Isabella Karle: Crystallographer Par Excellence

Isabella Karle's greatest contribution to crystallography was delivering the first experimental proofs that the mathematics developed by her husband J...
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Chapter 12

Isabella Karle: Crystallographer Par Excellence Lou Massa* Chemistry & Physics Departments, Hunter College & the Graduate School, City University of New York, New York, New York 10065, United States *E-mail: [email protected].

Isabella Karle’s greatest contribution to crystallography was delivering the first experimental proofs that the mathematics developed by her husband Jerome Karle in tandem with Herbert Hauptman were, in fact, sufficient to solve crystallographic structures. Such mathematics came to be called direct methods because they made it possible to go directly from measurements of X-ray intensities to the crystal structure. Today, the vast majority of crystal structures are solved by direct methods.

Isabella Karle (1921–2017) (1–7) was already a legendary figure in the world of crystallography when I first met her in 1985 at a meeting to celebrate 50 years of the Patterson function. She and her husband Jerome Karle were among the luminaries in attendance at the meeting at the Fox Chase Cancer Center in Philadelphia, Pennsylvania, where Arthur Lindo Patterson had spent most of his illustrious career. The important crystallographer Jenny Glusker, a student and collaborator of Dorothy Hodgkin’s at Oxford University, spent a year as a postdoctoral fellow at the California Institute of Technology with Robert Corey, had come here to work as a researcher with Patterson, and subsequently stayed on to develop her own significant career at Fox Chase. She was one of the organizers of the meeting. The four people whose work was most intimately connected to the invention and development of direct methods for solving the phase problem in X-ray crystallography were in attendance at the Patterson meeting: Isabella and Jerome Karle, Herbert Hauptman, and David Sayre. Solving the phase problem by direct methods, clearly worthy of a Nobel Prize, had been thought for decades to be © 2018 American Chemical Society Mainz and Strom; The Posthumous Nobel Prize in Chemistry. Volume 2. Ladies in Waiting for the Nobel Prize ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

not just a difficult problem, but one that was mathematically impossible to solve. Isabella proved experimentally that direct methods indeed solved the phase problem of X-ray structures. I thought that she deserved to win the Nobel Prize for her work when I met her at the Patterson symposium. On the day of the meeting, the weather in Philadelphia was unusually beautiful, and I was out of doors enjoying it while talking to the accomplished crystallographer Miriam Rossi. A student of mine at Hunter College, after obtaining a Ph.D. with Thomas Kistenmacher at Johns Hopkins University, she had spent a postdoctoral appointment with Jenny Glusker at Fox Chase. Also enjoying the weather, Isabella and Jerome Karle were out for a walk across an expansive lawn and were some distance from us. Recognizing them far afield, Miriam asked if I would like to meet the Karles, whom she already knew. I said I would love to meet them, so we trekked out across the lawn to join the Karles. Miriam presented me to them, and we chatted pleasantly for some minutes before realizing we should all get back to the symposium for the afternoon session. What I did not realize at the time was that I would spend more than 30 years working with the Karles, especially during long summers at the U.S. Naval Research Lab in Washington, DC, where their greatest discoveries in crystallography had occurred. When I started working with the Karles, our families became fast friends. Isabella was not just a great scientist; she was a warm, generous person who was welcoming to newcomers like us. Isabella and her family shared their lives and stories of their adventures with us. They lived on a small, serene lake in northern Virginia, just outside of Washington, DC. Once, during our first summer with them, Isabella invited us to a home-cooked dinner, which we all enjoyed enclosed within a screened-in porch while an enormous thunder storm, so typical of late afternoon summers in that area, howled all about us. After dinner, the Karles shared memories of their adventures traveling among various seminars they had attended in Europe and elsewhere. My wife and I were newlyweds back then, but not long after, our family began to grow with the arrival of two daughters born five years apart. Each of them spent their first summer on that same lake with the Karles. I remember climbing up into their attic to retrieve for each of our daughters the same bassinet the Karle children had used. Isabella, in her characteristically generous way, insisted we use it. As I grew closer to Isabella and her family, I learned more about how she grew up. Isabella’s parents were Polish immigrants who lived in Detroit, Michigan. The language spoken in the home was Polish. That was more or less Isabella’s only language until she went to public school at about the age of five. Her mother operated a fairly modest restaurant, mainly intended to supply lunch for workers in their area. At the very young age of five or six, Isabella took on the tasks of an accountant for her mother. She kept track of bills and funding for the family business. During her school years, her teachers took note of her scholarly abilities. After leaving high school and starting at a smaller college, she was ultimately offered a full scholarship to attend the University of Michigan. From elementary school through her university years, she was always at the top of her class (3, 5). As a senior at the University of Michigan, it would seem she met her intellectual match in the person of Jerome Karle. Jerome was an incoming 284 Mainz and Strom; The Posthumous Nobel Prize in Chemistry. Volume 2. Ladies in Waiting for the Nobel Prize ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

graduate student, but he was required to take an undergraduate physical chemistry lab course to get himself started. The students in the class were assigned to lab stations alphabetically according to family names, and so Isabella Lugoski was put next to Jerome Karle. Jerome had skipped lunch to enter the lab ahead of its starting time, and when Lugoski arrived to find herself next to Karle, she was mildly annoyed to see his rather complicated experimental setup entirely in place and ready to go. Their relationship did not immediately flourish. Jerome was an accomplished pianist and asked Isabella to attend a concert one evening. When she arrived wearing the same clothes she had worn in the lab that day, he was not impressed. Fortunately, things got better. They started attending movies quite regularly on weekends. What finally cemented the relationship was a bit of flu that sent Isabella back to Detroit to recuperate at her family home. Jerome made a follow-on trip to Detroit to bring Isabella the class notes she had missed in her absence from the campus. Their scientific cooperation, not to mention their life together, was well underway.

Figure 1. Isabella and Jerome as students, sometime during the World War II years, with their Ph.D. mentor Lawrence Brockway. (Photo credit: U.S. Naval Research Laboratory.) Both Isabella and Jerome took up their Ph.D. research under the guidance of Lawrence Brockway (8), seen in Figure 1. He was an early student of Linus Pauling and had carried out his thesis work in the experimental field of electron diffraction. The electron diffractometer built by Pauling and Brockway was the earliest such instrument in the United States (9). Electron diffraction proved to be useful in determination of the structure of molecules in the gaseous phase. Isabella and Jerome, under the tutelage of Brockway, became experts in the practice of electron diffraction experiments. During their Ph.D. work, they got married. The two remained close to Brockway after earning their doctorates in 1944, and Brockway was supportive of their work afterward (6). For example, immediately after his graduate work, Jerome departed for the University of Chicago to take part in research for the Manhattan Project. The importance of that site for the Manhattan Project was underscored by the presence of Enrico Fermi, Leo Szilard, Glenn Seaborg, and other such recognized scientists. Isabella completed her Ph.D. a few months after Jerome, who by then was already at work 285 Mainz and Strom; The Posthumous Nobel Prize in Chemistry. Volume 2. Ladies in Waiting for the Nobel Prize ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

in Chicago. At that point, she, too, joined the Manhattan Project at the University of Chicago. Working separately from Jerome at the age of perhaps 23, she was put in charge of studying the chemistry of plutonium halides and was particularly focused on how chlorides combine with plutonium (7). She determined what experiments were to be done and how to carry them out. Although this research had little to do with her electron diffraction studies, her Ph.D. background did prepare her for one aspect of the new work: The halogen gases and their reaction products had to be transported and captured by elaborate glass containers and tubing connections. She created the needed glass elaborations on her own and in a manner that would have pleased the alchemists that had invented much of the glassware contraptions still used in chemical experimentation. Isabella’s experiments produced big, beautiful crystals of plutonium chlorides (10). Of course, the crystal structures would not have been known because these would have been the first such crystals made with plutonium. William Zachariasen (11), a famous crystallographer, was present on the campus, and Isabella struck up a collaboration with him to determine the important but unknown structures. They found that plutonium formed chlorides in structures similar to the known uranium chlorides. The results, because of plutonium’s use in building an atomic bomb, were classified until after the war. However, it is impressive to contemplate how such an important investigation in the context of the war was assigned to such a very young woman who had just recently completed her Ph.D. schooling (12). As it happened, the research led to the desired results, namely, the discovery of the structure of the plutonium chlorides (13). Work at the Manhattan Project was serious and demanding, but amusing things also happened, which Isabella would sometimes recount for us at social gatherings. For example, she recalled once at a dinner party with our family a story about transporting her crystals to Zachariasen’s laboratory for X-ray diffraction studies. When her collaboration with Zachariasen began, she simply put the crystals in her pocket and walked across the university campus to make the delivery. Somehow, the security administration overseeing the project got wind of this informal transfer process and expressed alarm. The result was that henceforth Isabella had to be accompanied by two uniformed military guards brandishing weapons, one to her left and one to her right. Surely a pigtailed 23-year-old girl guarded in such a showy way brought unneeded attention to a strictly secret program. In the end, however, it all worked out; the crystals made in Isabella’s lab were delivered to Zachariasen’s lab, and their structure was determined. Over the years, we extracted many such human interest stories about Isabella’s time serving the Manhattan Project. At the end of the war, the Karles returned to the University of Michigan, which surely would have been arranged by their influential thesis advisor Brockway. Jerome was supported by a naval research project, and Isabella became a junior faculty member as an instructor in the chemistry department. Significantly, she was the first woman at the university to hold such a position. In present circumstances, it is hard to imagine how difficult things could be for a married couple in a university setting at that time. For one thing, it was almost unthinkable that a husband and wife could both hold professorships in the same department. For that reason, Isabella and Jerome recognized an offer from the U.S. Naval Research Laboratory (NRL) as 286 Mainz and Strom; The Posthumous Nobel Prize in Chemistry. Volume 2. Ladies in Waiting for the Nobel Prize ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

an exceptional opportunity for them to have permanent positions and a career together. Thus, they moved to NRL in 1946, where they both made their most important discoveries in the field of X-ray diffraction. Shortly after settling into their more or less secure positions at NRL, Isabella and Jerome started expanding their immediate family. Ultimately, they raised three daughters, each of them coincidentally earning advanced science-related degrees. The upbringing of the children proceeded in step with Isabella’s career. On trips to domestic and foreign conferences, the Karles often brought the children along. Isabella said the whole family once traveled about Europe in a little Volkswagen Beetle.

Figure 2. Isabella Karle at the electron diffractometer designed by Jerome Karle and built at NRL, a few years after the war. (Photo credit: U.S. Naval Research Laboratory.) The Karles, it was assumed, would work at NRL in the field of electron diffraction, which was the area of their expertise as students under Brockway at the University of Michigan. Indeed, in their initial years at NRL, that was the case. Jerome created an original design for an electron diffractometer, which was constructed in-house at the NRL electronics shop (6). Isabella was the first to take data with the new instrument (Figure 2) and analyze the corresponding structures of gas samples (14). Around 1950, Herbert Hauptman joined Jerome’s group at NRL. Significantly for their relationship, they had been classmates at City College of New York. The school is now part of the City University of New York, well-known for the number of its students who went on to be awarded a Nobel Prize. If I am correct the relationship of these two classmates developed in a way that, in my assessment, is tinged with unnecessary sadness. The way in which Isabella’s contribution to X-ray crystallography developed is a bit of a surprise. In those days, the electron and X-ray diffraction societies 287 Mainz and Strom; The Posthumous Nobel Prize in Chemistry. Volume 2. Ladies in Waiting for the Nobel Prize ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

were sufficiently small that they held meetings together, sometimes in Washington, DC, at the Carnegie Institution for Science. The Karles and Hauptman would attend meetings together, ostensibly as members of the electron community. In the process, however, they could not avoid hearing about the phase problem of X-ray diffraction, which was discussed in the context that it was mathematically impossible to solve. Roughly speaking, the problem arises as follows. The measured quantity is the intensity of the scattered X-ray wave. The molecular structure which resides in the crystal unit cell is to be determined. The peaks in the molecular electron density locate the atom nuclei and thus the geometrical structure of the molecule. The molecular structure factors are the Fourier transform of the electron density, and it is the square of these structure factors that are equal to the ideal measured X-ray intensities. The phase problem arises because the structure factor is complex (i.e., it has a real and an imaginary component). It is a vector in the complex plane. It can be represented as the product of a real magnitude times a complex exponential containing the phase angle of the vector in the complex plane. To square the structure factor to relate it to the experimental intensity is to lose the phase (i.e., the complex part of the structure factor). In the process of squaring a complex number, the phase disappears and leaves behind only the square of its real magnitude. Thus, it was assumed for decades that it was mathematically impossible to recover the phases from the measured X-ray intensities. The phases, however, are required to reconstruct the electron density as the Fourier transform of the X-ray scattering factors. The phase problem was deemed to be intractable. If structures were simple enough, one could solve them. Linus Pauling, for example, would simply guess the structures and then use the structure factor equation to verify his guess, but there was no direct way to go from measured intensities to the correct crystal structure. However, Jerome and Herb, the relative outsiders to the X-ray problem at that time, made a fundamental observation that had eluded the experts in the field: They noticed that the X-ray structure problem is overdetermined. The measured intensity data far exceeded in number the atomic Cartesian x, y, and z coordinates that determined the structure. Therefore, Karle and Hauptman were made certain that, contrary to prevailing opinion, there must be a solution to the X-ray phase problem. Another fact known to Jerome from his work in electron diffraction was that the electron density was everywhere positive (14–16). The conditions of positivity and atomicity were used to derive a set of determinant inequalities that were sufficient to solve the phase problem (17). Jerome and Herb quickly authored a monograph with the provocative title Solution of the Phase Problem (18). This was good. This was persuasive. But as Jerome described the situation to me “No one in the field believed us!” As alluded to earlier, Isabella entered the picture here in a perhaps surprising way. Because no one believed in the power of the mathematical equations, now called the equations of direct methods, Jerome asked Isabella if she would undertake proving experimentally that the equations, if implemented with X-ray data, really did solve X-ray structures. She accomplished just that, proving experimentally that direct methods solved X-ray structures. It was an Herculean task to succeed as she did in those early days of X-ray structures. One must realize there was no such thing as an off-the-shelf X-ray 288 Mainz and Strom; The Posthumous Nobel Prize in Chemistry. Volume 2. Ladies in Waiting for the Nobel Prize ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

diffractometer. Just to get going, Isabella had to read a book by Martin Buerger (19) of the Massachusetts Institute of Technology to get a sense of how one might undertake the collection of X-ray data. She borrowed an X-ray tube as her source of radiation. She put together an experimental arrangement allowing the measurement of the angle of scattering and recorded the intensity of the X-rays on photographic film. She estimated the relative intensities recorded on film using the human eye as a detector. Slowly but steadily, she solved by these means one structure after another, using her data and the equations of direct methods. She was important to the development of symbolic addition, for example, by emphasizing the use of probabilities to guide each step of the phase determinations (3, 20–22). Furthermore, she was solving structures that no one else could solve. Acceptance of direct methods was not immediate. The impossibility of solving the phase problem had been so ingrained in the culture of crystallography that the prejudice was not quickly overcome. But ever so slowly, this effort—the solution of one complicated structure after another (23, 24), and the teaching lectures given by Isabella at X-ray meetings—led to an acceptance of direct methods (2). Given that the direct methods were published in the early 1950s and only recognized with a Nobel Prize in 1985, one may surmise the acceptance was a slow and almost painful process. To alleviate any possible suspense regarding the matter, I will say here that Isabella did not share in the Nobel Prize awarded for the discovery of direct methods. More of that later. I want to pause here to raise other aspects of the direct methods narrative, which, in my assessment, did not end happily. Karle and Hauptman published their early work on direct methods in an issue of Acta Crystallographica in 1952 (25). In the same issue, David Sayre published his own work related to direct methods, which came to be called the Sayre equation (26). I think one can say this work was both independent of and different from the direct methods of Karle and Hauptman, but there was also a certain amount of overlap, particularly in the directness of going from measured data to structure. Importantly, the equations involved in both cases were held to be true within a certain range of probabilities but not with absolute certainty. In practice, however, the probabilities were sufficiently strong to deliver the correct structure. Tensions seemed to me to arise between Sayre and the partners Karle and Hauptman concerning how the credit should be attributed to the authors of direct methods and the Sayre equation, and, in particular, who was first to recognize that the equations should be interpreted as probability assertions. I knew all the parties I have mentioned here, and I am simply sharing my impressions of the tensions as I experienced them. I cannot prove who was right or wrong in these matters but am instead reporting, as something akin to a witness, matters related to one of the most important developments in crystallography (27). I knew the players in these developments. I worked with the Karles during summers at NRL for approximately 30 years. We would have lunch together every day of the summer, in the library of the Karles’ building. The conversations were personal and wide ranging. Looking back now, my feeling is that Jerome thought perhaps Herb was not keen to share the credit for direct methods (and the anticipated Nobel Prize), which may have contributed to his departing NRL to take a position at the Medical Foundation of Buffalo. While it is possible that Sayre 289 Mainz and Strom; The Posthumous Nobel Prize in Chemistry. Volume 2. Ladies in Waiting for the Nobel Prize ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

thought his notions regarding the use of probabilities in the determination of phase relations were taken over in the more widely appreciated direct methods, it is more likely that the two groups simply worked independently. Sayre was interested in my ideas related to quantum crystallography. After a seminar I presented at IBM’s Thomas J. Watson Research Center in Yorktown Heights, his home base at the time, we spent an afternoon discussing the Sayre equation, which was developed when he was a student at Oxford with Dorothy Hodgkin. We subsequently stayed in touch, exchanging Christmas cards every year with brief reports of our successes and failures in research. We were sitting near each other and conversing at a meeting of the American Crystallographic Association held at McMaster University in 1986, the year after the “crystallography” Nobel Prize was awarded to Jerome and Herb. The audience of many hundreds of crystallographers were all seated when Jerome and Herb walked into the auditorium. This immediately caused the entire audience, including me, to rise with loud applause. It was a standing ovation the likes of which I have never experienced in the context of a science meeting, not before and not at any time since. Only one person did not stand and did not applaud. That was a powerful statement. I knew Herb less than the others, but my wife Mary and I spent a bit more than a week with Herb and his wife Edith in the context of a seminar devoted to direct methods some 30 years ago in a hilltop town in Sicily called Erice. I am coincidently in Erice now as I write of these memories. I also had Herb visit with me at Hunter College in the context of a seminar I invited him to deliver to our chemistry department. The day of the seminar brought with it an odd occurrence. I must have assumed that Jerome Karle and Hauptman were quite good friends. Escorting Herb down the hall of our building, I happened to mention that I recently had begun working with Jerome. The remark surprisingly and literally stopped Herb in his tracks. He stood for some long seconds and stared at me as if trying to understand my meaning and perhaps to reassess me as well. Nothing more was said, and we continued on and had a perfectly pleasant day together. But the brief event was so intense I remembered it many months later when I first learned that Jerome and Herb had more or less stopped talking to one another. Remember they were classmates at City College. Direct methods, after decades, finally achieved wide acceptance. They came to be routinely used in computer programs to solve structures all over the world. Such success demanded belief. Finally, a Nobel Prize was awarded for the discovery. The Prize went to Jerome Karle and Herbert Hauptman, which of course was well deserved. Conspicuously absent in any Prize citation was the name of Isabella Karle. This was an intellectual injustice for the simple reason that Isabella was responsible for the experimental proof that the mathematics of direct methods did indeed correctly predict crystal structure. It was Isabella’s actions solving structures and actively teaching crystallographers (Figure 3) how to use direct methods that ever so slowly led to belief in and dependence on direct methods for solving crystal structures. Recognizing this perhaps more clearly than anyone, Jerome never got over the injustice of the Nobel Committee’s omission. The announcement of his award came to Jerome midflight from Europe to Washington, DC. The pilot was alerted by the Nobel Committee, and his voice 290 Mainz and Strom; The Posthumous Nobel Prize in Chemistry. Volume 2. Ladies in Waiting for the Nobel Prize ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

came over the public intercom to announce that Jerome Karle, a passenger on board, had just been awarded the Nobel Prize in Chemistry. That was all Jerome knew at the time. Isabella was at the airport waiting to meet him when he arrived and had to answer “no” when he asked whether she also got the Prize. He never got over the feeling that her exclusion was just not right. I mention in passing that it would not be unusual for the Nobel Prize to be awarded separately for theory and related experiments, as occurred, for example, in the case of the Braggs, in which William Henry Bragg was an experimentalist and William Lawrence Bragg was a theoretician.

Figure 3. Isabella teaching direct methods at the blackboard. This would have been decades before wide acceptance of the methods and the recognition afforded them by the award of the Nobel Prize to Jerome Karle and Herbert Hauptman. (Photograph by Bill Duax, reproduced with permission from the IUCr photographic archive.) One must assume that Isabella had been given serious consideration to receive the Prize. She deserved it. Why, then, did it not happen? I do not exactly know, and perhaps one cannot know without actual discussion with the committee members who made the decision. However, we can assume that political arguments would have played a role. The Nobel Committee’s decisions over the years seemed to demonstrate prejudice against the contributions of women. The recent American Chemical Society symposium in Washington, DC, in the summer of 2017, called “Ladies in Waiting for the Nobel Prize: Overlooked Accomplishments of Women Chemists,” underscores the point. And, it is at least interesting that Nobel Laureate Glenn Seaborg, during the 1985 Nobel festivities, indicated to Isabella’s daughter Jean that he did not understand why Isabella was not included in the Prize. What I admire most about Isabella is the greatness of her work, which carried on apace before and after the Nobel Prize (4). The work itself was the prize for her, not any external recognition for doing it. After the Prize, she just kept on as before, solving one important structure after another. The Prize omission, as far as I could 291 Mainz and Strom; The Posthumous Nobel Prize in Chemistry. Volume 2. Ladies in Waiting for the Nobel Prize ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

discern from her conversation, manner of working, and outward psychology, left her unaffected. That, I must admire. I gave a talk about crystallography and Isabella’s work recently at a Jesuit school in upstate New York called Le Moyne College. I ended by summarizing what must be considered a sad fact: Real conversation and friendship among such wonderful and important people as were involved in the discovery of direct methods and closely related ideas had all but stopped. This, from my perspective, was caused by the recognition, or lack thereof, related to the Nobel Prize. At the aforementioned school, my last slide (Figure 4) quoted a phrase that seemed familiar to the faculty, students, and friends of the school in the audience. The slide was paraphrasing Saint Paul, only slightly: “Let me do the work, but, ‘to God be the Glory.’”

Figure 4. A slide projected by the author closing his invited seminar at Le Moyne College in March 2018. The slide displays a contemplative view of Isabella Karle in the last year of her life, looking over the lake at her home, with Saint Paul’s remark paraphrased and superimposed. (Photo credit: Rey Lopez / Narratively. Reproduced with permission from reference (28).) Isabella personified, in my understanding of her, pretty much the right attitude toward conducting science: The work itself is the essential reward.

Acknowledgments The author thanks Dr. Vera Mainz for her reading of this paper and suggesting several important changes that have much improved it. Thanks to Jean Karle Dean, PhD, for reading the manuscript and sharing her important comments with the author. 292 Mainz and Strom; The Posthumous Nobel Prize in Chemistry. Volume 2. Ladies in Waiting for the Nobel Prize ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

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