HODGKIN, DOROTHY MARY CROWFOOT

(b. Cairo, Egypt, 12 May 1910; d. Ilmington, Warwickshire, United Kingdom, 29 July 1994),

crystallography, chemistry.

Hodgkin pioneered the use of x-ray diffraction techniques to solve the structures of complex organic molecules such as steroids, antibiotics, and proteins. Most notably, her determination of the structure of vitamin B₁₂ in 1956 revealed the existence of a hitherto-unsuspected chemical grouping, the corrin nucleus. For her contributions to the x-ray analysis of natural products, Hodgkin was awarded the Nobel Prize in Chemistry for 1964 and in 1965 received Britain’s highest civil honor, the Order of Merit.

Early Life . . Dorothy Mary Crowfoot was born in Cairo, Egypt, of English parents, in 1910. Her father, John Winter Crowfoot, worked for the Egyptian Educational Service; her mother, the former Grace Mary Hood (known as Molly), was an expert on ancient textiles. Dorothy was the first of four daughters. When World War I broke out in 1914, Dorothy and her sisters were evacuated to England, where they lived for the duration of the war in Worthing, West Sussex, in the care of a nanny and their paternal grandparents. In 1916 John and Molly Crowfoot moved to Khartoum, where John became the director of education for the Sudan. When the war ended, Molly took her daughters to Nettleham, Lincolnshire, while John remained in the Sudan. In 1920 the family moved again, to Beccles in Suffolk. There Dorothy attended the Parents’ National Educational Union School, where she first exhibited what was to become a lifelong fascination with chemistry in general and crystals in particular. In the years from 1921 to 1927, she attended the Sir John Leman School at Beccles, where she participated in chemistry classes normally reserved for boys. In 1924 she and her sister Joan spent several months in Khartoum, where a friend of their father's, the chemist Dr. A. F. Joseph, further simulated Dorothy’s interest in science by giving her a kit for analyzing minerals.

Although there was no family tradition of science, Molly Crowfoot encouraged her eldest daughter’s interest in chemistry, buying her copies of William Henry Bragg’s books, Concerning the Nature of Things(1925) and Old Trades and New Knowledge (1926), both of which were based on Christmas lectures for children at the Royal Institution. These books introduced Dorothy to the use of x-rays to solve chemical structures.

Dorothy took the Beccles school leaving certificate exams in 1927, earning distinction in six subjects—not including chemistry. After a year spent studying Latin and botany, she passed the entrance examinations for Oxford University, where her father had earned a degree in classics.

Oxford and Cambridge . From 1928 to 1932, Dorothy Crowfoot read chemistry at Somerville College, Oxford. Part I of the chemistry program normally involved three years of study and led to a BA degree; Part II required a further year spent doing a research project, leading to an honors degree. Crowfoot asked Herbert “Tiny” Powell, the university demonstrator in mineralogy, to act as her research supervisor. Powell assigned her a project involving the use of x-rays to study the structures of thallium dialkyl halide salts. This study was performed in a room in the University Museum. In 1932 Crowfoot became only the third woman to achieve a first-class honors degree in chemistry from Oxford University. She was also awarded half of the Vernon Harcourt Scholarship for 1932–1933.

In October 1932 Crowfoot moved to the Department of Mineralogy at Cambridge University as a PhD student, with John Desmond Bernal as her supervisor. Shortly thereafter she accepted a two-year research fellowship from Somerville College, with the prospect of a permanent fellowship on condition that she spend the first year of the award (1933–1934) at Cambridge. Crowfoot’s PhD project was an x-ray diffraction analysis of the sterols and related hydrocarbons. A large number of sterol crystals were characterized in terms of space group (type of three-dimensional lattice), unit cell dimensions, and growth habit. These studies helped discriminate between two proposed ring structures of the sterol nucleus and provided some clues about the stereochemistry of particular compounds. They did not, however, provide unambiguous information about atomic locations.

In her last few months at Cambridge, Crowfoot became involved in a project that profoundly influenced her subsequent career. In April 1934 Bernal acquired some crystals of the enzyme pepsin that had grown by accident in Theodor Svedberg’s laboratory at the University of Uppsala in Sweden. Fortunately, these had been brought to England in their mother liquor (the solution in which they formed). When Bernal subjected air-dried crystals of pepsin to x-rays, only a general darkening of the film resulted. However, crystals suspended in mother liquor gave a sharp diffraction pattern including spots corresponding to very small lattice spacings—the first demonstration of atomic regularity in a globular protein.

Crowfoot was not in the laboratory when the pepsin crystals were first analyzed, as she was seeing a consultant about pains in her hands—an early indication of the rheumatoid arthritis that afflicted her for the rest of her life. On her return, she joined in the further analysis of pepsin and coauthored with Bernal the resulting paper, “XRay Photographs of Crystalline Pepsin” (1934), published in Nature. It was no doubt Bernal who wrote the passage speculating that the pepsin molecule may consist of hexagonal nets rather than a polypeptide chain. Although Crowfoot maintained a close personal and professional relationship with Bernal until his death in 1971, she did not share his approach to research: she was cautious in her interpretations, while Bernal was bold, even foolhardy; she was tenacious in pursuit of a structure, while he was more interested in the next problem than the current one.

Insulin (I) . When Crowfoot returned to Oxford in September 1934, she was assigned space adjacent to Powell’s area in the University Museum. Robert Robinson, a professor of organic chemistry, helped her to find money to equip an x-ray laboratory. In addition to establishing an independent research program, she continued to work on her PhD thesis, which was successfully defended in 1936. That same year she was awarded a permanent fellowship from Somerville College.

X-ray crystallography was at something of a watershed in the mid-1930s. During his studies on mineral crystals, William Lawrence Bragg, then Langworthy Professor of Physics at Manchester University, had developed what he called the trial-and-error method of x-ray analysis. This involved generating a preliminary model based on crystalline symmetry and the sizes of the atoms present. The theoretical diffraction pattern of the model was then compared with the actual x-ray diffraction pattern of the crystal. Modifications of the model were then made and the comparison repeated until satisfactory agreement was achieved. In practice, the trial-and-error approach was feasible only for crystals with small numbers of parameters (that is, atomic coordinates not dictated by the symmetry of the crystal).

An alternative approach to x-ray analysis had been suggested by Bragg’s father. William Henry Bragg, whose books had inspired the young Dorothy Crowfoot, was Fullerian Professor of Chemistry at the Royal Institution. As early as 1915, the elder Bragg had pointed out that the mathematical technique of Fourier analysis could be used to determine the structure of a crystal so long as the amplitudes and phases of the x-rays diffracted by the crystal were known. The amplitudes could easily be determined, but the phases (how the crests and troughs of different x-rays were related in space) could not. The absence of this vital piece of the puzzle became known as the phase problem.

One solution to the phase problem was provided by John Monteath Robertson’s 1936 analysis of the plant pigment phthalocyanine. As the phthalocyanine crystal has a symmetry element known as a center of symmetry, all the x-ray beams diffracted by the crystal are either completely in phase (positive) or completely out of phase (negative) with one another. Therefore, one has to consider only the signs rather than the phase angles of the diffracted beams. Robertson showed that the addition of an atom of a heavy metal such as nickel did not change the crystal structure of phthalocyanine—the two crystals are isomorphous. However, the scattering from the nickel atom was so great compared to that from the lighter atoms that the signs of almost all diffracted beams became positive. Knowing the signs, Robertson used Fourier synthesis to construct a map of electron density in the phthalocyanine crystal.

However, the isomorphous replacement method was of limited utility for the vast majority of natural products, as these rarely contain centers of symmetry, and thus the phases of diffracted x-ray beams can have any values between 0° and 180°. Also, the summation of the Fourier series could be prohibitively time-consuming, although tables produced by Arnold Beevers and Henry Lipson greatly simplified the calculations involved.

A means of avoiding, rather than solving, the phase problem was suggested in 1934 by Arthur Lindo Patterson, who had worked with W. H. Bragg. Patterson’s idea was to square the amplitudes of the diffracted beams, which would make all values positive. Using the squares of the amplitudes in a Fourier synthesis results in a map of the interatomic vectors present in the crystal. Such Patterson maps could be extremely complicated in crystals with many atoms and, except in the simplest cases, did not have any obvious relationship to the atomic lattice of the crystal.

Svedberg’s studies had shown that proteins contain thousands of atoms. Nonetheless, the x-ray diffraction pattern of pepsin contained enough information to describe its structure at atomic resolution—so long as a solution could be found to the phase problem. When Robinson offered Crowfoot crystals of the protein hormone insulin that he had obtained from the Boots Pure Drug Company, she decided that insulin was a suitable molecule for her first independent investigation.

To make crystals large enough for x-ray analysis, Crowfoot used a published method to re-precipitate the insulin in the presence of zinc. These crystals were then air-dried before being subjected to diffraction. From the lengths and angles of the unit cell axes, she concluded that zinc insulin crystals had rhombohedral symmetry, which meant that they possessed a threefold rotation axis. The unit cell therefore contained either one molecule that itself had threefold symmetry or else 3n asymmetric molecules. From density measurements, the weight of protein in the unit cell was calculated to be 37,200 daltons.

Crowfoot published a more detailed analysis of zinc insulin in 1938, “The Crystal Structure of Insulin I: The Investigation of Air-Dried Insulin Crystals.” The diffraction pattern contained no spots corresponding to lattice spacings of less than 7 Å, suggesting to Crowfoot a lack of order at that level. A recalculation of the unit-cell volume resulted in a slightly revised molecular weight, 37,600. The 1938 paper also included a Patterson analysis of insulin in projection on the plane defined by the a and b axes of the unit cell. The two major sets of peaks were at about 10 Å and 22 Å from the origin of coordinates. The former peaks were reminiscent of atomic spacings found in fibrous proteins by William Astbury of Leeds University.

Although these studies provided almost no insight into the structure of the insulin molecule, at least one of the puzzling features of Crowfoot’s analysis was quickly resolved. Investigation of wet insulin crystals showed spots corresponding to lattice spacings as low as 2.4 Å, an indication that the “disorientation” reported earlier was in fact an artifact of drying.

In the late 1930s, Crowfoot also studied lactoglobulin and other proteins for which crystals were available. Thereafter, protein crystallography was set aside in favor of more promising lines of investigation.

Cholesterol and Penicillin . Some of Crowfoot’s diffraction of insulin crystals was performed at the Royal Institution, using W. H. Bragg’s powerful x-ray tube. While in London she met Thomas Lionel Hodgkin of the Workers’ Educational Association, whom she married on 16 December 1937. The Hodgkins had three children: Luke Howard (born 1938), Prudence Elizabeth (born 1941), and Toby (born 1946).

Unlike many scientists, Dorothy Hodgkin was able to work more or less normally during World War II. In fact, she benefited from the evacuation to Oxford of equipment and personnel from Birkbeck College, University of London, where Bernal was now a professor of physics. Hodgkin put Bernal’s student Harry Carlisle to work on the analysis of cholesteryl iodide. The approach taken is worth describing in some detail, as it was to form the basis of later studies on more complex organic molecules.

The unit cell of the cholesteryl iodide crystal contains two molecules related by a twofold screw axis (a symmetry element consisting of a 180° rotation plus a translation along the rotation axis). The screw axis is perpendicular to the more-or-less planar sterol molecules. This means that a projection of the crystal structure down the screw axis will have a center of symmetry, even though the crystal itself is not centrosymmetrical.

The strategy began with the use of Patterson maps to determine the positions of the heavy iodine atoms. Next, two-dimensional Fourier maps of a projection onto the ac plane of the unit cell were constructed using the phases calculated from the iodine atoms alone. (As the projection is centrosymmetrical, the phase angles can be only 0° or 180°.) The maps contained peaks corresponding to the approximate positions of atoms along the a and c axes of the unit cell, but provided no information about their positions along the b axis. A three-dimensional Fourier would have given the missing information, but the amount of manual computation required was prohibitive. Instead, Hodgkin and Carlisle constructed one-dimensional Fourier series parallel to the b axis only in the vicinity of the peaks observed in the projection. Because of the center of symmetry, the one-dimensional Fouriers contained peaks corresponding to pairs of real and unreal atoms, related to one another by a mirror plane of symmetry. These could be distinguished by consideration of bond lengths and angles. In a final step, the Fourier analyses were repeated using the phase contributions calculated for the carbon atoms as well as iodine atoms. In the end, approximate values for the a, b, and c parameters of all twenty-seven carbon atoms were determined. This represented the first three-dimensional analysis of a complex organic molecule.

Later in the war, Hodgkin became heavily involved in a project that was deemed to be of significant military importance: an analysis of the structure of penicillin. This antibiotic, which had been discovered by Alexander Fleming in 1928, was being intensively studied on both sides of the Atlantic. In Britain, the chemical analysis of penicillin was led by a group of Oxford University scientists that included Ernst Chain and Robert Robinson. In 1943, two forms of penicillin were crystallized: benzylpenicillin, or penicillin G, and 2-pentenyl penicillin, or penicillin F. Hodgkin’s initial investigations showed that penicillin G had the simpler crystal structure. By April 1944 she had obtained crystals of three salts of penicillin G: those of the potassium and rubidium salts were orthorhombic and isomorphous, while those of the sodium salt were monoclinic.

Patterson analysis located the positions of the metal atoms in the potassium and rubidium salts, but not in the nonisomorphous sodium salt. Hodgkin and her student, Barbara Low, could, therefore, proceed to a two-dimensional Fourier analysis of the rubidium and potassium salts, as had been done for cholesteryl iodide. The sodium salt was turned over to Charles Bunn of Imperial Chemical Industries for analysis using the “fly’s eye,” an optical device for testing crystal structures that did not require phase information.

The crystallographic analysis of penicillin was hindered by conflicting chemical evidence about whether the molecule existed in the form of an oxazolone or a β-lactam. The conformation of the penicillin molecule represented another unknown, although it was assumed to be approximately linear. By early 1945, Hodgkin’s Fourier analyses of the potassium and rubidium salts had incorporated phase information based on proposed positions of several atoms; however, further refinement did not improve the preliminary electron-density maps. Bunn had also generated maps for the sodium salt, but no more progress seemed possible with the fly’s eye. However, comparison of the two sets of data enabled Hodgkin to distinguish peaks corresponding to real atoms, which were in the same relationship to one another in both crystals, from peaks corresponding to spurious ones. From this, it appeared that the penicillin molecule was “curled” (roughly semicircular in projection) rather than linear.

New Fourier analyses based on the curled molecule improved the electron-density maps and strongly supported the β-lactam structure. However, the degree of superimposition of atoms in projections of the unit cell made it impossible to determine accurate parameters for all atoms. Therefore, Hodgkin decided to perform a three-dimensional Fourier analysis of the sodium and potassium salts of penicillin G, the first time such an analysis had been attempted. For the potassium salt, this analysis involved summing Fourier series with hundreds of terms at each of 216,000 positions in the unit cell. To carry out the large number of mathematical operations required, Hodgkin used a Hollerith punched-card computer that belonged to the Scientific Computing Service. By 1947, three-dimensional electron-density maps of penicillin G, in the form of contours drawn on stacks of Perspex sheets, confirmed both the β-lactam structure and the curled conformation. Perhaps more importantly, by unambiguously demonstrating the locations of atoms in three dimensions, Hodgkin’s studies on penicillin made x-ray crystallography the definitive technique for the structural analysis of organic molecules.

Vitamin B₁₂ . _. Ever since her return to Oxford in 1934, Hodgkin’s only position had been her Somerville College fellowship; unlike many fellows, she held no position in the university. In 1945 she applied for a new readership in chemical crystallography, but the post was awarded to Tiny Powell. Instead, Hodgkin was appointed as demonstrator. However, her status as a leading crystallographer was recognized in 1947 when she was elected a Fellow of the Royal Society.

The following year Hodgkin began work on a molecule whose structure was almost entirely unknown: vitamin B₁₂. This substance had been discovered as a cure for pernicious anemia in 1926 and was first crystallized in 1948 by Merck in the United States and Glaxo in the United Kingdom. When Hodgkin found that vitamin B ₁₂ contained cobalt, she realized that it might be amenable to x-ray analysis. However, the large size of the molecule suggested by elemental analysis—approximately one hundred atoms, not counting hydrogen—and particularly the lack of knowledge about its chemical structure, presented an unprecedented challenge for x-ray crystallography.

In the late 1940s, chemical investigations performed by Alexander Todd at Cambridge University and others provided fragmentary information about the vitamin B ₁₂ molecule. Acid hydrolysis produced a nucleotide monophosphate-like group, aminopropanol and several amides. In addition, the presence of a cyanide group had been demonstrated spectroscopically. Most atoms in the molecule, including the cobalt, were unaccounted for, although it was speculated that these included a porphyrin (a four-ring structure found in hemoglobin and chlorophyll).

The x-ray analysis of B₁₂ began in late 1949, with Hodgkin using crystals from Glaxo and John White of Princeton University using crystals from Merck. The two groups soon combined their efforts, providing independent confirmation (or refutation) at many steps along the way. In initial studies, a three-dimensional Patterson analysis was carried out on air-dried B₁₂ crystals. Advances in computing meant that calculation of three-dimensional Fourier series were now easier. Hodgkin used an analogue computer invented by Ray Pepinsky of Auburn University and also purchased a Hollerith machine. The Fourier maps located the cobalt atom within the unit cell and gave indications that it might lie in the middle of a planar group. This was presumably the proposed porphyrin, four nitrogens of which could form coordination bonds with cobalt. A three-dimensional Fourier map was then constructed using the phases of the cobalt atoms alone. In this, the planar group did not look much like a porphyrin, but the nucleotide-like group was tentatively identified as providing a fifth coordination bond to the cobalt atom through one of the nitrogen atoms on its “base.” By this time it was believed that the sixth coordination position was occupied by cyanide.

In 1950 analysis began on wet B₁₂ crystals; again, the cobalt atom was located by Patterson analysis and a three-dimensional Fourier map was made using the cobalt phases. This map had better resolution than that derived from the dry crystals, but the information about atomic locations provided was largely confirmatory. Two years later Hodgkin’s group began to study sulfocyanate and selenocyanate derivatives of B₁₂ in the hope that the sulfur and selenium atoms could be used to provide phase information for another Fourier analysis. It turned out that these crystals were not isomorphous, but the analysis did confirm the crystallographers’ suspicion that the cyanide group of B₁₂ coordinated the cobalt atom on the opposite side of the planar group from the nucleotide-like group. More importantly, the three-dimensional Fourier map of the selenocyanate derivative suggested that the planar group did not consist of four pyrrole rings joined by methylene groups, as in a porphyrin. Rather, it appeared that two of the rings were directly linked.

The final push came in 1953, when Todd’s group in Cambridge crystallized a hexacarboxylic acid produced by alkaline hydrolysis of B₁₂. To perform a three-dimensional Fourier on this simpler compound, Hodgkin sent data obtained in her laboratory by Jenny Pickworth and John Robertson to Kenneth Trueblood of the University of California at Los Angeles, who had access to the powerful SWAC computer. The resulting Fourier map confirmed the direct linkage between rings A and D of the planar group and contained much sharper peaks than those from the other crystals. Phase information derived from the positions of another twenty-six atoms was used in a second Fourier analysis. This showed the planar group very clearly, and it also suggested some of the groups attached to it. In general, the hexacarboxylic acid derivative of B ₁₂ differed from the parent molecule in that the nucleotide-like group was missing, and the sixth coordination of the cobalt atom was provided by a chloride ion.

The next Fourier analysis of B₁₂ itself used phase information from almost all atoms in the nucleotide-like, planar, and cyanide groups. This analysis produced a plausible three-dimensional structure of the entire molecule (shown diagrammatically in Figure 1).

The structure of vitamin B₁₂, published in Nature in July 1956, represented a giant step forward for x-ray crystallography. The Oxford-Princeton collaboration had provided structural information that was not available from traditional methods of organic analysis, which Hodgkin described in an earlier paper as “for any crystallographer something of a dream-like situation.” Even more impressively, the planar group of B₁₂ was a novel chemical entity, for which the term corrin nucleus was later coined. W. L. Bragg described the B₁₂ study as “breaking the sound barrier.”

Insulin (II) . Hodgkin was promoted to reader in x-ray crystallography in 1955. Five years later she was appointed to the Wolfson Research Professorship of the Royal Society and moved her group from the University Museum at Oxford to the Inorganic Chemistry Laboratory. The Royal Society also honored her with a Royal Medal in 1956 and

Despite having achieved the highest scientific and civil honors, Hodgkin still regretted not having pursued the structure of insulin. In the late 1950s, Max Perutz and John Kendrew had successfully used isomorphous replacement to solve the structures of hemoglobin and myoglobin, respectively. Frederick Sanger’s determination of the amino acid sequence of insulin had shown that the protein has a molecular weight of approximately 5,800, indicating that the “molecule” Hodgkin had described in 1935 was actually six molecules. This simplified the structural analysis and obviated the need for internal symmetry. In 1956 Hodgkin obtained crystals of pig insulin containing either two or four zinc atoms. However, she was unable to locate the zinc atoms by Patterson analysis and was also unable to make other heavy-atom derivatives. The key breakthrough came in 1964, when Hodgkin learned from visiting Swedish scientists that zinc could be removed from insulin crystals using chelating agents and then replaced with other metals. Guy Dodson, a postdoctoral fellow, made cadmium and lead derivatives; an undergraduate student, Thomas Blundell, made a uranium derivative. Another important step forward was the realization that phase information could be obtained by anomalous scattering effects (slight intensity differences between symmetry-related spots).

The diffraction patterns of the heavy metal derivatives of insulin crystals were analyzed using the linear diffractometer made by Uli Arndt and David Phillips at the Royal Institution; this machine recorded intensities on punched tape that could be fed directly into a computer. By 1969 Hodgkin’s group had generated an electron-density map at a resolution of 2.8 Å; using Sanger’s data, it was possible to identify the position of each amino acid. A 1.9-Å structure was published in 1971. However, Hodgkin was not satisfied until she achieved a resolution of 1.5 Å, which allowed her to identify the position of every water molecule in the insulin crystal. This structure was published in 1988, when she was seventy-eight years old.

Last Years . In 1966 David Phillips, who had worked with W. L. Bragg at the Royal Institution, moved to Oxford to set up a new Laboratory of Molecular Biophysics in the Zoology Department. Hodgkin’s group shared space with Phillips’s until her retirement from the Wolfson Professorship in 1977.

In her sixties, Hodgkin left the day-to-day running of her research group to others. She traveled extensively and became involved in the leadership of scientific and nonscientific organizations. She served as the president of the International Union of Crystallography (1972–1975), the president of the British Association for the Advancement of Science (1977–1978), and the chancellor of Bristol University (1970–1988). Long a passionate believer in social justice and peace between nations, she took public stances on many issues, including opposing nuclear weapons and the Vietnam War. From 1975 to 1988 she was president of the Pugwash Conferences on Science and World Affairs. She received the Lenin Peace Prize from the Soviet Union for 1987. Thomas Hodgkin, who (unlike Dorothy) was at one time a member of the Communist Party, had died in 1982.

Hodgkin had never allowed her arthritis to limit her scientific activities or extensive travel. In 1988, however, increasing frailty caused her to resign her remaining positions. A hip fracture in 1990 left her unable to walk. Four years later, a fall fractured Hodgkin’s other hip. She died at Crab Mill, a cottage Thomas had inherited from his parents, on 29 July 1994, and was buried in the churchyard at Ilmington. A memorial service was held in March 1995 at the Church of St. Mary the Virgin in Oxford.

Unlike other crystallographers of her generation, Dorothy Hodgkin was not associated with any particular technical breakthrough. She was always at the forefront in the use of computers to carry out crystallographic calculations. However, like others who had cut their teeth on more intuitive approaches, she did not welcome the day when x-ray analysis became automated. Hodgkin’s main contribution was in developing an approach to x-ray analysis that filled the gap between the trial-and-error methods used by W. L. Bragg and Linus Pauling in the 1920s and the brute force methods that became feasible in the late 1950s. This approach required profound insights into chemistry and crystallography but was capable of providing unambiguous structural information about organic molecules too complex for more traditional and indirect methods of analysis.

BIBLIOGRAPHY

Hodgkin’s papers are in the Bodleian Library at Oxford University. Probably the definitive biography is the microfiche appendix to Dodson’s Royal Society memoir (cited below).

WORKS BY HODGKIN

With J. Desmond Bernal. “X-Ray Photographs of Crystalline Pepsin.” Nature 133 (26 May 1934): 794–795.

“The Crystal Structure of Insulin. I. The Investigation of Air-Dried Insulin Crystals.” Proceedings of the Royal Society of London, series A, 164 (1938): 580–602.

With J. Desmond Bernal and Isidor Fankuchen. “X-Ray Crystallography and the Chemistry of the Steroids. Part I.” Transactions of the Royal Society, series A, 239 (1940): 135–182.

With C. H. Carlisle. “The Crystal Structure of Cholesteryl Iodide.” Proceedings of the Royal Society of London, series A, 184 (1945): 64–83.

With Charles W. Bunn, Barbara W. Rogers-Low, and A. Turner-Jones. “X-Ray Crystallographic Investigation of the Structure of Penicillin.” In Chemistry of Penicillin, edited by Hans T. Clarke. Princeton, NJ: Princeton University Press, 1949.

With Jennifer Kamper, Maureen MacKay, Jenny Pickworth, et al. “Structure of Vitamin B₁₂.” Nature 178 (14 July 1956): 64–66.

With Jennifer Kamper, June Lindsey, Maureen MacKay, et al. “The Structure of Vitamin B₁₂. I. An Outline of the Crystallographic Investigation of Vitamin B₁₂.” Proceedings of the Royal Society of London, series A, 242 (1957): 228–263.

With Margaret J. Adams, Tom L. Blundell, Eleanor J. Dodson, et al. “Structure of Rhombohedral 2 Zinc Insulin Crystals.” Nature 224 (1 November 1969): 491–495.

With Edward N. Baker, Thomas N. Blundell, John F. Cutfield, et al. “The Structure of 2Zn Pig Insulin Crystals at 1.5 Å Resolution.” Philosophical Transactions of the Royal Society of London, series B, 319 (1988), 369–456.

The Collected Works of Dorothy Crowfoot Hodgkin. Edited by Guy G. Dodson, Jenny Pickwork Glusker, S. Ramaseshan, et al. 3 vols. Bangalore, India: Interline, 1994.

OTHER SOURCES

Dodson, Guy G. “Dorothy Mary Crowfoot Hodgkin, O.M.” Biographical Memoirs of the Royal Society of London 48 (2002): 179–219.

Dodson, Guy G., Jenny P. Glusker, and David Sayre, eds. Structural Studies on Molecules of Biological Interest: A Volume in Honour of Professor Dorothy Hodgkin. Oxford: Clarendon Press, 1981; New York: Oxford University Press, 1981.

Ferry, Georgina. Dorothy Hodgkin: A Life. London: Granta Books, 1998.

Graeme K. Hunter

Dorothy Crowfoot Hodgkin

For her work with vitamin B-12, Dorothy Crowfoot Hodgkin (1910-1994) was awarded the Nobel Prize in chemistry.

Dorothy Crowfoot Hodgkin employed the technique of X-ray crystallography to determine the molecular structures of several large biochemical molecules. When she received the 1964 Nobel Prize in chemistry for her accomplishments, the committee cited her contribution to the determination of the structure of both penicillin and vitamin B₁₂.

Hodgkin was born in Egypt on May 12, 1910 to John and Grace (Hood) Crowfoot. She was the first of four daughters. Her mother, although not formally educated beyond finishing school, was an expert on Coptic textiles, and an excellent amateur botanist and nature artist. Hodgkin's father, a British archaeologist and scholar, worked for the Ministry of Education in Cairo at the time of her birth, and her family life was always characterized by world travel. When World War I broke out, Hodgkin and two younger sisters were sent to England for safety, where they were raised for a few years by a nanny and their paternal grandmother. Because of the war, their mother was unable to return to them until 1918, and at that time brought their new baby sister with her. Hodgkin's parents moved around the globe as her father's government career unfolded, and she saw them when they returned to Britain for only a few months every year. Occasionally during her youth she travelled to visit them in such far-flung places as Khartoum in the Sudan, and Palestine.

Hodgkin's interest in chemistry and crystals began early in her youth, and she was encouraged both by her parents as well as by their scientific acquaintances. While still a child, Hodgkin was influenced by a book that described how to grow crystals of alum and copper sulfate and on X rays and crystals. Her parents then introduced her to the soil chemist A. F. Joseph and his colleagues, who gave her a tour of their laboratory and showed her how to pan for gold. Joseph later gave her a box of reagents and minerals which allowed her to set up a home laboratory. Hodgkin was initially educated at home and in a succession of small private schools, but at age eleven began attending the Sir John Leman School in Beccles, England, from which she graduated in 1928. After a period of intensive tutoring to prepare her for the entrance examinations, Hodgkin entered Somerville College for women at Oxford University. Her aunt, Dorothy Hood, paid the tuition to Oxford, and helped to support her financially. For a time, Hodgkin considered specializing in archaeology, but eventually settled on chemistry and crystallography.

Crystallography was a fledgling science at the time Hodgkin began, a combination of mathematics, physics, and chemistry. Max von Laue, William Henry Bragg and William Lawrence Bragg had essentially invented it in the early decades of the century (they had won Nobel Prizes in 1914 and 1915, respectively) when they discovered that the atoms in a crystal deflected X rays. The deflected X rays interacted or interfered with each other. If they constructively interfered with each other, a bright spot could be captured on photographic film. If they destructively interfered with each other, the brightness was cancelled. The pattern of the X-ray spots— diffraction pattern —bore a mathematical relationship to the positions of individual atoms in the crystal. Thus, by shining X rays through a crystal, capturing the pattern on film, and doing mathematical calculations on the distances and relative positions of the spots, the molecular structure of almost any crystalline material could theoretically be worked out. The more complicated the structure, however, the more elaborate and arduous the calculations. Techniques for the practical application of crystallography were few, and organic chemists accustomed to chemical methods of determining structure regarded it as a black art.

After she graduated from Oxford in 1932, Hodgkin's old friend A. F. Joseph steered her toward Cambridge University and the crystallographic work of J. D. Bernal. Bernal already had a reputation in the field, and researchers from many countries sent him crystals for analysis. Hodgkin's first job was as Bernal's assistant. Under his guidance, with the wealth of materials in his laboratory, the young student began demonstrating her particular talent for X-ray studies of large molecules such as sterols and vitamins. In 1934, Bernal took the first X-ray photograph of a protein crystal, pepsin, and Hodgkin did the subsequent analysis to obtain information about its molecular weight and structure. Proteins are much larger and more complicated than other biological molecules because they are polymers—long chains of repeating units—and they exercise their biochemical functions by folding over on themselves and assuming specific three-dimensional shapes. This was not well understood at the time, however, so Hodgkin's results began a new era; crystallography could establish not only the structural layout of atoms in a molecule, even a huge one, but also the overall molecular shape which contributed to biological activity.

In 1934, Hodgkin returned to Oxford as a teacher at Somerville College, continuing her doctoral work on sterols at the same time. (She obtained her doctorate in 1937). It was a difficult decision to move from Cambridge, but she needed the income and jobs were scarce. Somerville's crystallography and laboratory facilities were extremely primitive; one of the features of her lab at Oxford was a rickety circular staircase that she needed to climb several times a day to reach the only window with sufficient light for her polarizing microscope. This was made all the more difficult because Hodgkin suffered most of her adult life from a severe case of rheumatoid arthritis, which didn't respond well to treatment and badly crippled her hands and feet. Additionally, Oxford officially barred her from research meetings of the faculty chemistry club because she was a woman, a far cry from the intellectual comradery and support she had encountered in Bernal's laboratory. Fortunately, her talent and quiet perseverance quickly won over first the students and then the faculty members at Oxford. Sir Robert Robinson helped her get the money to buy better equipment, and the Rockefeller Foundation awarded her a series of small grants. She was asked to speak at the students' chemistry club meetings, which faculty members also began to attend. Graduate students began to sign on to do research with her as their advisor.

An early success for Hodgkin at Oxford was the elucidation of cholesterol iodide's molecular structure, which no less a luminary than W.H. Bragg singled out for praise. During World War II, Hodgkin and her graduate student Barbara Low worked out the structure of penicillin, from some of the first crystals ever made of the vital new drug. Penicillin is not a particularly large molecule, but it has an unusual ring structure, at least four different forms, and crystallizes in different ways, making it a difficult crystallographic problem. Fortunately they were able to use one of the first IBM analog computers to help with the calculations.

In 1948, Hodgkin began work on the structure of vitamin B-12 the deficiency of which causes pernicious anemia. She obtained crystals of the material from Dr. Lester Smith of the Glaxo drug company, and worked with a graduate student, Jenny Glusker, an American team of crystallographers led by Kenneth Trueblood, and later with John White of Princeton University. Trueblood had access to state of the art computer equipment at the University of California at Los Angeles, and they sent results back and forth by mail and telegraph. Hodgkin and White were theoretically affiliated with competing pharmaceutical firms, but they ended up jointly publishing the structure of B-12 in 1957; it turned out to be a porphyrin, a type of molecule related to chlorophyll, but with a single atom of cobalt at the center.

After the war, Hodgkin helped form the International Union of Crystallography, causing Western governments some consternation in the process because she insisted on including crystallographers from behind the Iron Curtain. Always interested in the cause of world peace, Hodgkin signed on with several organizations that admitted Communist party members. Recognition of Hodgkin's work began to increase markedly, however, and whenever she had trouble getting an entry visa to the U.S. because of her affiliation with peace organizations, plenty of scientist friends were available to write letters on her behalf. A restriction on her U.S. visa was finally lifted in 1990 after the Soviet Union disbanded.

In 1947, she was inducted into the Royal Society, Britain's premiere scientific organization. Professor Hinshelwood assisted her efforts to get a dual university/college appointment with a better salary, and her chronic money problems were alleviated. Hodgkin still had to wait until 1957 for a full professorship, however, and it was not until 1958 that she was assigned an actual chemistry laboratory at Oxford. In 1960 she obtained the Wolfson Research Professorship, an endowed chair financed by the Royal Society, and in 1964 received the Nobel Prize in chemistry. One year later, she was awarded Britain's Order of Merit, only the second woman since Florence Nightingale to achieve that honor.

Hodgkin still wasn't done with her research, however. In 1969, after decades of work and waiting for computer technology to catch up with the complexity of the problem, she solved the structure of insulin. She employed some sophisticated techniques in the process, such as substituting atoms in the insulin molecule, and then comparing the altered crystal structure to the original. Protein crystallography was still an evolving field; in 1977 she said, in an interview with Peter Farago in the Journal of Chemical Education, "In the larger molecular structure, such as that of insulin, the way the peptide chains are folded within the molecule and interact with one another in the crystal is very suggestive in relation to the reactions of the molecules. We can often see that individual side chains have more than one conformation in the crystal, interacting with different positions of solvent molecules around them. We can begin to trace the movements of the atoms within the crystals."

In 1937, Dorothy Crowfoot married Thomas Hodgkin, the cousin of an old friend and teacher, Margery Fry, at Somerville College. He was an African Studies scholar and teacher, and, because of his travels and jobs in different parts of the world, they maintained separate residences until 1945 when he finally obtained a position teaching at Oxford. Despite this unusual arrangement, their marriage was a happy and successful one. Although initially worried that her work with X rays might jeopardize their ability to have children, the Hodgkins had three: Luke, born in 1938, Elizabeth, born in 1941, and Toby, born in 1946. The children all took up their parents scholarly, nomadic habits, and at the time of the Nobel Ceremony travelled to Stockholm from as far away as New Delhi and Zambia. Although Hodgkin officially retired in 1977, she continued to travel widely and expanded her lifelong activities on behalf of world peace, working with the Pugwash Conferences on Science and World Affairs. Hodgkin died of a stroke on July 29, 1994, in Shipston-on-Stour, England.

Further Reading

McGrayne, Sharon B., Nobel Prize Women in Science, Carol Publishing Group, 1993.

Opfell, Olga S., The Lady Laureates, Scarecrow Press, 1986.

Journal of Chemical Education, Volume 54, 1977, p. 214.

Nature, May 24, 1984, p. 309.

New Scientist, May 23, 1992, p. 36. □

Dorothy Crowfoot Hodgkin

1910-1994

English Chemist and Crystallographer

Dorothy Crowfoot Hodgkin was a pioneer in the use of x-ray crystallographic methods for the determination of crystal and molecular structures and is widely regarded as the founder of protein crystallography. She both developed the x-ray crystallographic methodology and used it to solve the molecular structures of a number of complex biologically important molecules. She also served as a much-admired mentor and role model for several generations of xray crystallographers throughout the world.

Dorothy Crowfoot was born in Cairo, Egypt. Her father was an archeologist and her mother an artist. She was educated in England and received two degrees from Somerville College of Oxford University, a B.A. in 1931 and a B.Sc. in 1932. She studied chemistry at Oxford and did her first crystallographic studies as an undergraduate. In 1933, she continued her studies at Cambridge University under the direction of x-ray crystallographer John D. Bernal. During her graduate studies, she took the first xray diffraction photograph of a protein (pepsin). She was awarded her doctorate by Cambridge in 1937. In 1935, she returned to Oxford University, where she became a member of the faculty. In 1937 she married Thomas L. Hodgkin, an historian whose specialty was Africa. They subsequently became the parents of three children.

During the 1940s, she used x-ray crystallographic methods, many of which she developed herself, to determine the molecular structures of cholesterol, penicillin, and hemoglobin. X-ray crystallographic methods require numerous repetitive calculations involving very large sets of data. Today, such calculations are performed quickly with the use of computers. There were, however, no high-speed computers available at the time Dorothy Hodgkin undertook her work, and each structure determination required lengthy, tedious calculations to be done by hand. Even the determination of the structure of a relatively small molecule was a lengthy enterprise; those of the complex molecules that she chose to study each required a number of years to complete.

The dramatic success of her research led to her election as a fellow of the Royal Society in 1947, and she served as the Society's Wolfson Professor during 1960-77. She was awarded the Nobel Prize for chemistry in 1964 for the determination of the structure of vitamin B₁₂ by x-ray crystallographic analysis. Vitamin B₁₂ is used to prevent and to treat pernicious anemia. In 1965, she became the second woman ever to receive the British Order of Merit; the only other woman so honored had been Florence Nightingale in 1907. Hodgkin was further honored with the position of Chancellor at Bristol University, and she served in this role from 1970-88.

One of her greatest successes came in 1969 when she announced the successful determination of the molecular structure of insulin, a protein used in the treatment of diabetes. It had taken her a total of 34 years to complete this major work.

In addition to her scientific undertakings, Hodgkin remained actively dedicated to the cause of world peace throughout her life. In 1957, she was a founder of the Pugwash Conference on Science and World Affairs and used every opportunity to speak or otherwise lend her support to the movement.

Hodgkin was not only a pioneer in x-ray crystallography and in the determination of the molecular structures of proteins, she was also a pioneer as a woman in the scientific research and academic establishments. Her distinguished success not only led to her own personal acceptance but made it easier for women who followed her. It is also worth noting that her accomplishments came in spite of the fact that she was crippled by rheumatoid arthritis for much of her life.

J. WILLIAM MONCRIEF

Hodgkin, Dorothy Crowfoot (1910–1994) British chemist; Nobel Prize 1964 for her work on determination of biological structures by X‐ray crystallography.