Professor Jenny Glusker of the Fox Chase Cancer Center in Philadelphia U.S.A., an Honorary Fellow of Somerville College, took as her theme for the 3rd Dorothy Hodgkin memorial lecture "Vitamin B12 and Dorothy: their impact on structural science" and demonstrated the extraordinary pioneering achievements of a scientist and mentor who still found time to raise a family, welcome visitors to her home and give every encouragement to her students.
Born in Cairo in 1910 to a father who was Director of Education in the Sudan and a mother interested in archaeology and textiles, Dorothy Crowfoot returned to England with her two younger sisters on the outbreak of the First World War. Professor Glusker explained that she was brought up by her grandparents and formed life-long political ideas through joining the Girl Guides and meeting poor people. Gaining a First in Chemistry at Somerville College in 1931, at the time highly unusual for a woman, Dorothy began her career in X-ray Crystallography - studying organometallic compounds as a Part II student under H.D. Powell, and then assisting J.D. Bernal in Cambridge to investigate the structure of sterols. Though not determining actual atomic positions, she was able to show by the size of the structural repeat and the direction of greatest refractive index that the accepted chemical formula of these compounds was wrong and they contained a 5-, not a 6-, membered ring.
In her Nobel Prize lecture in December 1964 on "X-ray analysis of complicated molecules", Dorothy described her subsequent research as resulting from "a series of lucky accidents". Awarded a fellowship from Somerville College to continue study of cholesterol iodide, she helped Bernal obtain the first diffraction pattern from a crystal of a biological material - the digestive enzyme pepsin. It was soon after these photographs were reported that she was offered crystals of insulin, the protein whose atomic structure would become her life's work and she did not declare "solved" until August 1969. World War II meanwhile saw another elegant proof from her, this time using a map of electron density she had drawn on transparent sheets, that atoms of penicillin were not arranged as many chemists thought to form two separate 5-membered rings, but a single 5-membered ring was fused to a 4-membered (beta- lactam) ring.
Jenny Glusker admitted she became a student of Dorothy in Oxford thinking that she could use infra-red spectroscopy to look at planar atomic groups in another biological molecule, vitamin B12 - but instead joined in the project to solve its structure by X-rays. It had been known from the mid 1920s that eating 1/2lb of liver a day was beneficial to patients suffering from the potentially fatal symptoms of pernicious anaemia. Identified as the effective factor, vitamin B12 was known to contain a cobalt atom, a ring system and a large porphyrin-like group. She described how nowadays the X-ray crystallographer and the computer substitute for a lens to "see" how atoms are arranged. As a student in the 1950s, she had to measure the intensities of some 3500 diffraction spots on each film by eye and then spend 6 weeks calculating the terms for an electron density map using an "adding machine", a task much speeded up with the arrival of the first supercomputers. She recalled Dorothy's enthusiasm for this new technology, though she was concerned about errors in typing in the data and anxious that nothing was published before it was thoroughly checked. Dorothy was extremely excited however when the formula emerged for the red crystals Jenny had investigated. The structure of the hexacarboxylic acid, a degradation product of the vitamin, confirmed the surprising conclusion that here was a cyano-metallic compound with biological significance.
Understanding how vitamin B12 acts, and its influence on metabolic cycles, is still the objective of studies today. The unexpected discovery of a cleavable cobalt-carbon bond has led to extensive research into free radical reactions. Professor Glusker said it was a pity that a paper by researchers at the University of Michigan in 1994, the first to describe the binding of B12 to a protein - methionine synthase, was published just too late to tell Dorothy that the cobalt atom may form a catalytic quartet with neighbouring histidine, asparagine and serine residues. In establishing the structure of the vitamin, Dorothy had shown skill, imagination and audacity in trying methods others had dismissed. She had investigated several variant and related forms of the vitamin, exploited anomalous effects in the scattering of X-rays by atoms, and insisted on using full three-dimensional data rather than draw conclusions, as others did, from projections. Having attached so much importance to obtaining a correct structure, she set standards and this work was described by fellow Nobel Laureate W.L. Bragg as having "broken the sound barrier".
Recalling 40 years of friendship, Max Perutz - another crystallographic Nobel Laureate - wrote that "some women intellectuals regard their children as distracting impediments to their careers, but Dorothy radiated motherly warmth even while engaged in writing crystallographic papers. Concentration comes to her so easily that she can give all her attention to a child's chatter at one moment and switch to lattice transformations the next without any sign of strain". Despite arthritis and the distractions of family, students and other projects, Dorothy's passion for science kept her active and productive in research throughout her life. She was widely praised her unerring instinct for problems and her belief in the power of X-ray crystallography was handsomely vindicated.
Sheila Gover, Laboratory of Molecular Biophysics, University of Oxford