authentic other honours both for her scientific character of the crystals. With these achievements, including her work on experiments the science of protein the diabetic hormone insulin, and crystallography was born. In a letter her work for peace and understand dated 1936 Bernal indicated to Dor ing among different nations. othy that cadmium insulin crystals Dorothy's father, J.W. Crowfoot existed and might be used for iso was Education Officer in Khartoum morphous replacement but it was and both parents were archaeolo not until 20 years later that Max gists. Dorothy was born in Cairo and Perutz established this method for came to England at the start of the 1910-1994 the solution of protein crystal struc First World War. As a child Dorothy tures. had become interested in crystals lished the first paper describing X Penicillin had been discovered in from growing them herself both at ray diffraction from a protein crys 1929 by Fleming but he had not suc home and at school, and from read tal'. The crystals, which had been ceeded in isolating it so that it might ing W.H. Bragg's Christmas lectures brought four weeks previously in the be used for practical purposes. The "Concerning the Nature of Things''. coat pocket of a visitor from Sweden, isolation was achieved by Florey and She came to Somerville College, Ox were shown to lose their crystallin Chain in Oxford in 1941 with the ford in 1928 to read Chemistry and ity when exposed to air; Bernal and result that the antibiotic was avail graduated in 1932 having done some Hodgkin noted that this probably able to treat casualties during the practical studies on thallium alkyl explained why previous attempts to Normandy landings in 1944, and halides, working in the Mineralogy obtain protein X-ray diffraction pat thereafter. Dorothy was drawn into Department with H.L. Bowman and terns had been unsuccessful. Their this research in 1942 working first H.M. Powell. The department was paper ends "At this stage such ideas with crystals of the degradation located in Ruskin's 'Cathedral of Sci [about the structures of proteins] are products and then - in 1944 - with ence' - the University Science Mu merely speculative but now that a the sodium, potassium and ru seum in Oxford. Dorothy occupied crystalline protein has been made to bidium salts of benzyl penicillin. part of a room where, at the British give X-ray photographs, it is clear The work involved close collabora Association Meeting in 1861, there that we have the means of checking tion with the chemical investigations had been the famous debate on the them and, by examining the struc of E.P. Abraham, E. Chain, W. Baker origin of species between Bishop tures of all crystalline proteins, arriv and R. Robinson. Through compari Wilberforce, Bishop of Oxford, and ing at far more detailed conclusions son of the isomorphous potassium the scientist T.H. Huxley. about protein structure than previ and rubidium salts and the sodium Dorothy continued her associa ous physical or chemical methods salt which crystallized in a different tion with Somerville for the rest of have been able to give''. This proph space group, the essential chemical her life except for a short time at ecy is born out by the multitude of structure of the molecule was estab Cambridge where she moved in 1932 protein structures now being re lished by the early summer of 1945. to carry out her Ph.D. with J.D. Bernal, ported and whose structures deter The conclusions reached were, in working on the structure of sterols mined by X-ray crystallography illu their final form, largely independent before returning to Oxford, with a Fel minate their biological function. of any other evidence on the details lowship at Somerville, two years later. In the following year, Dorothy of the molecular structure. The re She was Tutorial Fellow from 1935-55, grew crystals of insulin from a mi sults, so confidently presented, were Professorial Fellow from 1955- 77, crocrystalline suspension given to a triumph for the early days of natu and Honourary Fellow from 1977 her by Sir Robert Robinson and in ral product crystallography. The until her death. From 1960-1977 she later accounts she described the thrill structure containing the seemingly was Wolfson Research Professor of of seeing the regular array of tiny unstable P-lactam ring fixed with a the Royal Society. spots when she developed the first X five membered thiazolidine ring was In 1934 with J.D. Bernal she pub- ray photograph. She was acutely exceptional and drew amazement structural biology volume 1 number 9 september 1994 573 © 1994 Nature Publishing Group http://www.nature.com/nsmb obituary •

optical diffraction studies of penicil solutions. lin were carried out by C. W. Bunn at Insulin had first been crystallized Imperial Chemical Industries, by J.J. Abel in 1925 but difficulties Northwich, in his spare time until were experienced later in repeating Lord Melchett came round and saw the crystallizations. These difficul papers marked 'penicillin' and ex ties seemed to be associated with the pressed delight that ICI should be introduction of glass vessels instead involved in the work. The project of metal buckets for the initial ex was then given a proper job number. traction. In 1934 D.A. Scott discov Pernicious anaemia, long thought ered that zinc, presumably leaching to be incurable and usually fatal, had from the buckets, was an integral part been shown in 1926 to be treatable of the rhombohedral crystals. He by supplementing the diet with liver. was led to this discovery by observ The anti-pernicious anaemia factor, ing the occurrence of zinc in the pan

later called vitamin B12, was isolated creas. Dorothy first probed the struc in crystalline form in 1948 and later ture of rhombohedral insulin crys that year small deep-red crystals were tals with X-rays in 1935 and showed given to Dorothy. The formula of ap that the unit cell contained three proximately half of the molecule was equivalent units of about 12,000 M,. known from chemical studies (a The size of the molecule was way be nucleotide-like fragment, various yond the size that could be tackled amide groupings, and a large por in those days. The basic repeating phyrin-like nucleus containing co unit in the rhombohedral unit cell balt) but the rest of the molecule and was later recognised to be two insu how the fragments were linked to lin molecules and their arrangement gether were unknown. The struc was detected by use of the rotational ture, containing 93 non-hydrogen function in a joint paper of the atoms, was solved in 1956 and rep Hodgkin group with Michael resented the largest structure solved Rossmann in 1966. The dimers were Electron density map of penicillin over the thiazolide and ~-lactam at that time. As in the work on peni arranged into a hexamer by opera rings. The maps were drawn by hand onto transparent perpex cillin, structure solution was tion of the crystallographic three fold sheets, section by section, and stacked to represent the three achieved by the comparison of results axis. dimensional distribution (top figure). The molecular structure is shown below. (From Crowfoot, D., Bunn, C.W., Rogers-Low, B.W with a number of different crystal The solution of the insulin struc and Turner-Jones, A. In Chemistry of penicillin (ed H.T. Clarke et forms and derivatives. By this time ture was accomplished in 1969 by her a/.) pp. 310- 366 (Princeton University Press, 1949). computer technology had advanced team which included Guy Dodson, but it still took three weeks to calcu Tom Blundell, Margaret Adams, from chemists. The work was of im late the final three-dimensional map. Eleanor Dodson, M. Vijayan, mense importance for understand Several features not previously Marjorie Harding, B. Rimmer and S. ing the antibiotic which was to have observed in naturally occurring Sheat. The structure determination such revolutionary results in the chemical structures were found. The was difficult. The spacegroup R3 had treatment of disease. Her later work most unusual of these was the exist no centric projections which were extended these studies to the struc ence of the cobalt-containing ring important in those days for the de tures of other penicillins and to system, the corrin ring, which in A. tection and refinement of heavy atom cephalosporin. Eschenmoser's words has been de positions. Solution of this difficulty Structural analysis in those days scribed as "perhaps the finest gift that was accomplished by the develop was not easy: intensity measurement X-ray analysis has so far bestowed on ment of methods for incorporation of diffraction spots recorded with a the organic chemistry oflow molecu of anomalous scattering data into the Weissenberg camera were made vi lar weight natural products". The estimation of the protein-heavy atom sually (by a method which was still corrin ring, like porphyrin, has four structure factor amplitudes. The in use when I started in research in pyrrole units. Two are directly protein in the crystals was close 1962); Bragg and Lipson charts were bonded to each other whereas the packed and the protein contained no used to consider coordinates in a others are joined by methylene free sulphydryl groups and hence qualitative way in relation to inten bridges as in porphyrins. The cobalt production of good heavy atom de sities; Fourier calculations were car is co-ordinated by the nitrogens of rivatives was difficult. ried out in projection with Beevers the four pyrroles and by two other The breakthrough came when it Lipson strips, although later ligands. The novel bond from the was discovered that the zinc could be punched card machines were used; cobalt atom to the CS' carbon of the replaced by lead, although the crys and each structure was tested by the deoxyadenosyl unit in the coenzyme tals were non-isomorphous and did 'tly's eye' method of comparing the B, 2 provided clues to the vitamin's not immediately lead to a structure. optical diffraction pattern of a mask biological function. The work gave For insulin the crystallographic representing the trial structure with new insights into chemistry as well work was helped by knowledge of the the X-ray diffraction pattern. The as new methods for crystal structure chemical structure obtained by

Sanger in 1953. Once solved the Hodgkin in 1937 and they had three She was a tireless fighter for peace, structure of insulin provided defini children. Her children were still especially at a time when nuclear de tive description of the arrangement young when she was working on the struction during the Cold War ap

of atoms. The resolution was ex structures of penicillin, vitamin B12 peared a real possibility. This work tended to 1.5 A and a very detailed and other structures while at the was pursued both through informal account of both the protein's and its same time carrying a substantial and formal organisations. The water's structure was published in teaching load. Her tremendous in Pugwash movement was set up by 1988. Work on insulin has developed tellectual powers coupled with a re Bertrand Russell and Albert Einstein over the years - especially in Guy markable personality carried her in 1955 to promote East/West friend Dodson's laboratory in York - and through this busy time. ships and to seek co-operative solu has led to new insights, such as the rec In Oxford she was never overtly tions to disarmament and reduction ognition that in this instance the struc political but operated through a of international tension. The move ture seen in the crystals is slightly dif quiet word in the right place. She was ment was named after the small vil ferent in conformation to that one of those responsible for attract lage in Nova Scotia where the first recognised by the insulin receptor, and ing David Phillips to Oxford. In 1966 meetings took place. She became to the ability to design engineered Sir Lawrence Bragg retired from his president of Pugwash in 1975 and mutant insulins that have altered Directorship at the Royal Institution, her work was widely recognised. physiological properties for the treat London and a new home had to be But she also worked through her ment of special cases of diabetes. found for his team who had just personal contacts both for peace, Dorothy had the qualities of sim solved the first structure of an en for the Third World and for all plicity, directness, humility and a zyme, lysozyme. Oxford created an those less fortunate. wisdom about human beings, their ad hominem Professorship for David She travelled widely and estab affairs and abilities. Above all she dis Phillips and Professor J.W. Pringle lished many lasting friendships in played a great joy for her work and welcomed him to his Zoology De the former Soviet Union, in Viet in her life she was a constant source partment. Thus the Laboratory of nam, in Africa, in Arab countries, of inspiration and help to those Molecular Biophysics in Oxford was in India and in China, as well as her around her. In particular, through established and the Hodgkin group contacts in Europe and the USA. her work at Somerville she has left a became part of the Laboratory to the Thomas was Director of the Institute legacy of distinguished women sci mutual benefit of both. I joined the of African Studies at the University entists around the world, that in Laboratory in 1967 and although I of Ghana which meant that for sev cludes Pauline Harrison, Jenny was never one of Dorothy's students, eral years in the 1960s she operated Glusker, Majorie Harding, Margaret it was she who introduced me to from both Ghana ("where there's Adams, Eleanor Dodson, Judith Somerville and in an indirect way I rather more time to think") and Ox Howard and Carol Huber, among may count myself as part of the suc ford. Indeed, she was in Ghana when others. She married Thomas cession. the Nobel prize was announced.

JD. Bernal, John Kendrew, Dorothy Hodgkin and David Phillips at the Roya l Institution in 1965 just after the structure of lysozyme had been solved. structural biology volume 1 number 9 september 1994 575 © 1994 Nature Publishing Group http://www.nature.com/nsmb obituary •

It was especially poignant but also a source of great joy that she was able, accompanied by her daughter Liz, to attend the International Union of Crystallography meeting in Beijing in August 1993. She first visited China in 1959 at a time when there were very few Western visitors. Her friendships established on this occasion were ce mented later as Chinese scientists accomplished the synthesis of insu lin and later their own crystal struc ture determination. The affection and respect shown on that final visit last year is echoed by all who knew her in the international community.

Louise N. Johnson FRS David Phillips Professor of Molecular Biophysics Laboratory of Molecular Biophysics University of Oxford

1. Bernal, J.D. & Crowfoot, D. Nature 133, 794-795 (1934).

I am grateful to M.J. Adams for in formation on the early days with in sulin.

Dorothy Mary Crowfoot, chemist; born Cairo 12 May 1910; Fellow, Somerville College, Oxford 1936- 1977; FRS 1947; Royal Society Wolfson Research Professor, Oxford University 1960-1977; Nobel Prize for Chemistry 1964; OM 1965; Chancellor, Bristol University 1970- 1988; Fellow Wolfson College, Ox ford 1977-1982; married 1937 Tho mas Hodgkin ( died 1982; two sons, one daughter); died 29 July 1994.

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