profilef in chemi~tr y
edited bv FESTA Nottheast Missouri State Univerri* K~rksville.Ma. 63501 ROGER R.
Dorothy Wrinch and a Search for the Structure of Proteins Maureen M. Jullan hpanment 01 Geologcal Sciences Vlrgin a Polyiechnic Institute and State Univershy Blackrb~rg.V A 24061 Dorothy Wrinch was a Renaissance scholar whose depth, vision, leadership, and energy were resented rather than respected. Her work spanned mathematics, philosophy, sociology, chemistry, physics, and biology. She dedicated her life to the solution of one of nature's most important and challenging mysteries, the architecture of proteih molecules. While her theories did not mirror nature in quite the way she predicted, they were a critical stimulus t o research. Nevertheless, she herself remained an outsider and a restless, disappointed renegade. Dorothy Wrinch was born of English parents in 1894 a t Rosario, Argentina where her father was an engineer for a Brisith firm. She was educated in England and won a scholarship to study mathematics at Girton College, Cambridge University. Her circle of friends included Bertrand Russell with whom she studied ~ h i l o s o ~ h After v. she received her Cambridge BA and she w& appointed in 1918 t o a lectureship in pure mathematics at Universitv Colleee. London. In 1922 she married John Nicholson, & oxfor> 'physicist known for his work on atomic structure; their only child, Pamela, was born in 1928. At Cambridge, and later a t London and Oxford, Dorothy Wrinch was active in philosophical and mathematical circles. In addition to teaching mathematics, she addressed professional gatherings and wrote prolifically. By 1930, a t the age of 35, she had published 16 philosophical papers on the scientific method, and 20 papers in pure and applied mathematics. Her additional credentials included both MSc and DSc degrees from the University of London, and an MA from Oxford University. Then, in 1929, she was the first woman to receive a DSc from Oxford. That year, after having taught mathematics a t Oxford for seven years, she applied for a Rhodes Traveling Fellowship hut was unsuccessful in receiving the award. Her sponsors franklv informed her that she failed because she was a woman. She filed two more applications: one for a Rockefeller Fellowship to study mathematics a t GBttingen, Germany, and another for a fellowship in sociology to travel in America. Although she was welcomed hv the leadine mathematician a t Gottingen, she failed to get the ~ockefeli&,largely because ~ r o.~ o sand al the foundation offirials learned of the socioloev -.. considered it to be evidence that she was not solely devoted to mathematics. This was in fact true. Since the sociology application was also unsuccessful, she stayed in Oxford. Nevertheless, in 1930, she published a sociological study, "The Retreat from Parenthood," under the pseudonym, Jean Ayling ( 1 ). In the book she sketched a broad plan for reorg&i& medical services, home design, child ckre, and labor laws so that child rearing would be compatible with the professional lives of both women and men. At this time, she made a definitive decision to concentrate her energies on biological architecture. At Cambridge, she was a member of Joseph Needham's Theoretical Biology Club together with J. D. 890
Journal of Chemical Education
Langmuir and Dwolhy Wrinch examining a cyclol mate1 in of Smith College Archives.
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1936. Coultesy
Bernal, J. H. Woodger, C. H. Waddington, and Dorothy Needham. They were interested in what is now known as molecular biology. Dorothy Wrinch (2) describes her new direction Until 1933, my work was research in mathematics and mathematical physics. I had, however, long had a consuming interest in structural problems in physiology and chemistry,and I had always hoped to find specialists in this field with whom I could develop certain ideas. It proved impossible ta arrange such collaboration, since the mathematical ~ o i nof t new was difficultta link uo with the mint .~ of view of the piofessionalrhem~at.At this time, t h i n , it hecame clear to me toahandm theattempt todevelop that I had hut tw~~choicca,e~rher these ideas or tu under~uapprenticeship in chemistry sufficiently extensive to enable me ta formulate the ideas in a form suitable for development by specialist workers. I chose the latter course and spent a year's leave of absence from Oxford on the continent of Eurooe. .. beginning an apprentwship in many diff~rentlaboratories. Already in 1934 the work had propressed far mnugh toatrrnrr rhe Rockefeller Foundation. who in 1935 provided support fur my proiect tor 5 ymn ~
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By 1935, Wrinch had produced an original and remarkable theory of the gene. At the Theoretical Biology Club, she suggested that the specificity of genes resides in the specificity of the amino acid sequences (3).Thus, she made the connection between the linear sequence of the genes and that of the amino acids in the polypeptide chain. She then went on t o construct a molecular model of the chromosome. The cyclic tetranucleotides were assumed t o be a t right angles to the
chromosome axis. This structure was shown not to he correct by experimental birefringence data. However, the sequence hypothesis was important. Wrinch then turned her attention to the globular protein molecules and within a year or so produced a structural model (4). Beginning with the single hypothesis that peptide chains would he polymerized into sheets by links between CO and N H groups, Wrinch deduced that the sheets would fold into a series of closed octahedra which she called cyclols. The series was described by the general formula 72n2, where n was the integral numher-of a m h o acid residues. When Bergmann and Niemann (5)in 1937 deduced that egg albumin had 288 = 72 X Z2 residues in the molecule, Wrinch felt her hypothesis was proven. Here was an example with n = 2. This clever deduction startled the emergingworld of molecular biology. Controversy raged with Nobel prize winners lining up on either side; 1r;ingLangmuir was her leading advocate (see figure) and Linus Pauling her leading critic. The embroilment reached disastrous proportions with Wrinch being virtually blacklisted by most of the scientific community. She felt personally attacked. For example, in 1938,after a meeting with Linus Pauling she wrote (2), "The fact that they are against cvclols in anv fundamental and a ~ r i o r wav i in itself rather gives the show away. Hecause it is indenial,& that the theory had NOT vet been shown to be false and therefore onlv fools or men of &I wishes towards me will be against it a j&ri . . .." However more than a decade was to pass before anv correct protein structures were discovered. Although thesebroteins did not contain cyclols, Wrinch's ideas had nonetheless stimulated much thought and work. Wriuch's personal life was not happy. In 1937 her marriage was dissolved, and, two years later, she moved with twelveyear-old Pamela t o the United States. The Rockefeller Foundation supported Wrinch's work until 1940; she spent the academic year 1940-41 a t the Chemistry Department of Johns Hopkins University. In 1939 Pauling and Niemann (6) predicted from hond energy values and heats of combustion that a protein with the cyclol structure would he less stable than one with a polypeptide chain by about 28 kcallmole of amino acid residues. Although the details of their calculations were incorrect, as Wrinch pointed out a t the time (71, they were widely accepted. Wrinch's fellowship was up, she could not find a job, and World War I1 had begun. She was worried about Pamela who was quite sensitive about the controversy in which her mother was involved. Pamela had written a letter to Pauling himself (7). Your attacks on my mother have been made rather too frequently. If you both think each other is wrong, it is best to prove it instead of writing disagreeable things a h u t each other in papers. I thinkit would he best to have it out and see which one of you is really right. There are many quarrels in the world alas!! Don't please let yours he one; it is these things that help to make the world a kingdom of misery!! Wrincheventually found a position in 1941. With the help of O.C. Glaser of the Amherst College biology department, she was appointed a visiting professor a t Amherst, Smith, and Mount Holyoke Colleges. Not surprisingly, there was a fair amount of local opposition to her appointment. Some months later, Wrinch and Glaser were married, and they settled permanently in Massachusetts. After her year as a jointly appointed visiting professor, during which she gave seminars a t all three colleges, Wrinch was given a research position a t Smith, nominally in the physics department. Her association with Smith lasted for 30 years, until her retirement in 1971. There she had a few graduate students, conducted seminars for students and faculty, lectured, and continued her research. In the summen, she taught and lectured a t the Marine Biological Laboratories a t Woods Hole. Massachusetts. Her work flowed a t an incredible rate. 1" the 1940's she concentraced on developing technioues for interoretine X-rav data of romnlicated crvstal structures, and appiying ihese techniques td protein x-ray
data that she was ahle to obtain from experimentalists. Numerous papers and an important monograph "Fourier 'I'ransforms and Structure Factors" (9)were published. She studied mineralogy, hoping to deduce significant fraturcs of prutein structures by drawing analogies between the mornholoeies of their crvstals and certain minerals. Notebook after notebook was filled with her criticisms and ideas on Dauers coverine manv branches of science. Her total list of piblications evlntualfy reached 192. When Wrinch's husband died in 1952. she moved t o a facultv residence on the Smith College campus. After her retirement in 1971, she moved to Woods Hole. In the period following World War 11, Wrinch's life had almost taken a new turn. John von Neumann had invited her to become a consultant in his pimeering work on computers at Princeton hecause she had persuaded him that one of the major uses of computers would he to aid in the interpretation of the X-ray patterns of protein crystals. Wrinch was enthusiastic and full of ideas, hut her hoped-for move to Princeton never came about. Surely if von Neumann really wanted her, he could have used his vast personal influence and power to obtain necessary funds (8). I t appears that no one but Wrinch believed that proteins had the cyclol structure. For her part, she was convinced that the available experimental evidence had been incorrectly interpreted. Then one evening in 1954, a chemistry professor a t Smith came across an article written two vears earlier hv the Swiss chemist, Arthur Stoll(10) which ciaimed that t h i cyclol structure had been found in the ergot alkaloids. Ergot is a parasitic fungus that thrives on cereals, especially on the ears of rye (11). Ergot of rye is the starting material for many pharmaceutical preparations. The uterotonic property of ergot inspired Stoll to mepare a numher of ~artiallvsvnthetic ~ o ~ ~ o uwhich n d s have found a variety of unexpected clinical applications. The structure of the peptide portion of the ergot alkaloids gave Wrinch's theories experimental verification. The linkage between amine groups of neighboring peptide chains confirmed cyclol theory. The ergot alkaloids are, in a sense, simple versions of proteins, and Wrinch was absolutely delighted with this example (12). Thirteen years after Pauling and Niemann had "proved" that the cyclol hond was too unstable to exist, it had been actually found! Alas, the scientific community had moved on to other fronts and it paid little attention. Wrinch once told Marjorie Senechal(Z), "First they said my structure couldn't exist. Then when it was found in nature they said it couldn't he synthesized in a laboratory. Then when it was synthesized, they said it wasn't important anyway!' However she persisted and was ahle to get funding from the Ziskind Foundation and. later. the National Science Foundation. She spent the rest of her life working out the details of her theorv. Her dauehter. - . Pamela Wrinch Schenkman. died a fire in November 1975; Wrinch died three tragically months later a t the age of 82. What are the conclusious to be drawn from Dorothy Wrinch's life? She was brilliant. wittv. ambitious. hard working, and a t times was consideled jeaious, abrasive, and aeeressive. Her considerable talents hrideed manv fields. She acromplished much but was restless and dissatkfied. What mirht have hamenrd if she was less embittered. if her crossing of the boundaries between disciplines had been hetter ac: cepted, if her cvclol structure had appeared more in nature, if ;he had not felt sostrongly that 3he.was fighting the malefemale interface, or if her funding and iob situation had been hetter, it is impossihle to guess. ~ & h a < sthe zeal for attacking impossihle and important problems, together with an ineptitude for politics of science, would force conditions of disappointment on anyone. Michael Polanyi wrote to Dorothy Wrinch in 1948 (a), "You and I have much in common in the manner we managed to make our scientific careers less dull than usual." Indeed hers was. Volume 61 Number 10 October 1984
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Literature Cited 11) Ayling, Jeao (pseudonym), "The Retreat fmm Parenthd," Kegan Paul, Trench, Trubner & Co..Ltd., London,1930. 12) Scmchd,M.."Akophet~thautHonoxDmothyW&ch,Scientisf 1@9&1976:'Smith
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(7) wrineh, D., N ~ ~ 145.669 U ~ . 11940). (8) SensehaLM. lEditar)."Strueturraof Matter and PetternamSciencelnspid by the Work and Life of Dorothy Wrinch, 189&1976,"SchenLman Publishing Company Inc, Cambridge, MA, 1980. (9) Wrinch, D., "FourierTransfom aod StruddFactocto," American Society for X-ray sod Electron Diffraction, Monograph No. 2, Cambridge. MA. 1946. (10) Stoll, A,, PIag in Chem. of Or& Nor. Praducts.9.114 (1952). (11) Stoll, A,, Hoffman, A. and Petnilka, T., Helu. Chim. Acta, 34,1544 (1951). (12) WrinchD.. Nature, 179,536 (1957). ~
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