Dr. Dorothy Crowfoot Hodgkin:

Chemist, Crystallographer, Humanitarian

(1910 - 1994)

In 1932 Dorothy Crowfoot graduated from Somerville College at Oxford with a degree in chemistry (her interest in chemistry and crystals began when she was young and was encouraged by her parents and their associates to develop this interest). While studying in the department of mineralogy and crystallography, she employed the physical science of X-ray crystallography (first developed by W. L. Bragg) to aid her in determining the structural arrangement of the atoms in simple salts and minerals such as thallium dialkyl halides. This was the first of what would be many X-ray studies. Dr. Hodgkin discovered that crystals are a solid composed of atoms arranged in a regular and repeated pattern. She later took this method one step further and used it to analyze more complex molecules.

In 1933 Dr. Hodgkin began working with J. D. Bernal on her doctorate degree. Bernal strengthened her lifelong interest in structural biology. She felt that the scientific world had ceased to know any boundaries while conducting her research with him. Dr. Hodgkin stated in a published paper regarding her work with Bernal, "…we explored the crystallography of a wide variety of natural products, the structure of liquids and particularly water, Rochelle salt, isomorphous replacement and phase determination, metal and pepsin crystals, and speculated about muscular contraction."

Crystallography was a relatively new science when Dr. Hodgkin began her research. It was a combination of mathematics, physics, and chemistry. Max von Laue, William Henry Bragg, and William Lawrence Bragg were its early pioneers. They determined that atoms in a crystal deflected X-rays and that these deflected X-rays interfered or interacted with each other. A bright spot could be captured on photographic film if they interacted with each other. This brightness was canceled if they interfered with each other. These X-ray spots, or diffraction patterns, reveal a mathematical relationship to the positions of individual atoms within the crystal. By shining the X-ray through the crystal, capturing the pattern on film, and completing the mathematical calculations on the distances and relative positions of the spots, they were able to determine the molecular structure of almost any crystalline material. Through her research, Dr. Hodgkin was able to determine the structural layout of atoms and the overall molecular shape of numerous molecules. This is the information which contributes to molecular biological activity.

It was during this time that Dr. Hodgkin, along with Bernal, recorded the first X-ray diffraction pattern of a globular protein. These photographs were obtained from crystals of pepsin grown by John Philpot in Uppsala. These protein crystals were extremely difficult and tedious to work with in the early 1930s because of the lack of technology. Proteins are polymers, long chains of repeating units, that are larger and more complicated than other biological molecules. They perform their biological functions by folding over on themselves and assuming specific three-dimensional shapes.

Through this research, Bernal and Hodgkin were able to determine that "the arrangement of atoms inside the protein molecule is of a perfectly definite kind." They also determined that protein crystals should be studied with their mother liquid surrounding them and not air-dried as was the standard of the time. This marked the start of macromolecular crystallography which still dominates current structural biology. This also led to subsequent research on the structures of insulin, hemoglobin, and viruses.

Also at this time, she began her research of sterols which she continued after her return to Oxford. She completed detailed X-ray analysis of cholesterol iodide's molecular structure and over 100 steroids. She reported their unit-cell dimensions, reactive indices with respect to their crystallographic axes, showed the molecules crystal packing, and their hydrogen-bond scheme. This was a breakthrough in crystallography because it was the first analyses based on three-dimensional calculations and it established the stereochemistry at each carbon atom of the steroids.

In 1934, upon her return to Oxford University she crystallized and X-ray photographed insulin. This was only the second protein to be studied and was a major achievement for Dr. Hodgkin because she completed the crystallization and photographs on her own. This analysis was completed at a time when the crystal structures of even simple molecules was a great challenge. Her results changed the face of modern biology. While working at Oxford University, she was barred from research meetings of the faculty chemistry club because she was a woman. Later, her talent and perseverance prevailed and she won over the students and faculty members.

Dr. Hodgkin thought that it might be possible to determine the insulin structure by working with an isomorphous crystal. An isomorphous crystal is a derivative molecule where a single atom is replaced by a heavier one. She believed the zinc atom to be suitable for this type of manipulation. This was the beginning of research that would take her 34 years to complete.

In 1937 she obtained her doctorate from Cambridge University. Between 1942 and 1949 Dr. Hodgkin began work on the structural analysis of penicillin. After the discovery of penicillin, some of the best chemists in Britain and the United States were hard at work trying to determine its chemical composition. She amazed them all when she used X-ray analysis, not chemistry to determine its structural arrangement. The structures of three derivatives of benzylpenicillin (sodium, potassium, and rubidium) using isomorphous replacement, optical analogs, and difference maps were determined. Its structure was obscure until it was established by Dr. Hodgkin and her colleagues in 1945. She also used the first IBM analog computers to aid her in completing the X-ray calculations. This was the first use of an electronic computer as applied to a biochemical problem.

She determined that penicillin has an unusual ring structure with at least four different forms and crystallizes in different ways. This complexity causes it to be a difficult crystallographic problem. Dr. Hodgkin insisted that its core consisted of three rings of carbon atoms and a nitrogen atom. This 13-lactam structure was assumed to be too unstable to exist independently. This was the beginning of synthesis of chemically modified penicillin which has helped to save many lives. Scientists were able to make chemical modifications that were used as antibiotics (cephalosporins and thiosterpton) which Dr. Hodgkin also helped to determine their crystal structures. While completing her penicillin research, Dr. Hodgkin was named a fellow of the Royal Society, Britain's premiere scientific organization, in 1947.

Between 1948 and 1956 she continued to study at Oxford University and Cambridge University. She became a Fellow and Chemistry Tutor at Somerville at Oxford. As a tutor, she encouraged and guided her fourth year and doctoral students towards interesting results with crystal structures. One of her pupils later became well known, not for her work in chemistry, but for her political work. Margaret Thatcher worked as a fourth year student on X-ray crystallography in Dorothy Hodgkin's laboratory. Despite later political differences they always held a great affection for one another. While there she also continued her X-ray analysis of complex biochemicals.

In 1955 she took the first X-ray diffraction photos of cyanocobalamin crystals, obtained from Dr. Lester Smith of the Glaxo drug company; more commonly known as Vitamin B-12. This organic molecule was four times larger than penicillin. Until this point, normal chemical methods had revealed little about the structure of the central part of this molecule. They collected complete three-dimensional data for four B-12 crystals: air-dried, wet, SeCN (having the CN of B-12 replaced by SeCN), and a hexacarboxylic acid derived from B-12. She began her analysis by locating the positions of the heavy atoms, direct Patterson methods, and then calculating the three-dimensional Fourier series using observed F values and phases based only on the heavy atom's positions. Dr. Hodgkin pioneered the use of Patterson maps. The results gave an approximation as to the correct electron density series. Using these approximations to obtain the correct electron density distribution, she was able to determine the crystal structure of the hexacarboxylic acid derived from B-12. Dr. Hodgkin used the cobalt atom to phase the hexacarboxylic acid derivative of vitamin B-12 against the advice of others. They all believed the scattering power of the cobalt atom to be too weak with respect to the rest of the molecule.

Dr. Hodgkin concluded that vitamin B-12 is a porphyrin, a type of molecule related to chlorophyll, but with a cobalt center. This porphyrin ring was missing one bridging carbon atom so that the two pyrrole rings were directly linked, and the B positions of these rings were each fully saturated. They found that the molecule was spherical in form, contained chemical features not seen before, and had a unique chemical structure. She also worked with Kenneth Trueblood, a crystallographer with the University of California at Los Angeles, because he had access to state of the art computer equipment that helped to speed up the calculations of the data. They used mail and telegraphs to communicate their information between California and England. The atomic arrangement of this molecule was eventually determined through the techniques that she helped to develop.

It was later determined that this molecule was not the naturally active vitamin and in 1961 they determined the structure of the natural vitamin. This gave the hint at the biological structure of the vitamin. This B-12 coenzyme was the first known naturally occurring organometallic compound because of this cobalt-carbon bond. This discovery later allowed for the vitamin to be synthesized and used in the treatment and prevention of pernicious anemia. Until this time, pernicious anemia was considered a deadly disease until it was determined that it could be controlled by liver extracts. These liver extracts can be produced synthetically from the same mold that produces streptomycin. The active principle in liver extracts, vitamin B-12, was isolated in crystalline form as a deep-red cobalt-containing crystals. Vitamin B-12 is essential to the building of red blood cells.

They also determined the structure of several related compounds while researching this vitamin B-12. Their discovery was considered "to be the most brilliant application of the X-ray crystallographic approach" and lead to new areas within the field as to the use of heavy atoms to determine the structures of biological macromolecules. Because of her research, others were encouraged to tackle the task of determining the structures of proteins.

In 1956 she received the Royal Medal. In 1958 she became a member of the American Academy of Arts and Sciences. Between 1960 and 1977, Dr. Hodgkin was the first Royal Society Wolfson Research Professor at Oxford University, an endowed chair financed by the Royal Society. In 1961 Dr. Hodgkin began working with United States crystallographer P. Galen Lenhert. Together they completed the analysis of vitamin B-12 as it occurs in nature. They were honored by Cambridge University for "playing a leading part in determining by X-ray analysis the structure of penicillin and vitamin B-12, the antidote to pernicious anemia." Dr. Hodgkin was awarded an honorary doctorate by the university for her research.

In 1964 Dr. Hodgkin was awarded the Nobel Prize for Chemistry. This was awarded for her research on the structure of vitamin B-12. Dr. Hodgkin was only the third woman to ever win the Nobel Prize in chemistry throughout the 63 year history of the award. The other two were Madame Curie in 1911 and her daughter, Irene Joliet-Curie in 1935. The award was given to her not only for the determination of the structure of the vitamin B-12, but also for the unprecedented discoveries which extended the bounds of chemistry.

In 1965 she was named by Queen Elizabeth II as a member of the Order of Merit. This is the United Kingdom's highest royal order. Dr. Hodgkin was the first woman to be bestowed this honor since Florence Nightingale.

On August 14, 1969, Dr. Hodgkin completed the deciphering of the three-dimensional structure of the protein insulin. Insulin research had always been her first love. This discovery was expected to lead to an understanding of how it helps to lessen the symptoms of diabetes. Dr. Hodgkin's research on the structure of insulin was an adventure in persistence. It took her nearly 34 years to complete her research which began in 1935. She never imagined that this discovery would lead to practical applications. More recently, genetic engineers have been able to change the chemistry of insulin to improve its benefits for diabetics.

Insulin is amongst the smallest of all protein molecules because it is only 51 amino-acid molecules long and is considered by research scientists interested in the structures and biochemical functions of molecules to be one of the most important. Dr. Hodgkin attacked insulin crystals with X-rays. By measuring the intensity and the direction of the scattered particles, she was able to map the molecular configuration of the insulin molecule. She determined the geometry of the 777-atom molecule. Dr. Hodgkin replaced the zinc atoms in insulin obtained from pigs with atoms of three heavier elements: lead, uranium, and mercury. After mapping the electron densities of these three derivatives of insulin, the outline of the molecule was computed, but they were not able to determine the key sites for molecular activity through this research.

Dr. Hodgkin was able to determine that the insulin molecule is a six-part molecule; roughly triangular in shape, consisting of three pairs of molecules that enclose two zinc atoms within the core. These are bound together at the ends by groups of pheylanine (a specific amino acid) and secured midway by hydrogen bonds. This six-part structure forms the natural insulin hormone.

The advancements in computer technology played a major role in Dr. Hodgkin's ability to determine the structure of the insulin molecule. In a 1977 interview with Peter Farago in the Journal of Chemical Education, "In a 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." Her scientific endeavors after this discovery revolved primarily around the refinement of the structure of insulin and studies of its various forms.

In 1970 she was elected Chancellor of Bristol University. She supported the establishment of the Hodgkin Scholarship, which aided students from Third World countries, and founded Hodgkin House which accommodated overseas students. Both were named for her late husband who was a specialist in African studies. She was one of the first chancellors to take an active interest in the students and University events.

In 1971 she became a member of the United States National Academy of Sciences and in 1972 she was given the Bakerian Lecture. From 1972 to 1978 Dr. Hodgkin was President of the International Union of Crystallography. Her participation with this organization caused Western governments some alarm because she insisted on having crystallographers from behind the Iron Curtain participate in conferences. Her affiliation with these types of organizations caused her to have some problems with getting her entry visa to the United States. As recognition for her work increased and the Soviet Union disbanded, the restrictions on her United States visa were finally lifted in 1990.

In 1976 Dr. Hodgkin received the Copley Medal from the Royal Society and became a member of the USSR Academy of Sciences. In 1977 she officially retired, but continued to work on her causes for world peace. Between 1977 and 1978 she was president of the British Association for the Advancement of Science and in 1978 was awarded the Longstaff Medal. Between 1977 and 1983 she was a fellow of Wolfson College at Oxford. In 1982 she awarded the Lomonosov Gold Medal because of her high standing within the Soviet scientific community and in 1987 she was awarded the Lenin Peace Prize for her commitment to the Soviet cause and her efforts towards easing tensions between the East and the West while President of the "Pugwash". She helped to form this group in 1976. It was created to aid in the promotion of communication between scientists on opposite sides of Iron Curtain during the Cold War. During conferences on thermonuclear weaponry she was able to cool heated discussions and tempers with a few gentle, thoughtful words. In 1988 she became an honorary fellow at Bristol University. In July of 1994, Dr. Dorothy Crowfoot Hodgkin died from stroke at home in Shipston-on-Stour, England.

Dorothy Crowfoot was born in 1910 in Cairo, Egypt while both of her parents were working there. Her father was an archaeologist serving with the Egyptian Ministry of Education in Khartoum and her mother was a self trained amateur on botany, nature artist, and an expert on Coptic textiles. Her parents moved around the world as her father's government career evolved and Dr. Hodgkin and her sisters only saw them when they returned to England, which was only for a few months each year. In 1914 she and her sisters were left behind in England while their parents traveled to Egypt. Dr. Hodgkin always said that this helped to encourage her independent spirit.

In 1937 she married Dr. Thomas Hodgkin who was an expert on African affairs. He was the son of the late Robin H. Hodgkin provost of Queen's College at Oxford and cousin to Professor A. L. Hodgkin a recipient of the Nobel Prize for medicine in 1963. All of their children took up their parents scholarly and nomadic habits. Their eldest son Luke taught at the University of Algiers and attended Princeton University in 1963 on a lectureship in mathematics. Daughter Elizabeth taught at a girl's school in Zambia in 1964. Son Tobias worked in India in 1964 in a volunteer service similar to the American Peace Corps. In 1993 Dr. Hodgkin was a grandmother nine times over, and had three great-grandchildren. Dr. Hodgkin continued to travel extensively and touched every possible corner of the world throughout her life despite her lifelong struggles with rheumatoid arthritis that did not respond to treatment. This eventually crippled her hands and feet, but despite this she continued to travel and participate in her causes until the very end.

The Hodgkin's were said to keep an open house where everyone was always welcome and radiated warmth and hospitality. Their guests included the powerful, the famous, revolutionaries and refugees, as well as their own countless students, colleagues, and friends.

Over the years Dr. Hodgkin has worked with hundreds of scientists from around the world and created an international joint family where she acted as a motherly figure. Her "children" include 25 from the United Kingdom, 20 from the United States, 10 from Australia, 7 from India, 6 from Canada, 5 from New Zealand as well as others from Sweden, Switzerland, Italy, Chile, Denmark, New Guinea, Germany, Holland, Yugoslavia, China, Japan, Poland, France, Nigeria, and the former Soviet Union. To her students and colleagues she "was a teacher, mother, friend, and guide all rolled into one". She helped, advised, and encouraged crystallographers and scientists she came into contact with.

Dr. Hodgkin has held close relationships with scientific communities all over the globe. The scientific community in India, in 1973, asked her to deliver the Azad Memorial Lecture. She has held the Raman Professorship of the Indian Academy of Sciences and was an honorary fellow of the Indian Academy of Sciences. She has helped to promote international understanding through scientific and related activities.

She has always been a champion of world peace and disarmament. She was a strong supporter of national liberation struggles, proponent of the development of third world countries, and signed on with several organizations that admitted Communist party members. Dr. Hodgkin inherited these ideals from her mother who was strongly opposed to war because of the deaths of her four brothers. When Dr. Hodgkin was a child her mother would take her to League meetings in Geneva.

Not only had she been a major contributor within her own field of expertise, she tried to promote international goodwill and understanding between all of the people throughout the world. She has been described by colleagues as being a "warm, simple, affectionate, and caring" human being.

In M. Vijayan's memorial written about her after her death, he quoted Einstein as having said about Mahatma Gandhi: "Generations to come, it may be, will scarce believe that such a one as this ever in flesh and blood walked upon this earth." With all of her accomplishments, awards, and contributions to modern science, such can be said of Dorothy Crowfoot Hodgkin. One of her colleagues, M. F. Perutz said of Dr. Hodgkin, "she will be remembered as a great chemist, a saintly, gentle and tolerant lover of people and a devoted protagonist of peace". Professor J. D. Bernal, with whom Dr. Hodgkin conducted research, believed that successful analysis depended on the researcher's strategy. He said of Dr. Hodgkin, "She was one of these masters whose method of work is as exciting and beautiful to follow as the results that flow from it."

Dr. Hodgkin determined the molecular structures of penicillin, vitamin B-12, insulin, and countless other proteins through X-ray analysis. Through her research she was also able to improve the methods used in X-ray diffraction. She developed three-dimensional views of the molecular and atomic structures of extremely complex organic compounds, one more complicated and larger than the last. Her research allowed others to grow and expand their ideas. Two of which, Cambridge scientists John C. Kendrew and Max F. Perutz, were able to obtain clear, three-dimensional views of several proteins including hemoglobin and myoglobin. With each new discovery, Dr. Hodgkin expanded the technology of crystallography. By choosing projects others considered impossible, she helped to establish one of the characteristic features of contemporary science: the use of molecular structure to explain biological function.

Works Cited

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Dorothy Hodgkin." Crystallography World Wide. 20 September 1994.

Jaffe, Bernard. Crucibles: The Story of Chemistry from Ancient Alchemy to Nuclear Fission. New York: Dover Publications, Inc., 1976.

"Hodgkin, Dorothy Crowfoot". Facts on File 54 (1994): 560.

"Insulin Structure Deciphered". Facts on File 29 (1969): 783A.

"Nobel Prize Winner is a Grandmother." The New York Times 30 Oct. 1964: 23.

"Hodgkin, Dorothy Mary, nee Crowfoot." Larouse Dictionary of Scientists. 1994 ed.

Asimov, Isaac. Asimov's Biographical Encyclopedia of Science and Technology. Doubleday and Company, Inc.: Garden City, New York, 1972.

"Fifty Years of Pepsin Crystals," Nature 24 May 1984: 309.

"The Chemistry - Minded Mother," Time 6 Nov. 1964: 41.

"Insulin Design Traced," Science News 4 Oct. 1969: 307.

Mc Grayne, Sharon Bertsch. Nobel Prize Women in Science. New York, New York: Birch Lane Press, 1993.

"Dorothy Crowfoot Hodgkin". Notable Twentieth Century Scientists. 1995 ed.

"Hodgkin, Dorothy Crowfoot". Mc Graw Hill Modern Scientists and Engineers. 1980 ed.

Glusker, Jenny P. and Margaret J. Adams. "Dorothy Crowfoot Hodgkin." Physics Today May 1995.

Hodgkin, Dorothy Crowfoot. "The X-ray Analysis of Complicated Molecules." Science 150 (1965): 979-88.

Copyright © 1996, Linda Juliana Cohen. All rights reserved. Reprinted with permission.