Isabella L. Karle and a new mathematical breakthrough in

This daughter of immigrant parents is the answer to the question: How are mathematics, crystallography, frog venoms, poisonous mushrooms, DNA breakdow...
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Isabella 1. Karle and a New Mathematical Breakthrough in Crystallography Maureen M. Jullan Depanmen ol Geo ogcal Sclences V rg ma Paolecrm c nsl lule and Stale n ,. versry B acrsoug. VA 24061

How are mathematics, crystallography, frog venoms, poisonous mushrooms. DNA breakdown. ionic transnort across biological membranes, and a whole new method of structural analysis related? The answer is through Isabella Karle. She is an experimentalist, and her husband, Jerome Karle, is a theoretician. He and others worked out a mathematical theory which greatly extended the scope of crystallography; Isabella applied the techniques and made them popular and accessible to the crystallographic world. Her applications include many intriguing subiects i born in Detroit, Michigan, on Isabella i el en ~ L g o s kwas December 2. 1921. Her oarents had emimated from Poland and spoke only Polish at home; she never heard or spoke Enelish until she was in the first grade. Her mother was a seilkstress and her father a housgpainter. Hetore rntering aranimar schoul, Isahella's rnothrr had tilurht her in Polish to do the basicmathematical operations and to read and write. When Isabella started school, she progressed with almost unbelievable speed; there were only fifteen and onehalf years between her entering the first grade and her Ph.D. deeree! She won a four-vear undereraduate scholarshio to " the University of Michigan where she was also a teaching associate. Although she graduated from Michigan with highest honors, she could not get a graduate teaching assistantship in chemistry because women had never held them. Because of her outstanding academic record, the American Association of Universitv Women awarded her a fellowshio and she was able to begin her graduate studies. As a result of a stimulating physical chemistry course with Lawrence 0.Brockway a t Michigan, Isabella and fellow student, Jerome Karle, chose to study electron diffraction by gaseous molecules. Their apparatus, although excellent by the 1940's standards, had home-made electronic circuits and difficult-to-maintain vacuum systems. After the electron beam passed through the gas, images of the diffracted, con-

66

Journal of Chemical Education

l~abellaKarle at work at the Naval Research Laboratory in Washington. DC.

centric rings were photographed. The diameters and different reliltiv; intenshies of the rings depended on the geometric properties of thegasand the voltageoitheelcctn)n beam. A mathematical analysis of the measurements of the positions and intensities of the rings made it possible to calculate the interatomic distances and angles in the gas molecules. The computations were tedious; strips of paper with trigonometric functions strategically placed along the edge were lined up to aid the summations. A hand-cranked calculator was used for the arithmetic. Jerome and Isabella were married in 1942 and finished their graduate degrees in 1943 and 1944 within afew months of each other. Isabella was 22 when she got her Ph.D. After

graduation they worked in Chicago on the Manhattan Project and then a t the University of Michigan until the end of the war, when Jerome's military-related project was over and Isabella's teaching position held no future. Then they began to search for permanent places. Although academia was attractive to them, nepotism-rules made it to find suitable positions for both. Fortunately the Naval Research aho oratory in Washington, DC, offered them an opportunity to continue their research on gas electron diffraction. With the help of an excellent machine shop, they constructed two duplicate s t a t e - o f - t h e - a r t diffraction instruments to be sure that a t least one instrument was leakproof. The system featured tandem electromagnetic lenses which enhanced the aualitv - .of the electron beam. One of the first molecules analyzed was carbon dioxide in which for the first time vibrational parameters were determined by electron diffraction ( I ) . Isabella's research in electron diffraction led naturally to an intense interest in structure analysis by X-ray diffraction. In the work on electron diffraction of gases, a nonnegativity criterion was introduced in order to ohtain an appropriate experimental function for the background intensity. The nonneeativitv criterion came to full blossom in Isabella's " practical applications of a crystallographic technique called "Direct Methods" which revolutionized structure analysis. Inorder to appreciate what happened alittle history must he considered. In the 1930's A. L. Patterson had introduced the first general systematic structural approach with his "heavy atom technique." An atom of high atomic number, relative to the rest of the atoms in the crystal, was first located and then the rest of the atoms were found by successive approximations. Many structures have been and are being solved in this way. However there is a large numher of compounds with nearlv enuallv weiehted atoms such as carbon. oxveen. and nitrogen- for -these substances the patterson' m%od often fails. "Direct Methods" are mathematical techniques for phasing the diffraction pattern to which Jerome has made important theoretical contributions (2. 3). Isahella applied the theory to a large numher of structu~esand developed a systematic attack for the general problem. This method is called the "Symbolic Addition Procedure" ( 4 , 5 ) . T o give an idea of the importance of her work, a National Science Foundation Study (6) found that her 1966 paper (5) outlining the theory of the "Symbolic Addition Procedure" occurred sixth in the listing" of 100 chemical articles most cited in 1972. Isabella has annlied .. these mathematical techniaues to an interesting variety of substances. One example is the frog venom study (7). The frog skin secretions have been used by the South American natives as arrow-tip poisons. The toxins block specific nerve impulses which makes them ideal for medical studies in nerve transmission. Isahella studied the crvstals distilled from the froe venom. She found that different species of frogs produced toxins with very different structures, even in the case of frogs living on opposite sides of the same stream. Another study under way is the effect of radiation on DNA in human cells. Radiation causes genetic damage by hreaking the bonds between the atoms; abnormalities result when the new honds connect in a varietv of different wavs. For example one of the substances she studied was irradiated thvmiue (8) which is related to the nroduction of antibodies. s h e has also identified structures'of photon-generated dimers of nucleic acid bases, which could he reversed readily to undamaged monomers, and of polymers, which could not he readily reversed. Another example of Isabella's work is the study of the csclic p l s ~.e ~ t i dmolecule, e valinomvcin (9).which trans. o .. ports potassium ions across membranes in biological systems and also is an antibiotic for a type of tuberculosis. From a purely crystallographic point of view this molecule is the largest-by a factor of two-published structure analysed to

date without the heavy atom technique. Valinomycin contains 156 independent nonhydrogen atoms and 180 hydrogen atoms. Isahella Karle is the leading authority on peptide structures in the solid state (10).She demonstrated that although the folding of the peptide backbone is quite unpredictable, the conformation is independent of the polarity of the solvent. She has also been investigating the structures of antamanide ( 1 0 , a cyclic decapeptide isolated from poisonous mushrooms. This substance is an antitoxin which counteracts the deadly toxin phalloidin also found in the same mushroom. Antamanide selectively transports sodium and calcium ions across membranes. Most recently Isahella solved the structure of enkephalin, a natural analgesic occurring in the brain. The crystal consists of four enkephalin molecules, each with a different cunforrnation, and-s large number of solvent molecules surroundinr: rhe p r p ~ ~ d Iur e s a tofal of more than 210 i n d e ~ e n . dent carbon, nitrogen, and oxygen atoms (12). The Karle's have three daughters; the first, Louise, was horn in 1946, the second, Jean, in 1950, and the third, Madeleine, in 1955. Louise now has a PhD from the University of Washington in chemical spectroscopy and works a t Brookhaven National Laboratories; Jean has a PhD in organic chemistry from Duke University and is a t the Walter Reed Army Institute of Research near Washington, DC; and Madeleine is working a t the Smithsonian in the Museum of Natural History. Isabella's laboratory has included mans postdoctoral students as well as a numher of visiting schoiars from all over the world. She is a welcome lecturer particularly because of her detailed examnles of the "Svmholic Addition Procedure." A happy consequence of the Karle's international travels is that their dauehters have enioved manv interestine foreien was president of t h i ~ m e k and domestic [rips. In 1976 can Crvstalloerawhic Association and that same vear received the ~ a & &Medal of the American c h e m i c a l ~ o c i e t ~ . Her publication list is now past 200. Isabella L. Karle developed the practical aspects of a mathematical theory of crystallography which revolutionized the types and complexity of problems that may he attacked by. crsstal-structure analysis. Her research led to . anexponential increase in the sprri1 and inrility with which the questions uf identification and structural conf~gurati~n could he answered. Note added in proof: Isahella Karle received the Chemical Pioneer Award from the American Institute of Chemists in 1984, and Jerome Karle, along with Herbert Hauptman, was awarded the 1985 Nobel Prize in Chemistry for the mathematical theories discussed in this paper.

&e

Acknowledgment

The author would like to thank both Isahella and Jerome Karle for interviews a t the 1982 Spring Meeting of the American Crystallographic Association a t the National Bureau of Standards, Gaithersburg, Maryland. They also gave generous access to both published and unpublished material and kindly read this paper. Literature Cited 11) Karle. I. L.;Karle J. J. Chem.Pkys. 1949,17,1052. (2) Karle. J. "Tho Direct Method tor Cmtal Structure Determination, Mathematid and Philorophical Concept# in "Crystallographie Computing Techniques": Ahmod, F. R. Ed.;Munkspeard:Copenhagen. 1976. (3) Ksrle. J.: Hsuofman. H. Aclo Crvst. 1910.3 181. 14) Karle. I.L.:K& ~ . ' ~ c ~ryri.~1963. to 16,'969. ( 5 ) Karle. J.;Karle, I. L.Arlo Cryst. 1966.21.849.

(6) Small. G. Contract No. NSF-C795, September 1974. 17) Karle.1. L.; Karle, J.Aelo Cryst. 1969.B25.428. 18) Karle. I. L. Acla Cryst. 1969,825.21L9. 19) Ksrle. I. L. J . Amsr. Chem. Soe. 1975.97.4379, 110) Ksrle, I. L. "X-ray Analmir: Conformation of Peptidea in the Cmtslline State" in "The Peptides"; Gross, E. Moienhofer, J. Eda.: Academic Press: New Yark,1981: Vol 4, pp 1-54. I l l ) Karle. I. L. Pmc. 6th Amer. Peptide Symp. 1979,681. (12) Karle. I. L.;Ksrle, J.;Camerman,A.;Csmerman,N.. A d o Cgvsf. 1983.B39,625.

Volume 63

Number 1

January 1986

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