Prorein Science (1994). 3:2465-2469. Cambridge University Press. Printed in the USA. Copyright 0 1994 The Protein Society Dorothy Crowfoot Hodgkin (1910-1994) Within thisworld there aregreat scientists whose passing leaves the world saddened, but whogave so much to make the world a richer place. One of these, Dorothy Hodgkin, passed away on July 29, 1994. She was a dedicated scientist and a friend to all who knew her. In 1964 she won the Nobel Prize, unshared,in chemistry “for her determination by X-ray techniques of the structures of biologically important molecules.” These include the structures of cholesteryl iodide(which showed the skeleton of steroids), the chemical formulae ofpenicillin, vitamin BI2, and vitamin B12 coenzyme, and, later, the three-dimensional structure of the protein hormone insulin. She had the courage, skill, and sheer willpower to extend the method of X-ray diffrac- tion analyses of crystals to compounds thatwere far more com- plex than anything attempted before. Jack Dunitz, who worked in her laboratory forseveral years, wrote: “Dorothy had an un- erring instinct for sensing the most significant structural prob- lems in this field, she had the audacity to attackthese problems when they seemed well-nigh insoluble, she had theperseverance to struggle onward where others would havegiven up, and she had the skill and imagination to solve these problems once the pieces of the puzzle began to take shape.It is for these reasons that Dorothy’s contribution has been so special” (Dunitz, 1981). Dorothy Crowfoot Hodgkin in 1970 when she came to the Fox Chase Cancer Center to describe the newly determined crystal structure of Dorothy was born Dorothy Mary Crowfoot on May 12, 1910, insulin in the first Patterson Memorial Lecture entitled, “X-ray analy- in Cairo, Egypt. Her father, John Winter Crowfoot,was an ar- sis and the structure of insulin.” chaeologist and historian in the Egyptian Ministry of Education and subsequently the Principal of Gordon College at Khartoum and Director of Education and Antiquitiesin Sudan. Later he worked at theBritish School of Archaeologyin Jerusalem. Her geometric patterns of the mosaic pavements that were found mother, Grace May (Molly)(nCe Hood), was an expert on the (McGrayne, 1993). history of ancient textiles, and wrote a book on the flowering Dorothy obtained her undergraduate educationin chemistry plants of Sudan. Dorothy, theeldest daughter, had threesisters at Somerville College, Oxford, obtaininga Science Prize in 1930. with whom she remained close during her entirelife. She lived Her X-ray crystallographic research career started with her stud- with her family in Sudan fora time, but during thefirst World ies of thallium dialkyl halides with H.M. (“Tiny”) Powell, a War, because of the fear of attacks onBritish colonies, Doro- demonstrator under H.L. Bowman, the professor of mineral- thy and her sisters were sent back to England. There shelived ogy and crystallography. This comprisedthe research part of her with her grandmother and attendeda small private school. This undergraduate degree (Powell& Crowfoot, 1932). She gradu- experience, she believed, was the origin of her independent spirit. ated from college with a B.A. degree with first-class honors and In 1918, as soon as thewar was over, Dorothy’s mother returned a B.Sc. degree. Then it was necessary for her to look for a po- to England. Thereafter, both parents spent each summerin En- sition and “Uncle Joseph” introducedher to T. Martin Lowry, gland, and the rest of the year in Sudan. Dorothy attended to who advised herto work with John Desmond (JD)Bernal (af- a coeducational school, the Sir John Leman School,in Beccles, fectionately called “Sage”). She tookhis advice and obtaineda Suffolk, andher interest in science started early. She was encour- Ph.D. at Cambridge University in 1937, working with Bernal aged by a family friend, Dr. A.F. Joseph (“Uncle Joseph”), a from 1932 to 1936. Her work there, in that very exciting labo- soil chemist at the Cairo branch of theWellcome Laboratory. ratory, reinforced her lifelong interest in structural biochemis- When Dorothy left Sudan, Dr. Joseph gave her a portable chem- try. Somerville College was, however, eager for Dorothy to come ical laboratory completewith apparatus formineralogical anal- back to Oxford. They awarded her a Vernon Harcourt Schol- yses. The archaeological studiesof her parents also interested arship in 1932 and a Research Fellowship from 1933 to 1935, Dorothy. Just beforegoing to college, Dorothy assisted her par- even though she was attached to Newnham College, Cambridge. ents, who were living in Jerusalem, with excavations at Jerash During her years in Bernal’s laboratory Dorothy took many in Transjordan. She was particularly intrigued by the elegant X-ray diffraction photographs. In 1934, Bernal and Dorothy 2465 Obituary: Dorothy Crowfoot Hodgkin first reportedon the diffraction patternof a crystalline protein, bated Bishop Samuel Wilberforce on the subject of evolution pepsin, pointing out thatin order to obtain good diffraction pat- in an historic debate on June30, 1860, at a meeting of theBrit- terns, the crystals of proteins should not be dried, but should ish Association for theAdvancement of Science. The laboratory be studied surrounded by their mother liquor (Bernal& Crow- itself also had gothic qualities. Housed in a tiny gallery, the crys- foot, 1934). Air-dried protein crystals gave very poor, if any, tal mounting equipment andpolarizing microscope were reach- diffraction patterns, while those crystals thatwere kept in their able only by ladder-like steps. Using the steps was hard for mother liquor gave nice diffraction spots on photographicfilm. Dorothy, who was having trouble with arthritis, but she never In fact, Dorothywas not in the laboratoryon the day that the lost a crystal while climbing up or down. Very soon she had two first X-ray diffraction photographs ofa protein were obtained, graduate students, both of them, by chance, male. Her first because her parents had taken herto London tosee a specialist graduate student was Dennis Riley, who joined her in 1937. He about some health problemswhich were the beginning of rheu- was excited by a lecture she gaveon steroids and wrote: “Here matoid arthritis. Shesubsequently took many X-ray diffraction was I, a member of a prestigious college, choosing to do my photographs of proteins, and, in October1934, obtained X-ray fourth year’s research ina new borderline subject with a young diffraction photographsof crystals of insulin (Crowfoot, 1935). female who held no university appointment but onlya Fellow- Even though Dorothy corresponded with A. Lindo Patterson ship in a women’s college” (Riley, 1981). Riley worked on pre- on his vector map methodof analysis, the methods forinterpret- paring protein crystals and attempting to obtain diffraction ing these diffraction photographs could not, at that time,lead patterns for lactoglobin, insulin, and several otherproteins to a protein structure determination. In retrospect, she wroteof (Crowfoot & Riley, 1939). the Patterson maps of insulin that she had calculated: “These During World War I1 Dorothy was joined by Bernal’s collab- old patterns ... do correspond rather well to the pattern youget orators, C.H. Carlisle and Dr. Kathe Dornberger-Schiff. Harry just from the main chain distribution in insulin, in spiteof the Carlisle was Dorothy’s second graduate student and she inter- complexity of the pattern” (Hodgkin, 1987). ested him inthe structureof steroids, anotherresult of her work While working in Bernal’s laboratory Dorothy also became with Bernal. She now aimed to determine the molecular struc- interested in steroids and their structures. Bernal had shown that ture of cholesteryl iodide by locating each atom in the crystal X-ray diffraction photographs were not compatible with the structure. A crystallographic investigation of cholesteryl bro- then-acceptedWindaus-Wieland formula because the latter mide and chloride had formed part of her Ph.D.thesis at Cam- could not be fit into the unitcell in the orientation indicatedby bridge, but no molecular structure had yet come out of that the refractive index measurements (Bernal, 1932). Bernal’s pub- work. Dorothy pioneered the use of Patterson mapsin the de- lished note on the subjectled to a revision of the chemical for- termination of the structure ofcholesteryl iodide, as shewas al- mulae of steroids. Dorothy, with Bernal and Isidor Fankuchen, ways on the lookout fornew and better ways to solve structures. studied crystals of over one hundred steroids and reportedtheir The iodine positionswere found from the Patterson map, and unit-cell dimensions, refractive indices, and probable packing electron-density maps phasedon these positions were then cal- and hydrogen bonding (head-to-head or head-to-tail, for exam- culated. Dorothy hadan uncanny ability to pick out a molecule ple) in a monumental study (Bernal et al., 1940). from an electron-density map that contained symmetry-related It was then necessary for Dorothy tobegin her own scientific artifacts, such as were present in maps of the crystal structure career. In 1936, she became a Tutor and Fellow of Somerville of cholesteryl iodide, and later, penicillin. Cholesteryl iodide was College. She missed the camaraderie of Bernal’s laboratory, one of thefirst analyses based on three-dimensional calculations, however, andwent back often duringthese early years. Oxford and it established the relative stereochemistry at each carbon provided her witha scientific and intellectual environment free atom of the steroids (Carlisle & Crowfoot, 1945). This result was from most of the usual burden of administrative formalities, and verified by other subsequent crystallographic studies of steroids she was given much moral supportby the principal of Somerville (Crowfoot & Dunitz, 1948). Dorothy never published a result College, hematologist Janet Vaughan. Dorothy was made a Uni- until she was sure it was right. versity Lecturer and Demonstratorin 1946, but did not become Dorothy had many other graduate students, including Bar- a University Reader until 1955.