Martin Karplus – Biographical

Early Years in Europe

I was born in Vienna, Austria in 1930 [1]. Already before the Nazis entered Austria in 1938, our life had changed significantly, even from the viewpoint of an eight year old. Among our neighbors were two boys of ages comparable to my brother, Robert, and me. They were our “best friends,” and we played regularly with them. In the spring of 1937, they suddenly refused to have anything to do with us and began taunting us by calling us “dirty Jew boys” when we foolishly continued to try to interact with them.

On March 13, 1938, the German Nazi troops crossed the border into Austria and completed the Anschluss, the “joining” of Austria with Nazi Germany. A few days after the Anschluss, my mother, brother, and I left Austria by train for Switzerland on a “ski vacation.” My parents had been concerned about Hitler’s takeover of Austria for some time. For the previous three years, my Aunt Claire, who had studied in England, had been teaching English to me and my brother Bob. Well before March 13, train tickets had been purchased and a bed-and-breakfast “pension” had been reserved in Zurich.

The most traumatic aspect of our departure was that my father was not allowed to come with us and had to give himself up to be incarcerated in the Vienna city jail. In part, he was kept as a hostage so that any money we had would not be spirited out of the country. My mother reassured my brother and me, saying that nothing would happen to him, though of course she herself had no assurance that this was true.

At the end of the summer, the visas finally arrived, passage was booked, and the three of us were ready to leave for the United States. Although there had been no news from my father, he miraculously turned up at Le Havre a few days before our ship was scheduled to depart for New York. From my point of view, it was exactly what my mother had told me would happen: We would all go to America together. When my father joined us in Le Havre, Bob and I asked him what jail had been like. He told us that he had been treated well in jail and cheerfully described how he had passed the time teaching the guards to play chess. One aspect of my father’s personality, which strongly influenced both my brother and me, was to make something positive out of any experience.

A New Life in America

We arrived in New York Harbor early in the morning on October 8, 1938, and I stood on the deck watching the Statue of Liberty appear out of the mist. The symbolism associated with the Statue of Liberty may seem trite today (and somewhat deceptive given our present immigration policies), but in 1938 it was special for me. Most of the immigration formalities had been taken care of by Uncle Edu, so that a few hours after our arrival we boarded a train to Boston. During our initial weeks in the United States, we were lodged in a welcoming center in Brighton, where a large mansion had been transformed into an interim home for refugee families. We were taught about America (what it was like for foreigners to live in Boston), given lessons to improve our English, and aided in the steps required to be allowed to remain in the United States as refugees.

Soon we were ready to start a new life. My parents rented a small apartment in Brighton (part of Greater Boston), and Bob and I immediately entered the local public schools, as we had in Zurich. Motivated by their concern for our education, my parents then moved to Newton (a suburb of Boston), where the schools were recognized as superior to the Boston public schools. My parents bought a small house in a pleasant neighborhood in West Newton, and I attended the Levi F. Warren Junior High School.

My junior high teachers soon realized that I was bored with the regular curriculum, so they let me sit in the back of the classroom and study on my own. What made this experience particularly nice was that another student, a very pretty girl, was given the same privilege, and we worked together. The arrangement was that we could learn at our own pace without being responsible for the day-to-day material but had to take the important exams. Several dedicated teachers at Warren Junior High helped us when questions arose, particularly with science and mathematics. With this freedom, we explored whatever interested us and, of course, did much more work than we would have done if we were only concerned with passing the required subjects.

Beginning of Scientific Interests

When we moved to Newton, Bob was given a chemistry set, which he augmented with materials from the high school laboratory and drug stores. He spent many hours in the basement generating the usual bad smells and making explosives. I was fascinated by his experiments and wanted to participate, but he informed me that I was too young for such dangerous scientific research. My plea for a chemistry set of my own was vetoed by my parents because they felt that this might not be a good combination – two teenage boys generating explosives could be explosive! Instead, my father had the idea of giving me a Bausch and Lomb microscope. Initially I was disappointed – no noise, no bad smells, although I soon produced the latter with the infusions I cultured from marshes, sidewalk drains, and other sources of microscopic life. I came to treasure this microscope, and more than 60 years later it is still in my possession. One especially rewarding aspect of my working with the microscope was that my father, who was a thoughtful observer of nature, spent a lot of time with me and was always ready to come and look when I had discovered something. I had found an exciting new world and looked through my microscope whenever I was free. The first time I saw a group of rotifers I was so excited by the discovery that I refused to leave them, not even taking time out for meals. They were the most amazing creatures as they swam across the microscope field with their miniature rotary motors. (The rotifers come to mind today in relation to my research on the smallest biological rotatory motor, F1-ATPase.) My enthusiasm was sufficiently contagious that I even interested some of my friends. It was a special occasion when they came to my house and looked at the rotifers through the microscope.

This was the beginning of my interest in nature study, which was nurtured by my father and encouraged by my mother, even though it was still assumed that I would go to medical school and become a doctor. One day my closest friend, Alan MacAdam, saw an announcement of the Lowell Lecture Series (a Boston institution, originally supported by a Brahmin family – the Lowells), which organized evening courses on a wide range of subjects at the Boston Public Library that were free and open to the public. The series that had caught Alan’s eye was entitled “Birds and Their Identification in the Field,” to be given by Ludlow Griscom, the curator of ornithology at the Museum of Comparative Zoology at Harvard University. Alan and I occasionally walked in the green areas in Newton, particularly the Newton Cemetery, and looked for birds with my father’s old pair of binoculars. Together we attended the first lecture, which had a good-sized audience, although it was not clear whether most of the people came simply to have a nice warm place in winter rather than because of their interest in birds. I was enthralled by the lecture, which provided insights into bird behavior and described the large number of different species one could observe within a 50 mile radius of Boston. I was amazed that it was possible to identify a given species from “field marks” evident even from a glimpse of a bird, if one knew how and where to look. Alan did not attend the subsequent lectures, but I continued through the entire course. At the end of the fourth or fifth lecture, Griscom came up to me and asked me about myself. He then invited me to join his field trips, and a new passion was born. From that time on, my treasured microscope was relegated to a closet, and I devoted my free time to observing birds on my own, as well as with Griscom and his colleagues, with the Audubon Society, and other groups that organized field trips.

I entered Newton High School in the fall of 1944 but soon found that I did not have the same supportive environment as in elementary and junior high school. My brother, Bob, had graduated from Newton High School two years before and had done exceedingly well. My teachers presumed that I could not measure up to the standards set by my brother. Since I had always been striving to keep up with Bob and his friends, this just reinforced my feelings of inferiority. Particularly unpleasant were my interactions with the chemistry teacher. When my brother suggested I compete in the Westinghouse Science Talent Search, the chemistry teacher, who was in charge of organizing such applications, told me that it was a waste of time for me to enter and that it was really too bad that Bob had not tried instead. However, I talked to the high school principal and he gave me permission to go ahead with the application. I managed to obtain all the necessary papers without encouragement from anyone in the school. A test was given as part of the selection process, and I found a teacher who was willing to act as proctor. I did well enough to be invited as one of the 40 finalists to Washington, D.C. Each finalist had a science project for exhibition in the Statler Hotel, where we were staying. My project was on the lives of alcids, based in part on a trip to the Gaspé Peninsula and some of the field studies I had made during New England winters. The various judges spent considerable time talking with us, and the astronomer Harlow Shapley, who was the chief judge, charmed me with his apparent interest in my project. I was chosen as one of two co-winners. (At that time, there was one male and one female winner; Rada Demereck and I were co-winners.) The visit to Washington, D.C. was a formative experience. We met President Truman, who welcomed us as the future leaders of America. Moreover, winning the Westinghouse Talent Search made up for the discouraging interactions with some of my high school teachers. Their attitude contrasted with that of my fellow classmates, who voted me “most likely to succeed.”

College Years

I entered Harvard in the fall of 1947. There was never any question about my wanting to attend Harvard and I did not apply to any other school. In addition to the Westinghouse scholarship, I received a National Scholarship from Harvard to cover the cost of living on campus. Otherwise I would have had to live at home to save money. I would not have minded this, since I was not a rebellious teenager eager for independence and distance from my parents. However, as I soon discovered, much of the Harvard experience took place outside of classes at dinner and in evening discussions with friends.

At first I still intended to go to medical school but changed my mind during my freshman year. My teenage ornithological studies, fostered by Griscom and Donald Griffin, with whom I had gone on a field trip to Alaska, had already introduced me to the fascinating world of research, where one is trying to discover something new (something that no one has ever known). I began to think about doing research in biology, but concluded that to approach biology at a fundamental level (“to understand life”), a solid background in chemistry, physics, and mathematics was essential. I enrolled in the Program in Chemistry and Physics. This program, unique to Harvard at the time, exposed undergraduates to courses in both areas at a depth that they would not have had from either one alone. Although I shopped around for advanced science courses to meet the rather loose requirements, I also enrolled in Freshman Chemistry because it was taught by Leonard Nash. A relatively new member of the Harvard faculty, Nash had the deserved reputation of being a superb teacher. Elementary chemistry in Nash’s lectures was an exciting subject. A group of us (including DeWitt Goodman, Gary Felsenfeld, and John Kaplan – my “crazy” roommate, who became a law professor at Stanford) had the special privilege that Nash spent extra time discussing with us a wide range of chemical questions, far beyond those addressed in the course. The interactions in our group, though we were highly competitive at exam times, were also supportive. This freshman experience confirmed my interest in research and the decision not to go to medical school.

Harvard provided me with a highly stimulating environment as an undergraduate. I enrolled in a wide range of courses, chosen partly because of the subject matter and partly because of the outstanding reputation of the lecturers; these courses included one in Democracy and Government and another in Abnormal Psychology. More related to my long-term interests were George Wald’s Molecular Basis of Life and Kenneth Thimann’s class on plant physiology with its emphasis on the chemistry and physiology of growth hormones (auxins) in plants. Both professors were inspiring lecturers and imbued me with the excitement of the subject. These courses emphasized that biological phenomena (life itself) could be understood at a molecular level, which has been a leitmotif of my subsequent research career. Wald’s course also introduced me to the mechanism of vision, which led to my first paper on a theoretical approach to a biological problem [2].

Rather than taking the Elementary Organic course taught by Louis Fieser, I enrolled in Paul Bartlett’s Advanced Organic. It taught the physical basis of organic reactions. It was an excellent course, though difficult for me because one was supposed to know many organic reactions, which I had to learn as we went along. At one point, Bartlett suggested that we read Linus Pauling‘s Nature of the Chemical Bond, which had been published in 1939 based on his Baker Lectures at Cornell. The Nature of the Chemical Bond presented chemistry for the first time as an integrated subject that could be understood, albeit not quite derived, from its quantum chemical basis. The many insights in this book were a critical element in orienting my subsequent research in chemistry.

At the end of three years at Harvard I needed only one more course to complete the requirements for a bachelor degree. During the previous year I had done research with Ruth Hubbard and her husband, George Wald. (Although Hubbard was scientifically on par with Wald, she remained a Senior Research Associate, a nonprofessorial appointment, until very late in her career when she was finally “promoted” to Professor. This was not an uncommon fate for women in science.) I mostly worked with Hubbard on the chemistry of retinal, the visual chromophore. When I brought up my need to find a course for graduation, Wald suggested that I enroll in the physiology course at the Marine Biological Laboratory in Woods Hole, Massachusetts. This course was one of the few non-Harvard courses that was accepted for an undergraduate degree by the Faculty of Arts and Sciences. The physiology course was widely known as a stimulating course designed for postdoctoral fellows and junior faculty. The lectures in the course by scientists who were summering at Woods Hole, while doing some research and enjoying boating and swimming, offered students a state-of-the-art view of biology and biological chemistry.

In considering graduate school during my last year at Harvard, I had decided to go to the West Coast and had applied to chemistry at the University of California at Berkeley and to biology at the California Institute of Technology (Caltech). Accepted at both, I found it difficult to choose between them. Providentially, I visited my brother, Bob, who was working with J. R. Oppenheimer at the Institute of Advanced Studies in Princeton, New Jersey. Bob introduced me to Oppenheimer, and briefly to Einstein. When Oppenheimer asked me what I was doing, I told him of my dilemma in choosing between U.C. Berkeley and Caltech for graduate school in chemistry or biology. He had held simultaneous appointments at both institutions and strongly recommended Caltech, describing it as “a shining light in a sea of darkness.” His comment influenced me to choose Caltech, and I discovered that Oppenheimer’s characterization of the local environment was all too true. Pasadena itself held little attraction for a student at that time. However, camping trips in the nearby desert and mountains and the vicinity of Hollywood made up for what Pasadena lacked.

At Caltech, I joined the group of Max Delbrück in biology. He had started out as a physicist but, following the advice of Niels Bohr, had switched to biology. With Salvador Luria and others, he had been instrumental in transforming phage genetics into a quantitative discipline. His research fascinated me, and I thought that working with such a person would be a perfect entrée for me to do graduate work in biology.

After I had been in the Delbrück group for a couple of months, Delbrück proposed that I present a seminar on a possible area of research. I intended to discuss my ideas for a theory of vision (how the excitation of retinal by light could lead to a nerve impulse), which I had started to develop while doing undergraduate research with Hubbard and Wald. Among those who came to my talk was Richard Feynman; I had invited him to the seminar because I was taking his quantum mechanics course and knew he was interested in biology, as well as everything else. I began the seminar confidently by describing what was known about vision but was interrupted after a few minutes by Delbrück’s comment from the back of the room, “I do not understand this.” The implication of his remark, of course, was that I was not being clear, and this left me with no choice but to go over the material again. As this pattern repeated itself (Delbrück saying “I do not understand” and my trying to explain), after 30 minutes I had not even finished the 10-minute introduction and was getting nervous. When he intervened yet again, Feynman turned to him and whispered loud enough so that everyone could hear, “I can understand, Max; it is perfectly clear to me.” With that, Delbrück got red in the face and rushed out of the room, bringing the seminar to an abrupt end. Later that afternoon, Delbrück called me into his office to tell me that I had given the worst seminar he had ever heard. I was devastated by this and agreed that I could not continue to work with him. It was only years later that I learned from reading a book dedicated to him that what I had gone through was a standard rite of passage for his students – everyone gave the “worst seminar he had ever heard.”

After the devastating exchange with Delbrück, I spoke with George Beadle, the chairman of the Biology Department. He suggested that I find someone else in the department with whom to do graduate research. However, I felt that I wanted to go “home” to chemistry and asked him to help me make the transfer.

Once in the Chemistry Department, I joined the group of John Kirkwood, who was doing research on charge fluctuations in proteins, as well as on his primary concern with the fundamental aspects of statistical mechanics and its applications. I undertook work on proteins and the research started out well.

In the spring of 1951, as I was getting immersed in my research project, Kirkwood received an offer from Yale. Linus Pauling, who was no longer taking graduate students, asked each student who was working with Kirkwood whether he would like to stay at Caltech and work with him. I was the only one to accept and, in retrospect, I think it was a very good choice. Initially, I was rather overwhelmed by Pauling. Each day upon arriving at the lab, I found a hand-written note on a yellow piece of paper in my mailbox which always began with something like “It would be interesting to look at …” As a new student I took this as an order and tried to read all about the problem and work on it, only to receive another note the next day beginning in the same way. When I raised this concern with Alex Rich and other postdocs, they laughed, pointing out that everyone received such notes and that the best thing to do was to file them or throw them away. Pauling had so many ideas that he could not work on all of them. He would communicate them to one or another of his students, but he did not expect a response. After I got over that, my relation with Pauling developed into a constructive collaboration.

Given Pauling’s interest in hydrogen bonding in peptides and proteins, he proposed that I study the different contributions to hydrogen bonding interactions for a biologically relevant system, but I felt this would be too difficult to do in a rigorous way. Because quantum mechanical calculations still had to be done with calculating machines and tables of integrals (something difficult to imagine when even log tables have followed dinosaurs into oblivion), we had to find a system that was simple enough to be treated by quantum mechanical theory. I chose the bifluoride ion (FHF-) because the hydrogen bond was the strongest known, the system is symmetric, and only two heavy atoms are involved. (Today, such “strong” hydrogen bonds have become popular in analyses of enzyme catalysis, although there is no convincing evidence as to their role.)

The time at Cal Tech was very rewarding, all the more so because of the intellectual and social atmosphere of the Chemistry Department. The professors – like Pauling,  Verner  Schomaker, and Norman Davidson – treated  the graduate students and postdoctoral fellows as equals. We participated in many joint activities that included trips into the desert, as well as frequent parties held at our Altadena house, where Feynman would occasionally come and play the drums.

Postdoctoral Sojourn in Oxford and Europe

One day in October 1953, Pauling came into the office I shared with several postdocs and announced that he was leaving in three weeks for a six-month trip and that “it would be nice” if I finished my thesis and had my exam before he left. This was eminently reasonable, since I had finished the calculations some months before and I had received a National Science Foundation (NSF) postdoctoral fellowship to go to England that fall. Pauling’s “request” provided just the push I needed, even though the introduction was all I had written thus far. With so much to get done, I literally wrote night and day, with my friends typing and correcting what I wrote. In this way, the thesis was finished within three weeks, and I had my final PhD exam and celebratory party before Pauling left. After a brief visit with my parents in Newton, I took an ocean liner for England and arrived shortly before Christmas 1953.

During my two years in Oxford as a postdoctoral fellow, I spent much of the time traveling throughout Europe and taking photographs; they are the basis of several exhibitions. Also, I spent more time thinking about chemical problems than actually solving them. My aim was to find areas where theory could make a contribution of general utility in chemistry. I did not want to do research whose results were of interest just to theoretical chemists. Reading the literature, listening to lectures, and talking to scientists like Don Hornig and the Oxford physicist H. M. C. Pryce, I realized that magnetic resonance was a vital new area. Chemical applications of magnetic resonance were in their infancy and it seemed to me that nuclear magnetic resonance (NMR), in particular, was a field where theory could make a contribution. I concluded that a quantum mechanical approach could aid in interpreting the available experimental results and propose new measurements.

Five Years at the University Of Illinois: NMR and Coupling Constants

As my postdoctoral fellowship in Oxford (1953–1955) neared its end, I was looking for a position to begin my academic career in the United States. With my growing interest in magnetic resonance, I focused on finding an institution that had active experimental programs in the area. One of the best schools from this point of view was the University of Illinois, where Charles Slichter in Physics and Herbert Gutowsky in Chemistry were doing pioneering work in applying NMR to chemical problems. The University of Illinois had a number of openings in Chemistry at that time because the department was undergoing a radical renovation; several professors, including the chairman Roger Adams, had retired. Pauling recommended me to the University of Illinois and the department offered me a job without an interview. I accepted the offer from Illinois without visiting the department, something unimaginable today with the extended courtships that have become an inherent part of the academic hiring process. The University of Illinois offered me an Instructorship at a salary of $5000 per year; the department offered nothing like the present-day start-up funds, and I did not think of asking for research support.

Having had such a good time as a postdoctoral fellow traveling in Europe, I was ready to get to work, and Urbana-Champaign seemed like a place where I could concentrate on science with few distractions. The presence of four new instructors – Rolf Herber, Aron Kupperman, Robert Ruben, and me – plus other young scientists on the faculty, such as Doug Applequist, Lynn Belford, and E. J. Corey, led to a very interactive and congenial atmosphere.

I focused a major part of my research on theoretical methods for relating nuclear and electron spin magnetic resonance parameters to the electronic structure of molecules. The first major problem I examined was concerned with proton-proton coupling constants, which were known to be dominated by the Fermi contact interaction. What made coupling constants of particular interest was that for protons that were not bonded to each other, the existence of a nonzero value indicated that there was an interaction beyond that expected from localized bonds. In the valence bond framework, which I used in part because of my training with Pauling, nonzero coupling constants provide a direct measure of the deviation from the perfect-pairing approximation. To translate this qualitative idea into a quantitative model, I chose to study the HCC’H’ fragment as a function of the HCC’H’ dihedral angle, a relatively simple system consisting of six electrons (with neglect of the inner shells). I believed that it could be described with sufficient accuracy for the problem at hand by including only five covalent valence-bond structures. To calculate the contributions of the various structures, I introduced semi-empirical values of the required molecular integrals. Although the HCC’H’ fragment is relatively simple, the calculations for a series of dihedral angles were time consuming and it seemed worthwhile to develop a computer program. This was not as obvious in 1958 as it is now. Fortunately, the ILLIAC, a “large” digital computer at that time, had recently been built at the University of Illinois. If I remember correctly, it had 1000 words of memory, which was enough to store my program. The actual program was written by punching holes in a paper tape. If you made a mistake, you filled in the incorrect holes with nail polish so that you could continue the program; the output appeared on spools of paper. Probably the most valuable aspect of having a program for this type of simple calculation, which could have been done on a desk calculator, was that once the program was known to be correct, a large number of calculations could be performed without having to worry about arithmetic mistakes.

Just as I finished the analysis of the vicinal coupling constants [3], I heard a lecture by R. V. Lemieux on the conformations of acetylated sugars. I do not remember why I went to the talk, because it was an organic chemistry lecture, and the chemistry department at Illinois was rigidly separated into divisions, which had a semiautonomous existence. Lemieux reported measurements of vicinal coupling constants and noted that there appeared to be a dihedral angle dependence, although the details of the behavior were not clear. The results were exciting to me because the experiments confirmed my theory, at least qualitatively, before it was even published.

As happens too often with the application of theoretical results in chemistry, most people who used the so-called Karplus equation had not read the original paper [3] and thus do not know the limitations of the theory. They assumed that because the equation had been used to estimate vicinal dihedral angles, the theory said that the coupling constant depends only on the dihedral angle. By 1963, having realized organic chemists tend to write and read Communications to the Journal of the American Chemical Society, I published such a Communication [4]. In it, I described various factors, other than the dihedral angle, that are expected to affect the value of the vicinal coupling constant; they include the electronegativity of substituents, the valence angles of the protons (HCC’ and CC’H’), and bond lengths. The main point of the paper was not to provide a more accurate equation but rather to make clear that caution had to be used in applying the equation to structural problems. My closing sentence, which has often been quoted, was the following: “Certainly with our present knowledge, the person who attempts to estimate dihedral angles to an accuracy of one or two degrees does so at his own peril.”

In spite of my concerns about the limitations of the model, the use of the equation has continued, and the original paper [3] is one of the Current Contents “most-cited papers in chemistry”; correspondingly, the 1963 paper was recently listed as one of the most-cited papers in the Journal of the American Chemical Society [5]. The vicinal coupling constant model, which was developed primarily to understand deviations from perfect pairing, has been much more useful than I would have guessed. “In many ways my feeling about the uses and refinements of the Karplus equation is that of a proud father. I am very pleased to see all the nice things that the equation can do, but it is clear that it has grown up and now is living its own life” [6].

At Illinois, my officemate was Aron Kuppermann. Our instructorship at Illinois was the first academic position for both of us, and we discussed science, as well as politics and culture, for hours on end. Aron and I decided that, although we were on the faculty, we wanted to continue to learn and would teach each other. I taught Aron about molecular electronic structure theory [we published two joint papers on molecular integrals] and Aron taught me about chemical kinetics, his primary area of research. Aron is officially an experimentalist, but he is also an excellent theoretician, as was demonstrated by his landmark quantum mechanical study of the H + H2 exchange reaction with George Schatz. This work was some years in the future (it was published in 1975), but in the late 1950s we both felt that it was time to go beyond descriptions of reactions in terms of the Arrhenius formulation based on the activation energy and pre-exponential factor. My research in this area had to wait until I moved to Columbia University, where I would have access to the required computer facilities.

Move to Columbia and Focus on Reaction Kinetics

During the summer of 1960 I participated in an NSF program at Tufts University with the purpose of exposing high school and small college science teachers to faculty actively engaged in research. Ben Dailey, one of the organizers of the program, asked me one day whether I would consider joining the chemistry faculty at Columbia University, where he was a professor. Because I had already been at Illinois for four of the five years I had planned to stay there, I responded positively. I heard from Columbia shortly thereafter and received an offer to join the IBM Watson Scientific Laboratory with an adjunct associate professorship at Columbia.

The Watson Scientific Laboratory was an unusual institution to be financed by a company like IBM. Although the laboratory played a role in the development of IBM computers, many of the scientists there were doing fundamental research. The Watson Laboratory had been founded in 1945 near the end of World War II to provide computing facilities needed by the Allies. It had a special attraction for me in that it had an IBM 650, an early digital computer, which was much more useful than the ILLIAC because of its greater speed, larger memory, and simpler (card) input. (No more nail polish!) I was to have access to considerable amounts of time on the IBM 650 and to receive support for postdocs, as well as other advantages over a regular Columbia faculty appointment. This was a seductive offer, but I hesitated about accepting a position that in any way depended on a company, even a large and stable one like IBM. This was based, in part, on my political outlook, but even more so on the fact that industry has as its primary objective making a profit, and all the rest is secondary. By contrast, my primary focus was on research and teaching, which are the essential aspects of a university, but not of industry. Consequently, I replied to Columbia and the Watson Lab that the offer was very appealing, but that I would consider it only if it included a tenured position in the chemistry department, even though I agreed initially to be at the Watson Lab as well. Columbia acceded to my request and after some further negotiation, I accepted the position for the fall of 1960.

The environment at the Watson Lab was indeed fruitful, both in terms of discussions with other staff members and the available facilities. I was able to do research there that would have been much more difficult at Columbia. However, not unexpectedly, the atmosphere gradually changed over the years, with increasing pressure from IBM to do something useful (i.e., profitable) for the company, such as visiting people at the much larger and more applied IBM laboratory in Yorktown Heights, essentially doing internal consulting. I decided in 1963 that the time had come to leave the Watson Lab, and moved to the fulltime professorial position that was waiting for me in Chemistry at Columbia. (IBM closed the Watson Lab in 1970.)

I continued research in the area of magnetic resonance after moving to New York. One reward of being at Columbia was the stimulation provided by interactions with new colleagues, such as George Fraenkel, Ben Dailey, Rich Bersohn, and Ron Breslow. Frequent discussions with them helped to broaden my view of chemistry. In particular, my interest in ESR was rekindled by George Fraenkel and we published several papers together, including a pioneering calculation of 13C hyperfine splittings [7]. Although the techniques we used were rather crude, the results provide insights concerning the electronic structure of the molecules considered and aided in understanding the measurements.

My interest in chemical reaction dynamics had deepened at Illinois through many discussions with Aron Kuppermann, as already mentioned, but I began to do research in the area only after moving to Columbia. There were several reasons for this. There is no point in undertaking a problem if the methodology and means for solving it are not available: It is important to feel that a problem is ripe for solution. (This has been a guiding rule for much of my research – there are many exciting and important problems, but only when one feels that they are ready to be solved should one invest the time to work on them. This rule has turned out to be even more important in the application of theory to biology, as we shall see later.) Given the availability of the IBM 650 at the Watson Lab, the very simple reaction, H + H2  → H2 + H, which involves an exchange of a hydrogen atom with a hydrogen molecule, could now be studied by theory at a relatively fundamental level. Moreover, early measurements made by Farkas & Farkas in 1935 of the rate of reaction over a wide temperature range provided important data for comparison with calculations. A second reason for focusing on chemical kinetics was that crossed molecular beam studies were beginning to provide much more detailed information about these reactions than had been available from gas phase or solution measurements. The pioneering experiments of Taylor & Datz opened up this new field in 1955. It made possible the study of individual collisions and the determination whether or not they were reactive. Thus, calculated reaction cross sections, rather than overall rate constants, could be compared directly with experimental data. To do a theoretical treatment of this or any other reaction (including the protein folding reaction), a knowledge of the potential energy of the system as a function of the atomic coordinates is required, as described in my Nobel Lecture.

Richard Porter, a graduate student with F. T. Wall at Illinois, had done collinear collision calculations for the H + H2 reaction. Much impressed by Porter, I invited him to join my group at Columbia as a postdoctoral fellow. At Columbia, we rapidly developed a semi-empirical extension of the original Heitler-London surface for the H + H2 reaction, based on the method of diatomics in molecules and calibrated the surface with ab initio quantum calculations and experimental data for the reaction [8]. This surface, which is known as the Porter-Karplus (PK) surface, has an accuracy and simplicity that led to its continued use in many reaction rate calculations by a variety of methods over the years.

Within the approximation that classical mechanics is accurate for describing the atomic motions involved in the H + H2 reaction and that the semi-empirical Porter-Karplus surface is valid, a set of trajectories makes it possible to determine any and all reaction attributes, e.g., the reaction cross section as a function of the collision energy. The ultimate level of detail that can be achieved is an inherent attribute of this type of approach, which I was to exploit 15 years later in studies of the dynamics of macromolecules.

Recently, I was pleased to learn that our paper was cited by George Schatz [9] as one of the key twentieth-century papers in theoretical chemistry. Schatz states, “The KPS paper stimulated research in several new directions and ultimately spawned new fields.” One of these as cited by Schatz was molecular dynamics simulations of biomolecules, as described in my Nobel Lecture.

Return to Harvard University and Biology

In 1965, it was time to move again. Columbia and New York City were stimulating places to live and work, but I felt that new colleagues in a different environment would help to keep my research productive. I had incorporated this idea into a “plan”: I would change schools every five years and when I changed schools I would also change my primary area of research. It was exciting for me to work on something new, where I had much to learn so as to stay mentally young and have new ideas. The initial qualitative insights obtained from relatively simple approaches to a new problem are often the most rewarding.

I received numerous offers and decided to “return” to Harvard. After I had been at Harvard for only a short time, I realized that if I was ever to again take up my long-standing interest in biology I had to make a break with what had been thus far a successful and very busy research program in theoretical chemistry.

A key, although accidental, element in my choice of a problem for study in biology was the publication of Structural Chemistry and Molecular Biology, a compendium of papers in a volume dedicated to Linus Pauling for his 65th birthday. I had contributed an article entitled, “Structural Implications of Reaction Kinetics,” which reviewed some of the work I have already described in the context of Pauling’s view that a knowledge of structure was the basis for understanding reactions. However, it is not my article that leads me to mention this volume, but rather an article by Ruth Hubbard and George Wald entitled “Pauling and Carotenoid Stereochemistry.”

On looking through the article, it was clear to me that the theory of the electronic absorption of retinal and its geometric changes on excitation, which play an essential role in vision, had not advanced significantly since my discussions with Hubbard and Wald during my undergraduate days at Harvard. I realized, in part from my time in Oxford with Coulson, that polyenes, such as retinal, were ideal systems for study by the available semi-empirical approaches; that is, if any biologically interesting system in which quantum effects are important could be treated adequately at that time, retinal was it. Barry Honig, who had received his PhD in theoretical chemistry working with Joshua Jortner, joined my research group at that time. He was the perfect candidate to work on the retinal problem. I will not elaborate on our studies here as they are outlined in my Nobel Lecture.

Hemoglobin: A Real Biological Problem

Another scientific question that appeared ready for a more fundamental investigation was the origin of hemoglobin cooperativity, the model system for allosteric control in biology. Although the phenomenological model of Monod, Wyman, and Changeux had provided many insights, it did not attempt to make contact with the detailed structure of the molecule. In 1971 Max Perutz had just determined the X-ray structure of deoxy hemoglobin, which complemented his earlier results for oxy hemoglobin. By comparing the two structures, he was able to propose a qualitative molecular mechanism for the cooperativity. Alex Rich, now a professor at the Massachusetts Institute of Technology, had invited Perutz to present two lectures describing the X-ray data and his mechanism. After the second lecture, Alex suggested that I come to his office to have a discussion with Perutz. Perutz was sitting on a couch in Alex’s office and eating his customary banana. I asked him whether he had tried to formulate a quantitative thermodynamic mechanism based on his structural analysis. He said no and seemed very enthusiastic, although I was not sure whether he had understood what I meant. Having been taught by Pauling that until one expressed an idea in quantitative terms, it was not possible to test one’s results, I went away from our meeting thinking about the best way to proceed. Attila Szabo had recently joined my group as a graduate student, and the hemoglobin mechanism seemed like an ideal problem for his theoretical skills. The basic idea proposed by Perutz was that the hemoglobin molecule has two quaternary structures, R and T, in agreement with the ideas of Monod, Wyman, and Changeux; that there are two tertiary structures, liganded and unliganded for each of the subunits; and that the coupling between the two is introduced by certain salt bridges whose existence depended on both the tertiary and quaternary structures of the molecule. Moreover, some of the salt bridges depended on pH, which introduced the Bohr effect on the oxygen affinity of the subunits. These ideas were incorporated into the statistical mechanical model Szabo and I developed [10]. It was a direct consequence of the formulation that the cooperativity parameter n (i.e., the Hill coefficient) varied with pH. This was in disagreement with the hemoglobin dogma at the time and led a number of the experimentalists in the field to initially disregard our model, which was subsequently confirmed by experiments.

Protein Folding

In 1969 I was invited to spend a semester at the Weizmann Institute and I joined the group of Schneior Lifson. While there, Chris Anfinsen visited and we had many discussions of his experiments on protein folding, which had led to the realization that proteins can refold in solution, independent of the ribosome and other aspects of the cellular environment. What most impressed me was Anfinsen’s film showing the folding of a protein with “flickering helices forming and dissolving and coming together to form stable substructures.” The film was a cartoon, but it led to my asking him, in the same vein as I had asked Perutz earlier about hemoglobin, whether he had thought of taking the ideas in the film and translating them into a quantitative model. Anfinsen said that he did not really know how he would do this, but to me it suggested an approach to the mechanism of protein folding. When David Weaver joined my group at Harvard, while on a sabbatical leave from Tufts, we developed what is now known as the diffusion-collision model for protein folding [11]. Although it is a simplified coarse-grained description of the folding process, it showed how the search problem for the native state could be solved by a divide-and-conquer approach. Moreover, the diffusion-collision model made possible the estimation of folding rates. The model was ahead of its time because data to test it were not available. Only relatively recently have experimental studies demonstrated that the diffusion-collision model describes the folding mechanism of many helical proteins [12], as well as some others.

When David Weaver and I developed the diffusion-collision model in 1975, protein folding was a rather esoteric subject of interest to a very small community of scientists. The field has been completely transformed in recent years because of its importance for understanding the large number of protein sequences available from genome projects and because of the realization that misfolding can lead to a wide range of human diseases; these diseases are found primarily in the older populations that form an ever-increasing portion of humanity. Over the past decade or so the mechanism of protein folding has been resolved, in principle. It is now understood that there are multiple pathways to the native state and that the bias on the free-energy surface, due to the greater stability of native-like versus nonnative contacts, is such that only a very small fraction of the total number of conformations is sampled in each folding trajectory [13]. This understanding was achieved by the work of many scientists, but a crucial element was the study of lattice models of protein folding. Such toy models, as I like to call them, are simple enough to permit many folding trajectories to be calculated to make possible an analysis of the folding process and free-energy surface sampled by the trajectories [14]. However, they are sufficiently complex so that they embody the Levinthal problem, i.e., there are many more configurations than could be visited during the calculated folding trajectory. The importance of such studies was in part psychological, in that even though the lattice model uses a simplified representation, “real” folding was demonstrated on a computer for the first time. An article based on a lecture at a meeting in Copenhagen [15] describes this change in attitude as a paradigm of scientific progress.

Origins Of The CHARMM Program

When I visited Lifson’s group in 1969 there was considerable interest in developing empirical potential energy functions for small molecules. The novel idea was to use a functional form that could serve not only for calculating vibrational frequencies, as did the expansions of the potential about a known or assumed minimum-energy structure, but also for determining that structure. The so-called consistent force field (CCF) of Lifson and his coworkers, particularly Arieh Warshel, included nonbonded interaction terms so that the minimum-energy structure could be found after the energy terms had been appropriately calibrated. The possibility of using such energy functions for larger systems struck me as potentially very important for understanding biological macromolecules like proteins, though I did not begin working on this immediately.

Once Attila Szabo had finished the statistical mechanical model of hemoglobin cooperativity, I realized that his work raised a number of questions that could be explored only with a method for calculating the energy of hemoglobin as a function of the atomic positions. No way of doing such a calculation existed. We decided the time was ripe to try to develop a program that would make it possible to take a given amino acid sequence (e.g., that of the hemoglobin alpha chain) and a set of coordinates (e.g., those obtained from the X-ray structure of deoxy hemoglobin) and to use this information to calculate the energy of the system and its derivatives as a function of the atomic positions. This could be used for perturbing the structure (e.g., by binding oxygen to the heme group) and finding a new structure by minimizing the energy. Developing the program a major task, but Gelin had the right combination of abilities to carry it out [16]. He would have faced almost insurmountable difficulties in developing the program (pre-CHARMM) if there had not been prior work by others on protein energy calculations. Although many persons have contributed to the development of empirical potentials, the two major inputs to our work came from Schneior Lifson’s group at the Weizmann Institute and Harold Scheraga’s group at Cornell University. The CHARMM program is now being developed by a wide group of contributors, most of whom were students or postdoctoral fellows in my group; the program is distributed worldwide in both academic and commercial settings.

Pre-CHARMM, while not trivial to use, was applied to a variety of problems. An early application of pre-CHARMMwas Dave Case’s simulation of ligand escape after photodissociation from myoglobin; a study that was followed by the work of Ron Elber, which gave rise to the locally enhanced sampling (LES) and multiple copy simultaneous search (MCSS) methods now widely used for drug design.

The First Molecular Dynamics Simulation of a Biomolecule

Given that pre-CHARMMcould calculate the forces on the atoms of a protein, the next step was to use these forces in Newton’s equation to calculate the dynamics. This fundamental development was introduced in the mid-1970s when Andy McCammon joined my group. A basic assumption in initiating such studies was that potential functions could be constructed which were sufficiently accurate to give meaningful results for systems as complex as proteins or nucleic acids. In addition, it was necessary to assume that for these inhomogeneous systems, in contrast to the homogeneous character of even complex liquids like water, classical dynamics simulations of an attainable timescale (10 to 100 ps) could provide a useful sample of the phase space in the neighborhood of the native structure. There was no compelling evidence for either assumption in the early 1970s. When I discussed my plans with chemistry colleagues, they thought such calculations were impossible, given the difficulty of treating few atom systems accurately; biology colleagues felt that even if we could do such calculations, they would be a waste of time.

The original simulation, published in 1977 [17], concerned the bovine pancreatic trypsin inhibitor (BPTI), which has served as the “hydrogen molecule” of protein dynamics because of its small size, high stability, and a relatively accurate X-ray structure; interestingly, the physiological function of BPTI remains unknown. This development, which played an essential role in the Nobel Prize, is described in my Nobel Lecture.

The conceptual changes resulting from the early studies make one marvel at how much of great interest could be learned with so little – such poor potentials, such small systems, so little computer time. This is, of course, one of the great benefits of taking the initial, somewhat faltering steps in a new field in which the questions are qualitative rather than quantitative and any insights, even if crude, are better than none at all.

Epilogue

As I read through what I have written, I see what a fragmentary picture it provides of my life, even my scientific life. Missing are innumerable interactions, most of which constructive but some not so, that have played significant roles in my career. The more than 250 graduate students and postdoctoral fellows who at one time or another have been members of the group are listed in my Nobel Lecture. Many have gone on to faculty positions and become leaders in their fields of research. They in turn are training students so I now have scientific children, grandchildren, and great-grandchildren all over the world. I treasure my contribution to their professional and personal careers, as much as the scientific advances we have made together.

Contributing to the education of so many people in their formative years is a cardinal aspect of university life. My philosophy in graduate and postgraduate education has been to provide an environment where young scientists, once they have proved their ability, can develop their own ideas, as refined in discussions with me and aided by other members of the group. This fostered independence has been, I believe, an important element in the fact that so many of my students are now themselves outstanding researchers and faculty members. My role has been to guide them when problems arose and to instill in them the necessity of doing things in the best possible way, not to say that I succeeded with all of them.

Discussing my scientific family makes me realize that another missing element is my personal family, an irreplaceable part of my life. Reba and Tammy, my two daughters whose mother, Susan, died in 1982, both became physicians (thereby fulfilling my destined role); Reba lives in Jerusalem, Israel, and Tammy lives Portland, Oregon. My wife, Marci, and our son, Mischa, who is an intern at the Harvard Kennedy School, complete my immediate family. As many people know, Marci also plays the pivotal role as the Laboratory Administrator, adding a spirit of continuity for the group and making possible our commuting between the Harvard and Strasbourg labs. Without my family, my life would have been an empty one, even with scientific success.

Postscript

The biography up to this point is based, as already mentioned, on an article published in 2006 [1]. Molecular dynamics simulations have continued their rapid growth as a result of methodological improvements, force field refinements, and the availability of faster computers. The citation of methods for the study of complex systems in this year’s Nobel Prize in Chemistry will have the important consequence of legitimizing simulations and make likely their greater acceptance by experimentalists. The introduction of simplified potential functions, the specific focus of the Nobel Prize, certainly played a role in making possible molecular dynamics simulations of macromolecules. However, I am convinced that the latter are the essential element.

I dedicated my Nobel Lecture to the 244 Karplusians who have worked in my “laboratory” in Illinois, Columbia, Harvard, Paris and Strasbourg. Without them, I would not have received the Nobel Prize in Chemistry. Over the last forty years, many of them have contributed to the methodology and applications of molecular dynamics simulations. I find it curious, as I state in the written version of my Nobel Lecture, that molecular dynamics simulations were not mentioned in the description of the “Scientific Background” of the Nobel Prize. The large community involved in molecular dynamics simulations, which includes all of this year’s Nobel Laureates in Chemistry, has transformed the field from an esoteric subject of interest to only a small group of specialists into a central element of modern chemistry and structural biology. Without molecular dynamics simulations and their explosive development, no Nobel Prize would have been awarded in this area.

There is perhaps a parallel here between the fact that molecular dynamics was not mentioned in the Nobel Prize citation and the citation for Einstein’s Nobel Prize in Physics (1921). He was awarded the Nobel Prize for the theory of the photoelectric effect and not for his most important work, the general theory of relativity, which had already been verified by experiment and was the origin of his worldwide fame as a scientist. Interestingly, when he gave his Nobel Lecture, it was on relativity, even though he knew that he was supposed to talk about the photoelectric effect. Correspondingly, I traced the history of molecular dynamics simulations and their development in my lecture and did not emphasize the development of potential functions for simulations, the focus of the Chemistry Nobel Prize citation. The complex deliberations of the Physics Committee in reaching its decision concerning Einstein’s Nobel Prize are now known because his prize was awarded more than fifty years ago. The public will again have to wait fifty years to find out what motivated the Chemistry Committee in awarding this year’s Nobel Prize.

References

  1. This biolography is an abbreviated updated version of the article entitled, “Spinach on the Ceiling: A Theoretical Chemist’s Return to Biology,” Ann. Rev. Biophys. & Biomolecular Struc. 35, 1–47 (2006). It can be downloaded without cost.
  2. Honig B, Karplus M. 1971. Implications of torsional potential of retinal isomers for visual excitation. Nature 229, 558–560.
  3. Karplus M. 1959. Contact electron-spin interactions of nuclear magnetic moments. J. Chem. Phys. 30, 11–15.
  4. Karplus M. 1963. Vicinal proton coupling in nuclear magnetic resonance. J. Am. Chem. Soc. 85, 2870.
  5. Dalton L. 2003. Karplus Equation. Chem. Eng. News 81, 37–39.
  6. Karplus M. 1996. Theory of vicinal coupling constants. In Encyclopedia of Nuclear Magnetic Resonance. Vol. 1: Historical Perspectives, ed. DM Grant, RK Harris, pp. 420–422. New York: Wiley.
  7. Karplus M, Fraenkel GK. 1961. Theoretical interpretation of carbon-13 hyperfine interactions in electron spin resonance spectra. J. Chem. Phys. 35, 1312–1323.
  8. Porter RN, Karplus M. 1964. Potential energy surface for H3. J. Chem. Phys. 40, 1105–1115.
  9. Schatz GC. 2000. Perspective on “Exchange reactions with activation energy. I. Simple barrier potential for (H, H2)” J. Chem. Phys. 43:3259–3287. Theor. Chem. Acc. 103, 270–272.
  10. Szabo A, Karplus M. 1972. A mathematical model for structure-function relations in hemoglobin. J. Mol. Biol. 72, 163–197.
  11. Karplus M, Weaver DL. 1976. Protein-folding dynamics. Nature 260, 404–406.
  12. Islam SA, Karplus M, Weaver DL. 2004. The role of sequence and structure in protein folding kinetics: the diffusion-collision model applied to proteins L and G. Structure 12, 1833–1845.
  13. Dobson CM, Sali A, Karplus M.(1998). Protein Folding: A Perspective from Theory and Experiment, Angew. Chem. Int. Ed. 37, 868–893.
  14. Sali A, Shakhnovich E, Karplus M. 1994. How does a protein fold? Nature 369, 248–251.
  15. Karplus M. 1997. The Levinthal Paradox: yesterday and today. Fold. Des. 2, 569–576.
  16. Gelin, BR. April 1976. Application of Empirical Energy Functions to Conformational Problems in Biochemical Systems. Harvard PhD Thesis.
  17. McCammon JA, Gelin BR, Karplus M. 1977. Dynamics of folded proteins. Nature 267, 585–590.

From The Nobel Prizes 2013. Published on behalf of The Nobel Foundation by Science History Publications/USA, division Watson Publishing International LLC, Sagamore Beach, 2014

This autobiography/biography was written at the time of the award and later published in the book series Les Prix Nobel/ Nobel Lectures/The Nobel Prizes. The information is sometimes updated with an addendum submitted by the Laureate.

Copyright © The Nobel Foundation 2013

Archer J.P. Martin – Biographical

Archer John Porter Martin was born on March 1st, 1910, in London where his father was a general medical practitioner. He attended Bedford School from 1921 to 1929 when he entered Cambridge University to graduate in 1932. After a year in the Physical Chemistry Laboratory he obtained a post at the Dunn Nutritional Laboratory, where he worked under L.J. Harris and Sir Charles Martin, and in 1938 he moved to the Wool Industries Research Association at Leeds. From 1946 to 1948 he was Head of the Biochemistry Division of the Research Department of Boots Pure Drug Company at Nottingham and in 1948 he joined the staff of the Medical Research Council, first at the Lister Institute and later at the National Institute for Medical Research. He was appointed Head of the Division of Physical Chemistry at the Institute in 1952 and he was Chemical Consultant from 1956 to 1959. Since 1959 he has been a Director of Abbotsbury Laboratories Ltd.

Martin entered Cambridge University with the intention of becoming a chemical engineer but, due to the influence of Professor J.B.S. Haldane, then Reader of Biochemistry at Cambridge, he eventually specialized in biochemistry. His first researches, as an undergraduate, resulted in a method of detecting pyro-electricity by observing the attraction of a metal plate for crystals that had been immersed in liquid air. At Cambridge he worked on ultraviolet adsorption spectra and at the Nutritional Laboratory he was concerned with the attempted isolation of Vitamin E and in the pathological effects of prolonged Vitamin E deficiencies. In these latter studies he used solvent extraction and chromatographic methods which were to lay the foundation for his later work on chromatography. He also worked, along with others, on the B2 group of vitamin deficiencies in pigs.

At the Wool Industries Research Association he worked on the felting of wool, first with R.L.M. Synge and later with Consden and Gordon, and on amino-acid analysis. It was here that he developed his method of partition chromatography; more recently, with A.T. James, he has developed the method of gas-liquid chromatography.

Dr. Martin, a Fellow of the Royal Society (1950), was made Companion of the British Empire in 1960. He received the Berzelius Medal of the Swedish Medical Society (1951), the John Scott Award (1958), the John Price Wetherill Medal (1959), the Franklin Institute Medal (1959), and the Leverhulme Medal (1963).

In 1963, he was appointed to deliver special lectures (as “buitengewoon hoogleraar”) at the Technological University of Eindhoven, The Netherlands.

In 1943 he married Judith Bagenal; they have one son and three daughters.

From Nobel Lectures, Chemistry 1942-1962, Elsevier Publishing Company, Amsterdam, 1964

This autobiography/biography was written at the time of the award and first published in the book series Les Prix Nobel. It was later edited and republished in Nobel Lectures. To cite this document, always state the source as shown above.

Archer J.P. Martin died on July 28, 2002.

Copyright © The Nobel Foundation 1952

Interview with Jennifer A. Doudna, February 2021

“Embrace your interests, your passions, and really give it your all!”

We spoke to biochemist Jennifer Doudna on the International day of Women and Girls in Science, 11 February. Her collaboration with fellow laureate Emmanuelle Charpentier and her reaction to receiving the Nobel Prize were two topics that were up for discussion.

Why did you decide to pursue science?

Jennifer Doudna: I loved math when I was growing up. Nobody in my family was a scientist, but my father loved doing puzzles. So we did a lot of puzzles. I was growing up in a small town in Hawaii and I loved the natural environment there. I found myself fascinated by the evolution of plants and animals that survived in that native island environment. This was long before I knew anything about DNA, but I thought it was so interesting that I wondered about the chemistry of natural systems and natural organisms. I decided I wanted to be a chemist. Then when I learned about biochemistry, I thought that’s what I really want to do. I want to study the chemistry of living things. I set off on that journey in college and kind of never looked back.

Did you have a particular person, a mentor or role model, who really influenced you?

I would say it’s probably first and foremost my father, because even though he was not a scientist, he was very interested in science and he read everything. He was an avid reader and a literature professor. He gave me lots of books. He gave me Jim Watson‘s book about the double helix as well as books by Harold Morowitz and a lot of classic writers who wrote about science for a non-scientific audience. He really encouraged me early on to pursue my interests. Later when I was in grad school, he was the one person in my family that when we got together, his first question would always be, ‘What are you working on in the lab?’ He would really want to know, like he didn’t just want a one sentence answer. He really wanted to get into it. ‘What are you doing and why are you doing it? Why is it interesting?’ So that was great.

Beyond that, I did have some wonderful teachers. My biology and chemistry teachers in high school were very encouraging. I had multiple great professors in college who also encouraged my interest. My biochemistry professor in college gave me a chance to work in her lab over the summer, which was critical, where I really figured out, ‘Wow! I love lab work. This is really great. This is exactly what I want to be doing.’ When I got to grad school, I really got lucky. I got into a lab of a wonderful person who now is a Nobel Laureate himself, Jack Szostak. He was an incredible mentor, very passionate about science and encouraging for all of us that were in the lab at the time. I feel like I really lucked out.

Jennifer A. Doudna receiving her Nobel Prize medal and diploma

The Nobel Prize medal and diploma were presented to chemistry laureate Jennifer A. Doudna at her home in Berkeley on 8 December 2020.

© Nobel Prize Outreach. Photo: Brittany Hosea-Small.

Were you influenced by your father to be an avid reader too?

I have to say that in the roughly 10 years that I was pretty intensely working on CRISPR (like up until this year or 2020) I had to put a lot of things on hold. I’m an avid gardener and I gave up my garden. And I really stopped reading for pleasure. I had to mostly just read for work. Even trying to keep up with the scientific literature was very difficult. During that period of time, I had a young son, my mom was ill and then passed away. So we’re dealing with that. I was made division head in my department so I had a lot of administrative duties there. There’s this bunch of stuff. I really put all of that on hold.

What was really interesting for me was that last year in 2020, besides the year of this Nobel Prize, it was the year of the pandemic beginning. I think, like many people, I had to change many things about my lifestyle. I stopped travelling – I used to travel every week. Then I found that last spring, I just started slowly thinking, ‘Gee, I really ought to be composting.’ I started composting in my garden and that’s what took me up into my garden regularly. I started pulling a few weeds and pretty soon I had a very beautiful and active garden again. I loved it. I was in my garden every day and I had vegetables, flowers, fruit and lemons. It was really fun and I thought, ‘Oh my God, I don’t want to give that up again. You know, that’s too much.’ It was the same thing with reading.

There were a lot of very disturbing things going on in the US politically, so I had a number of sleepless nights. I found myself picking up books to help me kind of get through it. I love reading novels. I love reading science books. I love reading things that don’t have anything to do with work because I just I’m interested in them. Both the gardening and the reading are things that came back to me during the pandemic, and I’m going to fight to keep it in my life as we kind of slowly go back to “normal”. 

How do you cope with failure and with unexpected problems?

I sort of have three ways of coping. The first is that I always remind myself to take a long view of things; something that’s frustrating or disappointing in the moment, is it frustrating today or next week? I try to think about, ‘How am I going to feel about this in six months or a year from now, or 10 years from now?’ I also ask myself, in the scheme of problems in world, how big is this problem. Often it’s not very big. I try to remind myself of the context and I try to remember all the things I’m grateful for. I’m fortunate that I have a family, that I’ve had the successes and I’ve had my career.

That takes me to the second thing; I do really rely on friends, family and colleagues and I’ve been so fortunate to have a really great network of people who I rely on for support. I guess I actively now, even more than when I was younger, look for people that are going to be supportive and who I can in turn be supportive for as well. People that you can really build strong relationships with, I think is very valuable.

The third thing is because there was certainly some adversity when I was growing up in Hawaii, it sounds like a paradise, but it wasn’t. There were a number of issues when I was growing up. I had to learn to rely on myself. I had to kind of find an internal strength to deal with bullying, to deal with all kinds of name calling and resentment. I feel like I go back to that now, too. I kind of go to my inner core and I know that there’s a part of me that no one can touch and that no matter what happens, I know that I know who I am. I know what I value. If there’s adverse things going on there, there’s a part of me that no one can touch that way. That gives me some strength as well.

Do you have any advice for young researchers or students?

I honestly think the most important advice is to go for it. That means to embrace your interests, your passions, and really give it your all. I think that is what I’ve seen both for myself and [other] people. People that I’ve had the pleasure to work with in my laboratory, the most successful of them are people who are able to deal with their fears. We all have fears but sometimes you try something and there is failure, right? You have to deal with that.

I think for me and for people that I’ve seen that are highly successful, they deal with that. Each of us has to find our own way to deal with that as we just discussed. But I just think you have to embrace your passions. You have to really go for it. People that have been less successful in my opinion, are those that dabble in something, but then don’t really give it their all. They almost never give themselves a chance to succeed, as they back off too soon. I think for young people, I tell them go for it, find supportive mentors who will help you through the tough times, and then just keep going. Because if you have a good idea, it’s probably going to work out in some way. You may not be able to predict how, but you should just keep pursuing it.

Today it’s the International day for Women and Girls in Science. Do you think diversity is important in science?

Diversity is really important in science. First of all, I think that if you want to have the best scientific outcomes, you need a lot of different brains working on it. We all come to science (or anything really) with different perspectives, skill sets, interests, passions and ways of approaching a problem. The more of that we have, I think the more likely there is to be interesting science that gets done and frankly, interesting solutions to real problems. The pandemic is one very real example we’re dealing with right now where thank goodness there was creative work done years ago on using mRNA delivery. And now we have these wonderful vaccines, but it came together very quickly.

Jennifer Posing with CRISPR HQ

Nobel Prize-winning UC Berkeley biochemist Jennifer Doudna with a model of CRISPR-Cas9. Doudna spoke about the gene-editing process with Radiolab podcast in 2015.

Photo credit: UC Berkeley photo by Stephen McNally

Do you have any specific advice to young girls who want to go into science?

I would never want to stereotype, but I do think there’s more of a tendency by women and girls to underestimate themselves: ‘well, you know, I shouldn’t apply for that job or fellowship or graduate program because I’ll never get in.’ I feel like I hear it more frequently from my female trainees than from male. I don’t know all the cultural reasons for that, but I think it’s something that as women, we have to actively encourage both ourselves and other women and girls that might be following in our footsteps to actively put that little voice aside and trust that actually they’re probably better than they think they are.

Tell us about the first time you met your co-laureate Emmanuelle Charpentier.

She and I were both invited to a meeting in Puerto Rico in the spring of 2011. This was a conference sponsored by the American society for microbiology meeting that she might very reasonably be invited to. But for me, not so much because I’m really not a microbiologist at all. It just so happened that they were having one session on CRISPR, which at the time was a fairly esoteric area of microbiology, but interesting.

A friend and colleague, John, was at this conference and he said to me, ‘Oh, Jennifer, I’d love to introduce you to Emmanuelle.’ I had read her paper in Nature and it was a really nice work. I thought it’d be really interesting to talk to her. When I got introduced to her, she was this very chic woman that is quite petite and very attractive. I was immediately impressed by her kind of stylish, very natural look and fashion sense, not fancy but just really nice.

She said that she really had been looking forward to talking to me and I thought, ‘Oh, that’s cool.’ We had our session and then we went for a meal. She said, ‘Hey, I’d love to talk to you about the possibility of doing some work together.’ We started walking around old San Juan. The atmosphere there feels almost a bit French or European. It has these cobblestone streets and is quite lovely. She and I were just walking around these streets and talking about this protein, which at the time was called Csn1 and later was renamed Cas9.

We were talking about the possibility of working together to figure out how it was able to work in bacteria, to defend against viruses. There was a hypothesis that it might be a DNA cutter, but nobody had demonstrated that. How it would recognise viral DNA was unclear. That was really the basis of our initial interactions.

How was it to work with Emmanuelle Charpentier?

I loved working with Emmanuelle. She always had a great sense of humour, kind of a very dry sense of humour, even in email. She would say things like, ‘Oh, Jennifer, you have to excuse my Frenchy English.’ And I would say, ‘Oh my god, I’m so jealous of your Frenchy English. I wish I had Englishy French!’

She was in Sweden at the time. She was up at Umeå University so she was nine hours ahead of California time. When we were working really intensely on analysing data and writing a manuscript together, it was almost like working 24/7 because I would go to bed and she’d be getting up and she’d be working. By the time I got up, there would be a whole new set of things for me to work on and look at. It was just really intense and really fun.

How did you hear about the Nobel Prize? What was your reaction?

I’m embarrassed to say, I’d had a very long day. This is the day before the surprise of when it was announced. I had been at an all-day meeting. I was very tired that night. Of course I was aware about the Nobel announcements being made, but I just didn’t really think too much about it. I turned the ringer off on my phone and I went to bed. I fell asleep and fell into it very deeply. I woke up at just before 3:00 am, California time. My phone was buzzing and I could see that somebody was calling and then there were some unanswered calls and messages. I picked it up and it was a reporter from Nature magazine who I know, Heidi Ledford.

She said, ‘Hi, Jennifer, sorry to bother you early. But I really wanted to be the first to ask you how you feel about the Nobel.’ I was literally coming out of a deep sleep and I said to Heidi, ‘Oh my god, I haven’t had time to look at the news. I don’t know who won it?’ And she said, ‘Oh my god, you haven’t heard!’

I honestly got very nervous. I started to think that I might be dreaming. I said, ‘I can’t talk to you right now. I feel like I need to hear this from somebody official.’ I hung up and another incoming call was coming in and it was Martin Jinek, who was the scientist who did the CRISPR/Cas9 research in my lab in collaboration with Emmanuel, calling me from Switzerland. I answered the call and he said ‘Jennifer, oh my god. It’s just so fantastic as this is so exciting.’ Honestly, I have to say at that moment I knew it was real. The reason is that Martin is the most down to earth and humble person on the planet, and for him to be calling me at three in the morning from Switzerland, with this news, I knew it had to be real. Then of course I got connected to the Nobel Foundation, but that was the first five minutes of my realisation.

20201007 NobelDoudna bhs 013

Picture of Jennifer Doudna while she was receiving the news of her Nobel Prize in October 2020.

Photo credit: Brittany Hosea-Small

This interview has been edited for clarity and length.

First published: February 2021

Richard Henderson – Biographical

Richard Henderson

Early years

I was born in Edinburgh, Scotland, on 19th July 1945. My mother Grace Goldie, after two weeks convalescence, took me back on the train to Berwick-upon-Tweed, England, to re-join my father John Henderson, who was a baker at Bryson’s in Berwick. My mother was born in Edinburgh and my father in Tadcaster, North Yorkshire. They met in Edinburgh and started their married life in Berwick, where my father had been brought up. We lived in several rented flats in Berwick before moving when I was 3 years old to a council house across the river in Tweedmouth, where my father kept pigeons and then budgerigars. My mother persuaded Tweedmouth primary school to let me start early when I was four years old. I have no idea why she was so keen to get me out of the house. Just before my sixth birthday, my parents moved to the small rural village of Newcastleton, 2 miles north of the border between Scotland and England. My father was one of four bakers working in the local bakery, Oliver’s, graduating from baking bread to cakes. I attended Newcastleton primary school for 5 years (aged 6 to 10). Towards the end of primary school, the four most academic pupils in our class of 19 (Figure 1) were selected to attend Hawick High School, which is about 20 miles north of Newcastleton and was at that time accessible by a 45-minute morning and evening journey by steam train. We would set off at 8am every morning and get back at 5pm each evening. The total travel time of over an hour per day meant we were able to complete any homework during the train journeys. At Hawick, the classes were “streamed” by academic ability, with the entry year having 13 classes of about 35 pupils per class. The four of us from Newcastleton were in the most academic A stream (see Figure 2) and thrilled to be taught Chaucer, Shakespeare, Latin and French as well as Science, Mathematics and my favourite Metalwork. I also remember being delighted to find that mathematics lessons were subdivided into algebra, geometry and trigonometry.

An outing to Silloth

Figure 1. Primary school photo of an outing to Silloth, a seaside resort in Cumberland across the border in England, when I was 10 years old. The photo shows pupils from two classes, ours and the one from the year ahead. My three classmates Robert Davidson and Foster Harkness (rear left to right), and Maurice Carruthers (front right), who subsequently travelled by train to Hawick High School every day, are circled, with Richard Henderson in the centre of the front row.

My great aunt, who owned a corner shop in Edinburgh, sent me every week copies of all the children’s comics that were published in the 1950s, so I did read but definitely not literature. Although my mother tried to persuade me to read when I was young, I did not succeed in completing any novel until the compulsory school English syllabus forced me to read Walter Scott’s “Heart of Midlothian”, which I managed by reading 12 pages each night. When my paternal grandmother died, she left me a set of Arthur Mee’s “Children’s Encyclopedia”, which kept me occupied, especially on “Things to make and do”. Most children left school aged 15 at that time, so in our fifth and sixth form examinations, then called Highers and Lowers in Scotland, the entry year of about 400 pupils had dropped to about 55. For my final two years, at age 15 in Hawick and 16 in Edinburgh, my parents received a £50 family allowance to encourage them to encourage me to continue into higher level education.

Class photo

Figure 2. Hawick High School class 1A photo 1956. Three people from Newcastleton, circled left to right, are Richard Henderson, Robert Davidson and Maurice Carruthers.

When I was 15, the bakery where my father worked in Newcastleton ran into financial troubles. My father resigned and took a new job in Edinburgh about 3 months before I would sit my first national school examinations in June. My mother and younger brother Ross moved with him to Edinburgh, but it was decided that it would be best if I stayed on for 3 months with our next-door neighbours in Newcastleton, the Zurbriggens, so that I could sit the examinations without having to move to a new school. For my final (6th) year of High School, I moved to Boroughmuir in Edinburgh, following a recommendation by John Low, the headmaster at Hawick.

During that final school year at Boroughmuir, we were all asked whether anyone would like to apply to Oxford or Cambridge University, for which extra lessons geared to their entrance exams would be given, but only one Latin and Greek scholar decided to apply, unsuccessfully. Everyone else decided to apply to Edinburgh University, so when I started a Physics degree course at Edinburgh, I had four or five classmates from Boroughmuir and a similar number from Hawick. Our fourth and final year in Physics at Edinburgh University had a class of 45, including 4 others from Boroughmuir and one other from Hawick. Our final year Physics class photo is shown in Figure 3. The large representation from Boroughmuir arose from the enthusiastic teaching of our Boroughmuir physics teacher Bill Cow, or “Bilko”. Bill once played a recording to the 6th form physics class that he had made of a lecture by Dr Jack Dainty, Reader in Biophysics at Edinburgh University, in which he talked about his work on ion fluxes in Nitella, algae with giant cells. Bill’s view was that biophysics was an important developing area in the future of physics. Although it did not make a deep impact on my thinking at the time, it is possible that my later decision to follow a career in biophysics derived from this initial exposure to Bill Cow’s enthusiasm.

Class photo from Boroughmuir

Figure 3. Final year Physics IV class photo in 1966, with those from Boroughmuir, David Hogg, Andrew White, Harry Dooley, Brian Renwick and Richard Henderson (left to right) circled in red. Brian Mitchell from Hawick (yellow), and Craig Mackay who also came to Cambridge and became an astronomer (blue) are also marked. Andrew and Brian were the co-owners of our first, very old car.

My mother, Grace, and both grandmothers were my strongest supporters; my father and grandfather were very busy working and often tired after working all day. My mother had to leave school at 14 to help earn money for her family (her father had been unemployed from 1930–1938 in the Depression), but had really wanted to continue in school, so my higher education allowed her vicariously to fulfil some of her aspirations. She was very supportive and delighted when I did well academically.

The following are some brief memories of the four schools I attended.

1. My first school was Tweedmouth West First School (at age 4–5), which was a 10-minute walk from our house. I can remember even then being fascinated by numbers, and less interested in literary topics. There was a strong emphasis on learning arithmetic skills, and I can remember reciting the “times tables” while walking to school. My paternal grandmother, Jinny Henderson, lived next door to the school, and a great aunt on my father’s side a few doors farther down the same street, so occasionally I would visit my grandmother for lemonade and a biscuit on my way home.

2. When we moved to Scotland, I attended Newcastleton Primary School. Newcastleton is a small village midway between the Scottish and English towns of Hawick and Carlisle, each about 20 miles away in opposite directions. Its population then was about 800, but this has since dwindled to about 600. The two teachers I remember were Miss Russell and Mrs Fleming (when I was aged 6–10). During the summer when we moved, my mother realised that the Scottish schools were ahead of the English schools in their syllabus, so I was set some exercises by Miss Russell during the summer holidays, so that I could catch up. One difference was that my new classmates had all graduated to writing with “joined up” letters, whereas in Tweedmouth everyone was still writing using separate “printed” lettering. In those days also, the UK currency consisted of pounds, shillings and pence. So, when our class was set some problems involving the long-division of money, which my new schoolmates had already been taught, I remember having no trouble completing the task from first principles and getting the correct answer. However, I was told that my procedure was not correctly laid out and that I should not make up my own method. Towards the end of primary school, our class was subjected to a series of tests or qualifying exams that were used to decide on the type of secondary school education each pupil would be offered. Scotland had introduced universal free education up to age 15 in 1945, in a parallel reform to follow the 1944 Butler Education Act in England and Wales. I realised much later that the tests were the Scottish equivalent of the 11-plus exam, although, having started school earlier, I was only 10 years old at the time. The outcome of this testing was that 4 of us from a class of 19 were sent off to Hawick High School, leaving the remainder of the class to continue for another 3 years of secondary education in Newcastleton, which had a separate wing for older pupils.

3. At Hawick High school, when I was aged 11–15, the teachers I remember were “Jeemie” Allen, an excellent maths teacher and dahlia fancier, and Bill McLaren, who taught us for gym and rugby. One of my Hawick classmates, Myra Thomson, wrote to me after the 2017 Nobel Prizes were announced to remind me of the occasion when I was told off by Jeemie for simply writing down the answer to a maths question without bothering to write out the working. I remember being quite surprised when I was 14 to receive a school book prize, valued at 5 shillings, for being placed 3rd in maths, 3rd in science and 3rd equal in geography, having in earlier years always been nearer the bottom of the class. I chose a paperback book called “The Cockleshell Heroes” about a daring kayak raid to sink some German battleships in the French river port of La Rochelle during the second world war. This may have led to my later enthusiasm for kayaking. Although I gradually worked my way up in maths and science at Hawick, my language skills were always poor, and I was the only one in the class to fail the “Lower” in French. In Hawick, there was a shop I visited in the school lunch hour along with one or two friends, which sold ex-WD (War Department) electronics, so we would acquire very inexpensive components and build our own valve radios.

4. At the end of my 5th year of secondary school, the headmaster at Hawick recommended three schools in Edinburgh for my final (6th) year of secondary school, namely Royal High, George Heriot’s or Boroughmuir. The first two had (nominal) school fees whereas Boroughmuir was free, so we chose Boroughmuir Secondary School. My final year of school, at age 16, was spent at Boroughmuir, with Bill Cow, an excellent Physics teacher, and Dr Young our chemistry teacher, who had a Ph.D. and had worked on explosives during the war. Since we had already finished our science “Highers” examinations at the end of the 5th form, the 6th form science had no special curriculum. One difference between Hawick and Boroughmuir was that the sciences were taught in an integrated class by a single teacher at Hawick, whereas there were separate physics, chemistry and biology classes at Boroughmuir. Boroughmuir also had selective entry, so that the overall academic level and teaching standards were higher than at Hawick, which was an all-inclusive comprehensive school. A few of us expressed an interest in biology and studied some plant biology in our free periods. Dr Young also allowed us to choose any chemistry experiment we wanted to do on Friday afternoons, when we had a double period of Chemistry. One member of our class decided to take advantage of our teacher’s wartime experiences to test a different explosive each week, so every Friday at around 3.30pm we all had to crouch down below the bench while that week’s test explosive was ignited. Only once was the explosion strong enough to leave marks on the walls. My abysmal performance in French was rectified by having tuition in the 6th year in a class that had only two pupils. I had failed Lower French at Hawick and my classmate had failed Higher French at Boroughmuir. After an entire year of individual tuition, I scraped through the French exam with a bare pass and was thus able to meet the entrance requirements for the University of Edinburgh.

In my academic education, I thus benefitted greatly from the post-war education reforms, which opened new opportunities for working class children and brought in free secondary school education for all. At one stage aged 13, I tried to drop French in high school, but our headmaster called me into his office and told me that I should not do that if I wanted to keep open the option of going to University, because a language at O-level (Scottish Lower) was an entry requirement. I don’t think I even knew of the existence of Universities at that point.

University of Edinburgh (age 17–20)

I pursued a B.Sc. in “Natural Philosophy” which was the traditional name for Physics. This consisted of 4 years of physics, maths and mathematical physics. Peter Higgs was our mathematical physics lecturer in 1962–64, at just about the time he was writing his famous paper predicting what came to be known as the “Higgs boson”. I was delighted finally to be allowed to focus entirely on the subjects I found most interesting.

During my undergraduate years, I took many jobs during the Christmas, Easter and Summer breaks, partly to earn enough money to pay for running a car, and partly to get direct experience of different working environments. With two school friends, we bought a car (£10 each) when we were 17. The car, a 15-year-old Morris 8 Series E, was very unreliable, so the three of us learned a lot about car engines, clutches, gearboxes, back-axles and half-shafts, since they all seemed to need frequent repair or replacement, mostly from scrapyards. Although only one of us had passed his driving test, he taught the other two. During the three summers from 1963 to 1965, I worked in the technical drawing office at the electrical engineering company Ferranti designing a slide projector, at the UK Atomic Energy Authority (UKAEA) at AWRE Aldermaston in a small group evaluating lithium-drifted germanium detectors for gamma rays, and with Dr John Muir in the Physics Department on a summer project using microwaves to analyse the dielectric properties of kaolinite clay, with support from a Carnegie Trust Vacation Scholarship. Each of these three positions exposed me to different cultures. In the company, it was very hierarchical: the man in charge of the drawing office did not cope well with the more competent students. At UKAEA, a science campus operating as part of the civil service, there were many brilliant scientists who were a pleasure to work alongside, but their research was part of bigger projects, so their enthusiasm was muted. In contrast, those carrying out research in the university were enthusiastic, highly motivated and clearly excited about their work. I therefore decided that an academic research career would be my best option.

Decision to choose biophysics for graduate research

During my final year as an undergraduate, I spent a long time trying to decide which of the many exciting directions that physics was taking would be most interesting for me in a future research career. I can remember considering fusion research which promised to provide unlimited power generation, solid state physics which has transformed our lives through development of a multitude of semiconductor devices, high energy particle physics which has led to a deep understanding of nuclear structure, or astrophysics which has transformed our understanding of the universe from the big bang to black holes, neutron stars and gravitational waves. In the end, I decided that biophysics had great potential in bringing the power of physics to understand biological phenomena. One of the most important factors in making this choice was that I was keen to do individual hands-on research either myself or with one or two close colleagues, rather than to work as part of a large team, which would have been essential for some of the other directions. The final year physics exam in Edinburgh consisted of 6 papers on successive days on different topics ending with a final essay paper with a broader scope, and encouragement to be somewhat light-hearted. I wrote an essay on “Time”, in which I explained that time consisted of the past, present and future. Since the past and present could simply be looked up in a history book or encyclopaedia, only the future was interesting. This then led into a consideration of where physics was heading, with a discussion of the above range of topics and ending up with the conclusion that biophysics had great potential and might offer rewarding opportunities for the individual.

Having decided on biophysics, the question was then where to go for a Ph.D. research project. Since, at the age of 20, I had no desire to do any more studying, attending lectures or sitting exams, this ruled out all American Universities, and on further investigation also ruled out Leeds (R.D. Preston, successor to Astbury) and Norwich, where Jack Dainty had moved to a Professorship, his promotion having been turned down by Edinburgh. Both those biophysics departments had compulsory M.Sc. degrees that took at least a year before they would allow students to pursue research for Ph.D. That left only King’s College London, which I visited in November 1965. I talked with many people at Kings (Randall, Wilkins, Jean Hanson, Jack Lowy, Watson Fuller, Struther Arnott), and eventually wrote back after my return to Edinburgh asking whether I might be allowed to work on surface forces with Dr Anita Bailey. King’s did not offer me a place immediately but said they would let me know next Spring. Having made my plan after a lot of investigation, I thought it might be tactful to go and tell our new Professor, Bill Cochran, who had arrived from Cambridge in 1964 and quickly built up an outstanding solid-state physics group, about my decision to go into biophysics. Without hesitation, he quickly advised me that I should write to his friend Max Perutz at the Medical Research Council (MRC) Laboratory of Molecular Biology in Cambridge (MRC-LMB). Somehow, in spite of all my efforts to talk to many other people in Edinburgh and to contact and visit other places around the UK, I had not managed to identify the MRC-LMB. This was primarily because most research in UK universities at that time was listed in the Science Research Council (SRC) Handbook. The MRC-LMB in Cambridge was listed only in the MRC Handbook, which was not available in the Physics Department. In contrast, King’s College Biophysics was both a Biophysics Department in the University and an MRC Biophysics Unit, so was listed in both handbooks.

I therefore wrote to Max Perutz in January, received a reply in February and visited the MRC-LMB on a Saturday morning in March for the student Open Day, arriving on the overnight train from Edinburgh and returning on the same evening. There were about 20 students visiting, almost all from Cambridge. David Blow gave an informal talk about some of the research. I was also interviewed individually by Max Perutz and John Kendrew. Kendrew simply asked whether I had any questions. I said I was concerned that I had studied no biology or chemistry, only physics and maths, but he said I should not worry: I could easily pick up biology and chemistry as I went along. The laboratory was a hive of activity with more people at work on a Saturday morning at MRC-LMB than in other places I had visited midweek.

On my return to Edinburgh I therefore immediately wrote to say I would be very interested in becoming a Ph.D. student at MRC-LMB. Perutz wrote back two days later accepting me. That year two physics students started as Ph.D. students at MRC-LMB. Peter Gilbert who was a Physics undergraduate from Cambridge was the other. I had also learned from Cochran that another physics student from Edinburgh, Keith Moffat, had gone to MRC-LMB the year before to start a Ph.D. with Max Perutz, so I also wrote to Keith and asked him to tell me a bit more about Cambridge, especially the College system, about which I knew very little. Keith very kindly replied with a 4-page letter giving a thumbnail sketch of the positive and negative aspects of each college. Keith recommended Darwin and Corpus Christi, largely because Corpus had just opened new postgraduate accommodation in 1964 in the George Thomson Building. I spent a year living in the George Thomson building, and later became a fellow at Darwin and an Honorary Fellow at Corpus.

Cambridge (age 21–24)

I carried out research for my Ph.D. at the MRC Laboratory of Molecular Biology in Cambridge (MRC-LMB), with a thesis on “X-ray analysis of chymotrypsin: substrate and inhibitor binding”. With David Blow, my supervisor, and Tom Steitz, who was a Jane Coffin Childs postdoctoral fellow at that time, we worked out the mechanism of action of this enzyme, which was the first serine protease to have its structure determined. It was also the third or fourth protein structure to be determined at atomic resolution, after myoglobin (1959) and lysozyme (1964). The structures of chymotrypsin, ribonuclease and carboxypeptidase were all determined in 1967. By 2018, there were atomic coordinates for 140,000 macromolecular structures deposited in the Protein Data Bank (PDB).

Before I started my postgraduate work in Cambridge, I applied in June 1966 to attend a 2-week Summer School in Molecular Biology and Biophysics in Oxford, which was held to mark the inauguration of the Laboratory of Molecular Biophysics in Oxford, under Professor David Phillips. My application had arrived after all the places had been filled but Max Perutz had also written to Phillips in support of my application. Consequently, I received another letter a few weeks later from Oxford to say that “due to a withdrawal” I could now be offered a place. Thus, after a week or two at MRC-LMB, I spent 2 weeks in Oxford listening to 50 superb lectures by 25 outstanding scientists, including David Phillips, Max Perutz, Fred Sanger, Maurice Wilkins, Aaron Klug and Mark Bretscher. The only lecture for which my notes were almost a blank, save for the word “supercilious”, was by Sydney Brenner. Brenner was arrogant but also very clever, and shared the 2003 Nobel Prize in Physiology or Medicine for his work developing the nematode as a model organism. One of the highlights of life at MRC-LMB in the 1960s was the Saturday morning coffee meeting in the “Molecular Genetics” kitchen where Brenner would entertain six or ten weekend researchers with his wide-ranging, acerbic comments, phenomenal memory and ability to provide an integrated overview of all aspects of molecular biology as it was then.

Having learned only a limited amount of chemistry at school, since the syllabus for Scottish Higher Science at that time stopped with inorganic chemistry, with only the briefest mention of organic chemistry, I attended Cambridge University Part IA organic chemistry in which Peter Sykes was the most memorable lecturer, and also spent one term doing ten afternoon laboratory practicals in synthetic organic chemistry, the most memorable of which was the synthesis of methyl orange.

Towards the end of my Ph.D., I spent some time thinking about what to do next. I had realised by then that MRC-LMB was a superb laboratory with many truly outstanding scientists, and that its success depended on a very deep investigation and understanding of a few very narrow research topics. However, with my own very narrow training in physics and mathematics, I also realised that I would need a much broader grasp of a wider range of problems if I were to be able to choose a productive research topic and research direction, following the philosophy of Peter Medawar’s description of scientific progress as “The Art of the Soluble”. I therefore looked around for a postdoctoral opportunity where I would be able to get a much broader overview of the importance of different research areas across biology. I had been impressed by two scientists at Yale. One was Fred Richards (1925–2009) for his work on the structure and mechanism of ribonuclease, where his broad knowledge and insight had allowed him to provide the definitive explanation of the mechanism of action of the enzyme ribonuclease; although his structural work lagged significantly behind that of another US group at Buffalo led by David Harker, who had determined a better structure for ribonuclease, Richards was much more successful at explaining its importance and in relating structure to mechanism. The second impressive person at Yale was Jui Wang (1921–2016) in the Chemistry Department, who had proposed a hydrolytic mechanism for chymotrypsin that was appealing and showed deep insight into the chemistry of catalysis. I therefore wrote to both enquiring about the possibility of postdoctoral work. Wang replied immediately offering me a place, whereas Richards’ reply, although equally encouraging, did not come for 6 weeks: he was a keen yachtsman and was away sailing. I therefore decided to join Jui Wang and wrote two postdoctoral fellowship applications to the Helen Hay Whitney Foundation (HHWF) and the Jane Coffin Childs (JCC) Memorial Fund. Maclyn McCarty, the chairman of HHWF came to interview Jonathan Greer and me in Cambridge, and we were both subsequently offered HHWF fellowships. Since the HHWF stipend was higher than that of any other postdoctoral fellowship at that time, I accepted their offer, withdrew from JCC, and went to Yale accompanied by my wife Penny and our new-born daughter Jennifer, arriving in New Haven on 20th June 1970. It was Jennifer’s first birthday on the day we arrived at Yale.

Postdoctoral (age 25–27)

I thus ended up as a Helen Hay Whitney Foundation Postdoctoral Fellow at Yale University, in the group of Prof. Jui Wang for 2 years in the Chemistry Department, then spent my third year with Prof. Fred Richards in the Department of Molecular Biophysics and Biochemistry, with a bench in Tom Steitz’ lab. I tried to work on voltage-gated sodium channels in nerve and muscle membranes with the goal of determining the structure, but after 2 years decided that this goal was premature because the methods were inadequate, so then decided to tackle a simpler membrane protein, which was the light-driven proton pump bacteriorhodopsin, which had just been discovered by Walther Stoeckenius in 1971.

When I first arrived at Yale, based on my postdoctoral fellowship application and my own thinking at that time, I had planned to embark on two projects. The first was to label a peptide substrate of chymotrypsin with 13C at its carbonyl carbon and to carry out 13C Nuclear Magnetic Resonance (NMR) analysis to explore the chemical environment in the active site. The second was to choose another enzyme, perhaps slightly more interesting than chymotrypsin, and to purify, crystallise and solve its structure. I had written to David Blow to tell him about my plans and he replied to say that he thought Bob Shulman, then at Bell Labs in Newark, New Jersey might be already trying the 13C experiment, so he recommended that I should contact him. I did contact him and was invited to give a seminar at Bell Labs in 1970, where I met Shulman and Dinshaw Patel, his NMR right-hand man. After my seminar, in which I explained how I planned to go about obtaining an equilibrium concentration of the 13C-labelled enzyme-substrate complex using a high concentration of the substrate leaving group to increase the level of the desired structure by mass action, Shulman said it was a very good idea and they would do it. Since he had much better NMR facilities at Bell Labs than at Yale, I agreed to leave it to them and indeed George Robillard carried out and published the experiment, which provided some interesting insights.

I discussed my second proposed project with Wang. This was to purify and crystallise another enzyme. For this, I had selected NADP reductase from spinach, and purified it with one of Wang’s Ph.D. students, Jim Keirns. We succeeded in producing small pale-yellow crystals of spinach NADP-reductase before discovering that Martha Ludwig, by then at Ann Arbor, Michigan was already making progress on it. After some discussion with Wang, he explained that there were thousands of enzymes and, since I was still a young postdoc, it would be much better to pick a new longer-term problem that would come to fruition in 20 years, rather than aiming to take a small incremental step in a topical field. After a day or two, I realised that this was very good advice, and abandoned my initial plans to work on enzyme mechanisms and enzyme structure.

At that time, there was a lot of enthusiasm to understand the structure of membrane and membrane proteins, so I asked myself what was the most interesting membrane protein and chose voltage-gated sodium channels. Voltage-gated sodium and potassium channels had been at the heart of the 1963 Nobel Prize winning work of Alan Hodgkin and Andrew Huxley, and for someone with a physics background these were very attractive research targets. In addition, Wang had published some theoretical speculations about the mechanism of ion channels, and was keen for someone to look for microwave emissions from ion channels in nerve membranes as they opened and closed during the action potential. We therefore ordered some microwave equipment, and I began synthesizing some small molecules which I hypothesized might bind to and block sodium channel currents in nerves. After synthesizing 3 or 4 compounds, I then spent a week or two looking around at Yale to find someone who could measure nerve action potentials, ending up by making contact and collaborating with Murdoch Ritchie, who was chairman of the Pharmacology Department on the Medical School campus on the other side of New Haven. Although all my compounds had absolutely zero effect on nerve impulse propagation, this initial contact nevertheless led to a fruitful 3-year collaboration with Murdoch Ritchie and two others based in Ritchie’s laboratory, namely David Colquhoun, who was a sabbatical visitor from London, and Gary Strichartz, another postdoctoral fellow.

Our experiments on ion channels that eventually produced some useful insights began with the idea of producing radiolabelled tetrodotoxin using a tritium gas electrical discharge. Prof. Martin Saunders, also in the Yale Chemistry Department, had a moribund basement laboratory that was full of spider webs, but also housed a fume cupboard, vacuum equipment and 10 Curies of pure tritiated water, T2O. After arranging to have the basement lab reactivated, I managed to produce some tritium-labelled tetrodotoxin, purify it using flat-bed electrophoresis, and in collaboration with Ritchie demonstrate specific tetrodotoxin binding to nerves and nerve membranes from a variety of sources. We published a number of interesting papers, but my early steps to extract and purify these volt-age-gated sodium channels (VGSCs) were disappointing, because the channels extracted using either Triton X-100 or deoxycholate detergent, were quite unstable with a lifetime of a few minutes at room temperature or a day at 4ºC. I guessed that it might take another 30 years to solve the stability problem so decided to abandon working on VGSCs and choose instead a simpler membrane protein, with the criterion that it should be stable after detergent solubilisation and available in reasonable quantity. The microwave experiments also failed.

In June 1971, I had attended a meeting in San Francisco of the American Society for Biochemistry and Molecular Biology (ASBMB) and heard a wonderful talk by Walther Stoeckenius describing his discovery of the purple membrane from Halobacterium halobium (subsequently renamed as Halobacterium salinarum) and his finding with Dieter Oesterhelt and Allen Blaurock that it was composed of a two-dimensional crystalline array of a single membrane protein to which the chromophore retinal was bound via a Schiff base in a 1:1 stoichiometry, responsible for its characteristic purple colour. After following the work that Stoeckenius and his colleagues Allen Blaurock and Glen King were doing during the next year or two to try to elucidate the structure of the purple membrane, I felt they were heading completely in the wrong direction. Therefore, in early 1973, I decided it would be an opportune time to try one or two new ideas to solve the structure of bacteriorhodopsin, the single protein in purple membrane. Bacteriorhodopsin fitted perfectly the criteria of being stable and available in large amounts. By chance, Don Engelman, then Assistant Professor at Yale, had worked with Stoeckenius as a postdoc a couple of years earlier and knew him well, so Don and I phoned up Stoeckenius and asked whether he could send us a culture of H. halobium, which he kindly did. Neither of my initial ideas, either to use heavy atom derivatives to determine the phases of the powder pattern rings by multiple isomorphous replacement, or to solubilise bacteriorhodopsin and crystallise it in three dimensions for X-ray crystallography, worked out but these were the two approaches I was pursuing when my 3-year postdoctoral fellowship at Yale came to an end.

Penny and I made many friends at Yale and have kept in touch with them over the subsequent decades. During our years in New Haven, Penny gave birth to our second child Elizabeth, born in January 1971, but she had hydroencephalus at birth and died just over seven months later. Our third child, Alastair, was born on 22 March 1973, a few months before our planned return to the U.K.

Back to Cambridge – 1973 until now

Phase I – bacteriorhodopsin at low resolution

We returned to Cambridge on 20th June 1973 to the MRC-LMB on a 5-year appointment, exactly three years after our departure in 1970 (on an American J-1 visa which had a 3-year limit). Jennifer was now four years old and Alastair three months. During my ultimately fruitless efforts to make any progress in analysing the structure of the purple membrane and bacteriorhodopsin using X-ray powder pattern phasing or three-dimensional crystallisation, I was impressed by a talk that Nigel Unwin gave in October 1973 in the annual MRC-LMB symposium. He spoke about electron microscopy (EM) using a phase plate made from a single thread of spider web silk coated with gold. He was clearly thinking that his images of tobacco mosaic virus contained features that represented the protein structure as well as the negative stain he was using to embed the structure. After his talk, we discussed using EM to study the structure of bacteriorhodopsin in its natural two-dimensional crystalline form without using any heavy metal stain. We worked together very productively for about 18 months, ending up with a low-resolution, three-dimensional structure of the first membrane protein, determined by a novel method. The structure showed seven well-resolved trans-membrane a-helices oriented almost perpendicular to the membrane plane, with the implication that this a-helical architecture might be found in other membrane proteins, as indeed it has. After that early success, I switched my efforts from X-ray diffraction to electron diffraction, and eventually to electron microscopy. Nigel switched from working on viruses using negative stain to working on membrane proteins and two-dimensional or helical crystals without using heavy metals, so our 1973–1975 collaboration had a profound impact on the direction of both of our future scientific careers. We were jointly awarded the 1999 Gregori Aminoff Prize of the Royal Swedish Academy of Sciences. A photograph of us taken around that time is shown in Figure 4.

Nigel Unwin and Richard Henderson

Figure 4. Nigel Unwin and Richard Henderson (left to right) sitting on the steps of the original entrance to the MRC Laboratory of Molecular Biology in the 1990s.

Phase II – bacteriorhodopsin at high resolution

After spending about 7 or 8 years unsuccessfully trying to extend the resolution of our bacteriorhodopsin map from low resolution (7 Å) to high resolution (3 Å), where we expected to resolve the chemistry of the structure (i.e. to see the amino acid side chains and understand the mechanism), I eventually concluded that the methods that our group had been trying (model building, molecular replacement and heavy atom derivatives) were simply not powerful enough, and that we would have to embrace the necessity of recording high resolution electron cryomicroscopy (cryoEM) images. We did this from 1984 until 1990, by visiting and collaborating with a number of other laboratories (EMBL Heidelberg with Jacques Dubochet and Jean Lepault; Fritz Haber Institute Berlin with Fritz Zemlin and Elmar Zeitler; and Berkeley with Ken Downing and Bob Glaeser) as well as trying to improve our in-house EM capabilities in Cambridge. Eventually, the problems of high-resolution cryomicroscopy imaging and computer-based image processing were largely solved and we obtained a high-resolution map in 1990, into which we were able to build a nearly complete atomic model of bacteriorhodopsin. In the end, it was only the second membrane protein structure to be determined at high resolution. The first was Hartmut Michel’s bacterial reaction centre membrane protein complex from R. viridis solved by crystallisation and X-ray crystallography, for which he shared the 1988 Chemistry Nobel Prize with Johann Deisenhofer and Robert Huber. After 1990, Sriram Subramaniam and I did some trapping of intermediates to help work out the mechanism of the bacteriorhodopsin light-driven protein pump. Our bacteriorhodopsin work was essentially completed by 1999.

On a more personal note during this period, Penny and I arranged an amicable divorce in 1988, Jennifer married Richard Morris in 1993, I married Jade Li in 1995, and Alastair married Laura Williams in 1999. The resulting clan including 6 grandchildren all came to Stockholm on 10th December 2017 (Figure 5).

Phase III – single particle cryoEM

From 1995, following publication of a review I wrote on “The potential and limitations of neutrons, electrons and X-rays for atomic resolution microscopy of unstained biological molecules”, I was convinced that the future of cryoEM would involve imaging of single particles embedded in vitreous ice, a specimen preparation method that had been developed by Jacques Dubochet’s group in the 1980s. This “single particle cryoEM” method was potentially very powerful because it did not require the protein of interest to be crystallised nor did it require the use of crystallographic methods, which was what I had worked on exclusively until that point using X-ray and electron diffraction. Single particle electron microscopy had started with the image processing methods of Joachim Frank and Marin van Heel, as well as Owen Saxton and Wolfgang Baumeister, prior to the development of Dubochet’s plunge-freeze method of producing thin films of amorphous ice, but it was the combination of the two that promised to be particularly powerful.

We worked from 1995 until 2013 to analyse the problems and barriers to making progress, and gradually understood and solved them. The most important were the need for brighter sources, better vacuums, more stable cold stages and better detectors. The electron microscope companies, under pressure from users, addressed the first three. Our group in Cambridge, collaborating with another group at Rutherford-Appleton-Laboratory (RAL) near Oxford, worked out how to improve the detectors, and other people developed better computer programs to take advantage of some of the features of the new detectors (Steve Ludtke, Niko Grigorieff, and Sjors Scheres). As a result, almost overnight in early 2013, everyone started to obtain maps with much higher resolution. This was termed the “Resolution Revolution” by Werner Kühlbrandt (Science (2014) 343, 1443). From that point on, there was great enthusiasm from the entire structural biology community and a wider adoption of single particle cryoEM methods, so that now in 2018 cryoEM has become the prime method for many structural biology problems.

Other contributions

I was Joint Head of the Structural Studies Division at MRC-LMB (1986– 1999), Director of MRC-LMB (1996–2006) and a member of the Medical Research Council, which is the governing Board of MRC (2008–2014). Previous Directors were Max Perutz (1962–1979), Sydney Brenner (1979–1986) and Aaron Klug (1986–1996). The current Director is Hugh Pelham (2006–2018). All previous directors at MRC-LMB were also Nobel Prize winners. Probably the most significant achievement that we made during my Directorship was to advocate in 1999 the construction of a new building to house the MRC Laboratory of Molecular Biology in the 21st century, to carefully time the initiative to request funds for the construction to coincide with an upswing in the economic cycle around 2003, and to negotiate the subsequent hurdles for land acquisition and planning permission. This resulted in a superb new 30,000 square metre building, which opened in 2013, is attuned to the needs of modern molecular biology, and has the flexibility to have space reconfigured to parallel the changing needs of research. During my time as Director, Hugh Pelham as Deputy Director took a deep interest in the design and layout of the new building and carried the early planning through to completion during the first half of his Directorship. At the same time, Dr Megan Davies, the Assistant Director from 1996 and Head of the MRC Centre in Cambridge, ensured that our relationships with MRC in London and the local biomedical community in Cambridge were strengthened. An initial invitation soon after I started my Directorship to have dinner with Dr Keith Peters, the Regius Professor of Physik (an old term for Medicine) and Head of the Clinical School, developed into an annual strategic tête-à-tête that helped to keep the interests of MRC-LMB aligned with those of the Clinical School and the NHS Addenbrooke’s Hospital Trust.

Gathering of family members

Figure 5. Clan gathering in Stockholm. Left to right: Joshua Morris, Jessica Morris, Grace Morris, Rosie Morris, Rachel Henderson, Jade Li, Alastair Henderson, Richard Henderson, Jennifer Morris, Richard Morris, Tom Henderson, Laura Henderson.

Nobel ceremony

My wife, Jade Li, and I spent a wonderful 10 days in Stockholm for the awards of the 2017 Nobel Prizes, with the good fortune to be able to hear the Physics lectures about how gravitational waves were observed for the first time, to meet the Physiology or Medicine laureates who had worked out the molecular basis of circadian rhythms, and also the literature and economics laureates, Kazuo Ishiguro and Richard Thaler. A photograph of our family taken on the stage of Stockholm Concert Hall immediately after the awards is shown in Figure 5.

From The Nobel Prizes 2017. Published on behalf of The Nobel Foundation by Science History Publications/USA, division Watson Publishing International LLC, Sagamore Beach, 2018

This autobiography/biography was written at the time of the award and later published in the book series Les Prix Nobel/ Nobel Lectures/The Nobel Prizes. The information is sometimes updated with an addendum submitted by the Laureate.

Copyright © The Nobel Foundation 2017

Sir J. Fraser Stoddart – Biographical

Sir J. Fraser StoddartI was born in the capital of Scotland on Victoria Day in the middle of World War II. The nursing home in Edinburgh where this cliff-hanger of an event took place, during the early evening of 24th May 1942, was located at 57 Manor Place. It was not anticipated that a little boy weighing in at just under two kilograms would live until the next morning. I have the doctor’s bill, dated 7th October 1942, confirming that I defied the odds he gave against my survival. The bill reads, “Dr. Douglas Miller presents his compliments to Mrs. Stoddart and begs to intimate that his fees for professional attendance amount to ₤4:4/-.” It is not the realization that my parents were obliged to pay the princely sum of Four Guineas – equivalent to my father’s monthly salary at the time – to have me brought into this world that resonates with me most of all; rather it is the four and a half months the doctor was prepared to wait before sending out his bill to my mother. How times have changed.

My mother, christened Jane Spalding Hislop Fortune, but known as Jean to the family, had made her own way into the world on 23rd May 1911 at Seggarsdean Farm, in the vicinity of Haddington, a small town about 20 miles east of Edinburgh, in East Lothian. One claim to fame for this town is that it is the birthplace of John Knox, the Scottish minister who was the leader of the Reformation in Scotland and the founder of the Presbyterian Church of Scotland. While still a toddler, Jean Fortune made the move with her parents and two elder brothers, Jim and Tom, to Colstoun Mains which is located three miles south of Haddington. This farm on prime agricultural land was to become the seat of the Fortunes for most of the 20th century. From all reports, my mother was quite a sickly child and did not achieve as much as she might have done at school, leaving the Knox Academy in Haddington when she was 14. Her health improved during her teenage years on the farm and eventually she attended the Edinburgh College of Domestic Science on Atholl Crescent, graduating in February 1935 with a First Class Institutional Management Diploma. Following brief experiences as the manageress of private boarding schools in Yorkshire and Devonshire she became, with financial support from her father, the proud owner and proprietor of the Edenholm Private Hotel in Dunbar, a seaside resort on the North Sea, some eight miles east of Haddington. Old photographs indicate that it was around this time in 1937 that my mother and father met, became engaged and were married in St Cuthbert’s Church in Edinburgh on 16th October 1938, just before the onset of World War II in September of 1939. My maternal grandmother rented a holiday home in Dunbar every summer in the late 1940s so that she could bring all her grandchildren under one roof for a few weeks. I have vivid memories, while in the company of my cousins, of watching pigs swim in a paddock on the outskirts of the town during the Great Floods of 1947 that hit the United Kingdom. These holidays by the seaside bring back happy memories, aside from when my grandmother found the urge to have us all visit the unheated swimming pool, open to the chill waters of the North Sea. How we all dreaded the experience that she informed us was good for our constitutions, yet apparently not hers!

Seated between my father, Tom, and my mother, Jean c. 1946.

Figure 1. Seated between my father, Tom, and my mother, Jean c. 1946.

My father, Thomas Fraser Stoddart, always referred to as Tom by the rest of the family, was born on 20th January 1910 in Irvine, Ayrshire on the West Coast of Scotland. His father was a golf professional who, together with his wife, ran the Bogside Golf Course until he retired in 1945. As summer is the high season for golf, Tom Stoddart, together with his two younger sisters Anna and Clem (short for Clementine), were packed off each summer to the farms of cousins in East Lothian. It was at Howden that my father struck up a close, life-long relationship with his cousin, Tom Scott, while also being bitten by the farming bug. After attending Irvine Academy, my father continued his education at the West of Scotland Agricultural College in Glasgow where, after three years’ training, he gained First Class Certificates in most of his classes and won the McAlpine Memorial Prize as the best student of his year in agricultural botany. I can vouch for the fact that my father knew all that there was to know about grasses to be found in the Lowlands of Scotland. When he graduated from the college in December 1932, the then Principal and Professor of Agriculture was to comment in a testimonial that “He is a young man of energetic and painstaking habits, is methodical in his work, and is possessed of more than the average endowment in grit and determination. These attributes, combined with his sound theoretical and practical knowledge, mark him out as one well fitted for a responsible position in agriculture and dairying.” That position turned out to be the manager of the University of Edinburgh’s farms, one of them being Shothead, in the neighborhood of Balerno on the west side of the city, within sight of the Pentland Hills.

Edgelaw

When I was only six months old, my father decided to forsake the comparative comfort and relative security of being a farm manager to take on the tenancy of Edgelaw Farm about a dozen miles south of Edinburgh. Part of the Rosebury Estate, it was the middle of three farms on a dead-end road, which defined its remoteness and lack of electricity until I was almost 18. These circumstances, coupled with the fact that I was an only child, were to define much of my early life’s experiences in what I was later to refer to as the ‘University of Life’.

Edgelaw Farm House.Kneeling in the middle of the middle row with 11 of my Melville College classmates on my 11th birthday.

Tethered to a young Ayrshire bull c. 1959.

Figure 2. Top: Edgelaw Farm House c. 1963. Middle: Kneeling in the middle of the middle row with 11 of my Melville College classmates on my 11th birthday. Bottom: Tethered to a young Ayrshire bull c. 1959.

I grew up during the 1940s and 1950s in a post-World War II society coping with the rationing of food, clothes, and petrol (gas), and without access to modern-day conveniences in the home and workplace that we take for granted these days. The consequences for me were that I had to live out a very simple lifestyle, and I also had to find ways of amusing myself in a home where only a few rooms through the winter months were habitable. The need for warmth meant that  we often lived as a small and close-knit family huddled together in the kitchen, which was fired by a Rayburn cooker that not only provided localized heat, but also hot water for the scullery, wash-house and single bathroom, in addition to some limited cooking space. It was augmented by another gas cooker that was fueled from a large cylinder of rural (liquid) gas. Other rooms in the farmhouse had to be heated by open coal- and wood-burning fires that were often influenced in an unpredictable manner by the wind and rain outside. Up would go the cry that the fire in the drawing room was ‘smoking’, which meant that the room was filling up rapidly with smoke and would soon have to be evacuated. The one and only telephone was located in the hall, which was rarely, if ever, warm, and so conversations tended to be short during the winter months. Light through the long, dark winter months was provided by a vast array of Tilley and oil lamps.

I remember, as if it was only yesterday, the day ‘the electricity,’ as it was called, came to the farmhouse for the first time. It was Christmas Eve 1959 when we received word that the meter man would not be coming to install the meter until the New Year. The disappointment in the household was palpable. We had been so looking forward to celebrating Christmas and the New Year and the long-awaited (17 years!) arrival of ‘the electricity’ with family and friends. I had helped the electrician – a character if ever there was one by the name of Phil MacKay – during the preceding months wire the farmhouse, steading and cottages, and so was pretty knowledgeable when it came to wiring. Unbeknown to my parents, but egged on by Phil, I waited until the cows had been milked and the assembled company were all getting ready to sit down and have a Christmas Eve supper. At that point, I fetched a pair of stepladders, climbed up to a point near the ceiling where the meter would eventually be installed, and joined up the first pair of wires between the house and the grid with a pair of pliers. As I expected, nothing of significance happened. On bringing the second pair of wires together, however, there was blinding flash and much of the house was ablaze with light for the first time. There was a lot of noise. My mother was beside herself. She was convinced that someone would report us to the police and we would all end up in jail! Reason prevailed. My mother was soon convinced that by closing the curtains (drapes) in all the rooms we could harbor our secret and have ‘the electricity’ after all. And so, it was that for more than a week we had ‘the electricity’ for free and we used it to full advantage. In later years, we became much more conscious of switching off lights, for that practice had some bearing on the size on ‘the electricity’ bill. I reckon we all read more and I had no excuse not to do my homework. A television set arrived not so long afterwards and life was never quite the same ever again.

The whole episode brought out the daredevil side of my character. I discovered on the farm that defying regulations and breaking rules was a way to achieve distant goals on a shorter time-scale and, while there might be a price to pay, there would always be supporters, even secret admirers, and after the deed had been done there was no going back.

From a young age, I was addicted to solving jigsaw puzzles and would stack them up when completed between sheets of newspaper. I ascribe my early fascination in stereochemistry and topology to this addiction, which was to give way gradually to one of the more sophisticated of toys in Britain in the 1950s, namely ‘Meccano’. The opportunity to construct a gadget I had designed myself and then put it to work after a fashion was to find expression later on when my passion for the chemical synthesis of unnatural products began to develop. There is also little doubt that my ‘Meccano’ set whetted my appetite many years later for constructing artificial molecular machinery from the bottom up. My interest in tinkering with machines and motors was increased considerably during those times on the farm, when I would take car and tractor engines apart, decoke them, replace the spark plugs and put them back together again, with the prospect that I would be going through exactly the same routine a few months later. The early internal combustion engines were not all that effi cient or reliable: they demanded a lot of care and attention.

The late 1940s through the 1950s into the mid 1960s were times of rapid development in agriculture. My parents had no choice but to embrace change like there was no tomorrow. The horse and cart gave way rapidly to the tractor and trailer. The binder and all the labor-intensive and time-consuming paraphernalia that followed in its wake yielded more gradually to the combine harvester and the baler. Our 32 cows, distributed between three byres, were some of the first in the district to be milked by machine. Not all change was seen to be desirable: right up to the last days of the farm in 1968, my mother remained a strong advocate of producing eggs from free-range hens. With the onset of mechanization, collaboration between farmers was commonplace. For all the 26 years that my father ran a flock of 160 lambing ewes, the sheep-shearing was completed in one day (weather permitting) by the shepherds from Colstoun Mains, who would arrive in the early morning with all their motorized clippers. It was an occasion when my mother captured their hearts and souls with a wholesome dinner in the middle of the day that was surely second to none.

The farm had two cottages – one for the byreman and the other for the ploughman as well as a bothy (a single-room cottage) that was home to an Irish laborer for part of the year. The cottages experienced a fairly regular turnover of families usually with quite a number of children who were my playmates. We were left free to run wild around the farm and also to roam the countryside at will on our homemade buggies and old bicycles. Creativity and risk-taking came into our play on the grandest of scales in a playground we fashioned to changing circumstances. We invented our own games and learned the hard way about the dangers of climbing on roofs, burrowing through passages between bales of hay in the hay shed, and speeding down hillsides on carts adorned with a variety of wheels in the summer and on homemade sledges in the winter. The concept of playdates had still to be invented.

My formal education began when I was four years old with mornings only attendance at the local village school in Carrington, around three miles from the farm. My mother recalled that when she collected me from the school at noon on the first day and inquired as to how I had got on, my answer was to ask if I could go the next day for the whole day. At first there were only four other children, all girls, including one, Muriel Logan, a very bright girl from Aikendean Farm. As a consequence of the gender imbalance, I learned to knit, particularly stockings, rather well. By the time I Ieft the village school in 1950, the number of pupils had risen sharply to 28. In this rapidly changing educational environment, where the older pupils helped to look after the younger ones, I discovered very quickly that Miss Morrison did not hesitate to use the tawse – a leather strap having one end cut into thongs that was used by schoolteachers in Scotland in the 1950s as an instrument of punishment – for poor performance, let alone bad behavior.

At the age of eight, my mother decided that I should go to one of the many fee-paying boys’ day schools in Edinburgh. She chose Melville College – formerly the Edinburgh Institution and now, as a result of a merger, Stewart’s Melville College – because she was attracted to its predominantly red and black uniform. I was obliged to take an entrance examination which, apparently, I passed with flying colors as a consequence of all that I had learned in the village school from Miss Morrison. I was blessed with some really outstanding primary school teachers – Miss Christie and Miss Pratt come to mind, both of them now in their nineties and still going strong today. They recall a very shy little boy, shyness being a trait that was to take me more than three decades to overcome.

Before I reached the age of 16, when I could negotiate the journey to school on a Lambretta scooter, my mother would drive me in the family’s 1938 Hillman Minx – purchased from James Ross and Sons for ₤155 – the three miles to the nearest bus terminal in Rosewell, at that time a small coal-mining village, to catch the 7:40 a.m. bus to Edinburgh. The popularity of cigarette smoking amongst the office workers and shop assistants meant that you could cut the atmosphere with a knife on the top deck of the bus towards the end of the 45-minute journey to St Andrew’s Square. The bus journey was followed by a mile-long walk down George Street to the school on Melville Street. I was to realize many years later that the education I received at Melville was second to none, maybe because the 1950s were less than two centuries removed from the period of the Scottish Enlightenment that was graced by eminent scholars, such as philosopher David Hume, economist Adam Smith, poet Robert Burns and chemist Joseph Black. I was taught by teachers, most of whom could have been university professors, in Latin, English Language, English Literature, French, History, Geography, Mathematics, Physics and Chemistry. The school’s music master, W. O. (Bill) Minay, was the organist at St. Cuthbert’s Church – where my parents were married on 19th October 1938 – at the west end of Princess Street. It was from Bill Minay that I took piano lessons for many years. With a huge amount of practice and no little encouragement from him, I was able to play the first two movements of Beethoven’s First Piano Concerto. Although enjoyable, that experience told me I was not cut out to be a concert pianist.

Seated to the right of Mr Richardson, the Headmaster with the other nine school prefects in 1960.

Third from the left in the back row of the 1960 First Hockey Eleven.

Figure 3. Top: Seated to the right of Mr Richardson, the Headmaster with the other nine school prefects in 1960. Bottom: Third from the left in the back row of the 1960 First Hockey Eleven.

Sport was also a major part of the school curriculum. Rugby, cricket and field hockey were compulsory, along with swimming all the year round. During our last three years in school we found ourselves in army-style uniforms as part of a Cadet Force, in which I rose to become the Signals Sergeant. In my final year, the Headmaster appointed me to be the Second Prefect of the School, a position that gave me adequate opportunities to develop leadership skills. This experience was to prove invaluable when I became Head of the School of Chemistry at Birmingham – and later, the Director of the California NanoSystems Institute.

My mother was a terrific cook and an awesome baker, knowing instinctively when to add and mix ingredients, and rarely, if ever, measuring or weighing anything out. She knew just the right moment to stop whisking, heating and beating mixtures. She went about all these activities and more, including dress-making and patching up clothes, while feeding hens, mucking out henhouses, rearing chickens, gathering eggs and selling them in the neighboring villages and townships. My early successes at practical work in chemical laboratories owed much to watching this remarkable time and motion machine in action. My father, by far the best educated and most well-read farmer in the district, set very high standards for himself, expressed most intensely when a heifer was being groomed to perfection, prior to being sold at the Lanark Stock Market, or a flock of lambs, suitably washed in the dipper and individually manicured to perfection, were on their way to the auctioneer at the St. Boswells Sheep Sales.

I was to witness, from a very young age, the essential mating activities that were an integral part of maintaining a herd of dairy cows and orchestrating in October and November the running of around 150 ewes with tups (rams), at an approximate ratio of 50:1 to ensure the arrival of around 250 lambs during a frantic three-week window in March. While tending to cows calving throughout the year on a fortnightly basis, often in the middle of the night, was more or less routine, the lambing season never failed to reduce myself and my parents to states of utter physical and mental exhaustion, from a combination of lack of sleep and very long working days, for spring was also the time to be in the fields from morning to night sowing wheat, barley and oats, to be followed immediately thereafter by potato planting and the sowing of kale and turnips (swedes). In the summer months, I enjoyed nothing more than walking round the 365-acre (one for every day of the year) farm with my father in the evenings of long light. He knew all there was to know about the flora and fauna of the countryside. He was also a walking dictionary – a kind of Google before its time – that was useful for me in building up a vocabulary, and when we were engaged in the evenings in solving crossword puzzles in The Scotsman. My vocabulary was also broadened through my friendship with the farmhands, who taught me to swear from a young age. Later in life, my mother reflected that, much to her chagrin, I could swear like a trooper well before I could talk.

Edinburgh

During my four years as an undergraduate student at Edinburgh (1960–1964), I managed to hold my own in Mathematics, Physics, Chemistry and Biochemistry classes, in the face of stiff competition from many very bright students drawn, in large part, from the east coast of Scotland, many coming from the elite Edinburgh schools. A cohort of English students – who entered the Scottish higher educational system having covered much of the first-year science curriculum at A-level in England – got off to a flying start in their first year, but in subsequent years we Scots started to pull ahead of most of them. The chemistry teaching at Edinburgh in the early 1960s was not particularly taxing or stimulating, apart from some excellent lectures given by Tom Cottrell, John Knox, Peter Schwartz and Dai Rees. Organic chemistry, under the leadership of Professor Sir Edmund Hirst, was heavily skewed towards carbohydrate chemistry. A transformation occurred in my third year during a laboratory course in quantitative analytical chemistry. During his introduction, the somewhat abrasive Dougie Anderson announced to more than 100 of us that we would be pipetting by mouth enough cyanide to kill the whole of Edinburgh! After having made this spine-chilling remark, he went on to state that he had been running the 10-week course for more than a decade and in that time no student had ever completed it. Here was my opportunity, I thought, to apply the multitasking skills I had acquired from working on a mixed-arable farm for a couple of decades. I used this experience and finished the course inside seven weeks, gaining a mark close to 100%. This achievement earned me my first visit to the office of Sir Edmund who told me that Dr. Anderson would like to offer me a paid position in his research group during the following summer. I jumped at the opportunity. I felt much more at home in this new research environment, where I was given the opportunity to unravel the structural complexities of plant gums of the Acacia genus. There was little doubt from what was already published in the literature that these acidic polysaccharides – accompanied mysteriously by a small amount of protein – were high molecular weight polyelectrolytes constituted around a branched carbohydrate backbone. I was to continue researching these biomacromolecules well beyond a fourth-year research project into the pursuit of a PhD degree as a postgraduate student. My main contribution to the field was to challenge the “main-chain” hypothesis, implying a brush-polymer constitution, and replacing it with a much more highly branched constitution without having the foresight to describe it as a dendrimer before its time. My postgraduate research was to leave me with one lasting impression – namely, that the many gum trees in the Sudan, from whence the nodules I studied came, had never managed to produce between all of them through all of time, two gum molecules which were identical in size and constitution. After this period of handling highly heterogeneous mixtures, I longed to grow acquainted with a molecular world where homogeneity ruled the roost, at least for a time.

Standing on the right with Douglas Anderson and my fellow postgraduate students at Kings Buildings, University of Edinburgh.

Second on the right in the third row back with Walter Szarek and Ken Jones at the front taken at Queen's University in Canada.

Figure 4. Top: Standing on the right with Douglas Anderson and my fellow postgraduate students at Kings Buildings, University of Edinburgh c. 1965. Bottom: Second on the right in the third row back with Walter Szarek and Ken Jones at the front taken at Queen’s University in Canada c. 1968.

Between continuing to work on the farm, and becoming bitten by the research bug, I had to settle for graduating with a BSc Honours Degree in Chemistry and being the top Upper Second, in fifth place overall, in the 1964 Class of 45 students. By contrast, my postgraduate research was a resounding success and I was able to graduate with a PhD degree in just over two years in November 1966, having met the love of my life, Norma Scholan, who had joined the Anderson group as a fourth-year undergraduate research student. Norma made up for my lackluster performance in my Finals by coming top of her class of over 80 Final Year Chemistry students in 1966. In the years to come our two daughters, Fiona and Alison, were to graduate in Chemistry – from Imperial College London and the University of Cambridge, respectively – with First Class Honours degrees just like their mother before them, leaving me the dunce of the family!

Kingston

During the first 25 years of my life I had travelled very little and I yearned to go to North America, with enthusiastic support from my parents and somewhat less so from Norma, who had transferred her allegiance to the Biochemistry Department in the Medical School to begin her postgraduate work in steroid biosynthesis, under the tutelage of George Boyd. For my part, Sir Edmund sprung into action and did not take long to arrange for me to go to Queen’s University in Kingston, Ontario as a National Research Council of Canada Research Fellow. Here I would join the Chemistry group, headed up by Ken Jones, one of his own postgraduate students from his Bristol days. The 1960s witnessed the end of an era in UK chemistry departments, arranging for the department’s best students to go overseas to pursue postdoctoral fellowships in research. How times have changed for the better.

I left Prestwick for Montreal aboard a British Overseas Airways Corporation (BOAC) plane, taking to the air for the first time in my life, on 1st March 1967, with Sir Edmund’s words ringing in my ears, “Whatever you do in research, Stoddart, make sure you work on a big problem.” I was not at all sure what he meant by a ‘big problem’ but I was determined to heed his advice to the best of my limited ability. I suspect he anticipated that I would remain a carbohydrate chemist for the remainder of my professional life but that did not turn out to be the case. In the event, as soon as I set foot in the Jones laboratory, Ken confided in me that come 1st April he would be leaving for Curitiba in Brazil to spend one whole year there on sabbatical leave. This totally unexpected piece of breaking news, although quite a shock for me at the time, was to work to my advantage in the long run. I found myself assisting Walter Szarek, a former graduate student in Ken’s group, who had returned to Queen’s from Rutgers University to take over its supervision. It was good early experience for me in helping Walter run and mentor a medium-sized research group.

Communications between Canada and Brazil were dependent on the back and forth delivery of airmail letters, with a complete turnaround of information taking about three weeks, by which time the news was often obsolete. We were quickly relieved of this frustration when the Canadian postal service was brought to a halt by strikes for months on end. These circumstances left me with enough time on my hands to go in search of Sir Edmund’s ‘big problem’. I stumbled upon it in the chemistry department library under the guise of a short communication by Charles Pedersen in the Journal of the American Society (JACS) in the Spring of 1967, describing the efficient template-directed synthesis of dibenzo[18]crown-6 in 48% yield. This breaking news, coming out of the Dupont Laboratories in Delaware, flew in the face of all the teaching I had experienced as an undergraduate student at Edinburgh, where I had been led to believe that, while making five-, six-, and seven-membered rings was commonplace, large-sized rings were a totally different kettle of fish. I also realized that these macrocyclic polyethers – or crown ethers as Pedersen had called them – shared some of the constitutional features (OCCO repeating units) with the sugars. So, I set off on a mission to pursue what I referred to as ‘lock-and-key chemistry’ by simply marrying conceptually Pedersen’s crown ethers with Emil Fisher‘s carbohydrates. Of course, it was easier said than done, for I was only one pair of hands with many other things on my mind. One of them was to return to Edinburgh in the Fall of 1968 to say goodbye to the farm – for my parents had decided that after my leaving for Canada it was simply too much for them to handle on their own – and the other was to get married in Glasgow in the presence of close family members to Norma on 8th October 1968. We returned to Canada the next day via Montreal, my newlywed wife occupying her time during the flight by completing mountains of immigration paperwork. At the airport, we were greeted by a customs officer who took one look at us, summed up the situation, crumpled the papers into a ball, threw them into a waste-paper bin (trash can) with the words “we grow trees in Canada and far too many of them get turned into paper” and waved us through to begin our married life in a foreign country with a welcome we were never to forget. Perish the thought that such a welcome would occur at an international border in today’s world.

Our remaining 15 months at Queen’s were blissful ones. We lived at 432 Alfred Street after I had negotiated to rent the house from the owners, Thelma and Dave Buchan, who had more or less become my Canadian ‘aunt and uncle’ during my first 18 months as a boarder in their home. Norma had completed research for her PhD degree, like myself in just over two years, but not without a never-to-be-forgotten incident following the decision that I would type the manuscript on my portable Olivetti typewriter. It was approaching midnight and I was typing the last few pages of her thesis. Norma decided I needed a cup of coffee and duly set the cup down on the table next me. The next time I triggered the carriage return it hit the cup fair and square on its side and propelled most of the contents right over the stack of 150 typed pages. Norma retired to a corner of the room sobbing her heart out. After a kiss and a cuddle, I sent her off to bed and then stayed up all night, retyping much of the thesis by the following morning. When disaster strikes, it is best to waste no time in putting the experience to rest.

During my stay at Queen’s I found it easy to interact with the faculty. Saul Wolfe, in particular, took me under his wing and transmitted to me the importance of being on top of the current literature. He brought to my attention the teachings of Kurt Mislow at Princeton on the importance of applying molecular symmetry to stereochemistry. Mislow had just introduced the concept of topism for analyzing the topic relationships between atoms and ligands in molecules. Amongst other attributes, it rendered the interpretation of NMR spectra a much easier task and helped to save me the embarrassment of coming to a wrong conclusion more than once. I had the opportunity to travel down to Princeton with Saul to meet this sage of stereochemistry. There were other opportunities to listen to lectures by the intellectual leaders of their time in organic chemistry, among them the famous Harvard professor and synthetic chemist par excellence, R.B. Woodward, whom I recall holding an audience in the palm of his hand in Ottawa for more than three hours. Then the Queen’s chemistry department invited Saul Winstein from the University of California at Los Angeles (UCLA) to give the MacCrae lectures in the Spring of 1969. Winstein was considered by many to be the intellectual leader in physical organic chemistry at that time and would almost certainly have been the recipient of a Nobel Prize in Chemistry had he not died very suddenly of a heart attack, at age 57, in November of that same year. What I recall most vividly about the MacCrae lectures was the manner in which Winstein launched into a 20-minute diatribe against H. C. Brown, reflecting the bitter controversy that raged between them for years over classical (HCB) versus non-classical (SW) carbocations. I could not have known in 1969 that almost 30 years later I would be making my way to UCLA to become the second holder of the Winstein Chair, following Donald Cram who shared the 1987 Nobel Prize in Chemistry with Charles Pedersen and Jean-Marie Lehn from the University of Strasbourg.

Saul Wolfe was a pupil of the highly influential and renowned carbohydrate chemist, Ray Lemieux, for whom I had acquired an enormous respect after hearing him give a series of remarkable named lectures (Purves, if I recall correctly) at McGill University, which ultimately led me to write a monograph on the Stereochemistry of Carbohydrates. I set out on this mission with the support of Ken Jones, who had returned from Brazil, without realizing the responsibility one assumes when writing a book! My attendance at a symposium hosted by the US Army Laboratories at Natick led to my meeting Ernest Eliel, the author of The Stereochemistry of Carbon Compounds, a classic published by McGraw-Hill in 1965. It had been my bible from my Edinburgh days and so I decided that I would approach Dr. Eliel at the end of his inspirational talk and ask him if he would be kind enough to look over and comment on my manuscript. I sent him the manuscript and within a very short space of time it came back plastered in red ink. This experience taught me that having my manuscripts scrutinized by experts wherever possible would save me no end of embarrassment in the fullness of time. On this occasion, no doubt, Ernest saved my bacon: he and his wife Eva were to become close friends of myself and Norma for the rest of their lives.

Sheffield in the seventies

As the 1960s came to a close, Norma convinced me that it was time to return to Old Blighty, where we would give some thought to raising a family. Sometime in the summer of 1969 Ken Jones came back from a conference in the Caribbean with the news that David Ollis from Sheffield had given a lecture (with demonstrations) on the conformational behavior of a 12-membered ring compound known as tri-o-thymotide, or TOT for short, that had captured everyone’s imagination. I decided to apply for an ICI Fellowship to go to Sheffield but initially failed to make the cut. Three months later I heard the good news that I had, after all, landed this prestigious fellowship, as one of the successful candidates had decided not to accept the offer. We decided it would be practical to ship our goods and chattels across The Pond and enjoy an ocean liner experience onboard the West German flagship Bremen during the week before Christmas. Five days after leaving New York we arrived in Southampton to be greeted by thick fog, which made the drive north to Edinburgh, stopping off in Sheffield on the way, all the more challenging.

There were several reasons for going to Sheffield. One was to attend the Annual Sheffield Stereochemistry Meeting, where I had the opportunity to hear Jean-Marie Lehn speak for the first time. It was such a pleasure to listen to this young French chemist with a research agenda in the making that was destined to chart new territory for the subject beyond the molecule or, as Lehn named it subsequently, supramolecular chemistry. Another reason for being  in Sheffield was to introduce myself to David Ollis. When the subject of my start date came up he insisted I should be present in the department for the   1st of January 1970. This edict infuriated Norma, and I was not best pleased either, given the fact that we were heading to Scotland where New Year’s Day is a national holiday. The crossing of swords with Ollis would go on for the best part of two decades.

On my return to the chemistry department on 1st January it became apparent that I was not going to be allowed the independence to carry out the kind of research that was the fellowship’s official remit. In addition, when Ollis learned that I would be spending some of my time writing the final chapter of the book, he immediately expressed his displeasure, stating quite emphatically that “people at my stage should not be writing books”. Norma, who was illustrating the manuscript with India ink and stencils, convinced me to ignore his decree and the monograph was published in 1971 by Wiley. If the welcome to Sheffield was muted from on high, Norma and I were made to feel very welcome by the postgraduate community, particularly by David (Dave) Brickwood (whom I was delegated to supervise), Stephen (Steve) Potter and Richard (Dick) Taylor. Little do they really know how much they helped us through those difficult times.

I was working in my laboratory (E19) on Good Friday in 1970 when Ollis walked in to tell me that at a meeting of the Organic Staff the day before, it had been decided that I should be offered a Lectureship in Chemistry – a position that had unexpectedly fallen vacant with the resignation of the youngest member of the staff – from 1st October. I was, of course, happy to have some long-term job security, although it in no way earned me my independence. It was 1973 before Andrew Coxon became my first independently supervised postgraduate student. For my first lecturing assignment, I was handed a poisoned chalice in the shape of teaching the first-year medical students (all 180 of them) organic chemistry, in the knowledge that the course would soon be discontinued. The refrain from the students was very much along the lines of “Why are we having to take this course when it’s about to be withdrawn?” It was a tall order to hold their attention in lectures and laboratory classes, but I did my very best to engender their enthusiasm by introducing all sorts of innovations into my teaching. Nonetheless, when brought before a group of medical staff in the presence of their dean, I was informed by him that “we might as well be teaching our students biblical studies”. It was a crushing put-down but I reasoned that I should not have been the person from the chemistry department finding himself in this particular lion’s den!

Despite the fact that my progress in research was being forestalled at every turn by the antics of the professors in the department, Andrew Coxon, and later Dale Laidler, made some notable advances in their research with carbohydrate precursors to crown ethers, to the extent that when I was invited to speak at international conferences and symposia I had some interesting results to talk about under the banner of ‘lock-and-key chemistry’. A major turning point in my fortunes came in 1976, when I was invited to give no less than 17 lectures and seminars, nine in the UK, including Oxford, Imperial College London, Edinburgh and Glasgow, four in the US, including Columbia, Princeton and Dupont, and four in Canada, including McGill and Queen’s. I was also fortunate in being invited to give a talk at the Centennial American Chemical Society Meeting in New York in early April. This invitation afforded me the opportunity to listen to Donald Cram speak and to meet with him one-on-one – along with his shopping bag full of CPK space-filling models – for the first time. Once again, I found myself in the company of an eminent American chemist, who not only enthused about his own research, but also about mine, an experience for me that was uplifting beyond my wildest dreams. Don was also the RSC Centenary Lecturer in May 1976. He insisted that I would be one of the supporting speakers in Manchester and, two days later, in London, at University College. When the powers that be at the RSC questioned my double act, Don swept aside their protestations with the comment that “apart from Fraser and myself, those in the audiences in the two places will be different” and, of course, no one could argue with him, for he was right! David Ollis was livid, but Don was drawing considerable satisfaction from the situation because he knew how I was being treated on home turf. Don also presented his Centenary Lecture in Sheffield and went out of his way to say he had come because of my presence in the department. He went on to lavish praise on my research group, leaving Ollis red with rage!

During these meetings, Don encouraged me to apply to the Science Research Council (SRC) for a Senior Research Fellowship to spend the first three months of 1978 on sabbatical leave at UCLA. This short stay in the UCLA Department of Chemistry and Biochemistry was a real breath of fresh air and served to increase my yearning to move to the US one day in the future. Interest in hiring me  had been mooted in a number of different US universities, but then something else happened in the UK that I could live with very comfortably, and that left Norma happy that our two girls, who had arrived on the scene in 1973 (Fiona) and 1976 (Alison), could continue their education in the UK. That development involved the SRC, who were ready, willing and able to support my secondment to the ICI Corporate Laboratory in Runcorn, under the auspices of a brand new Cooperative Research Scheme for three years, from 1978 to 1981. It also received the backing of a number of ICI’s senior management, including Tom McKillop and Bernard Langley. I was over the moon. I was free at last to carry out my own research in a highly supportive and amazingly well-equipped environment, staffed with research scientists who were second to none. We sold our home on Derriman Avenue in Sheffield and moved across the Pennines to a brand-new house in Curzon Park in Chester, with a six-month layover in a small rented property in Little Sutton, on the Wirral. The next three years were amongst the happiest that we spent as a family in England.

Runcorn

I joined Warren Hewertson’s Catalysis Group at ICI’s Corporate Laboratory and supervised a couple of postgraduate students in Runcorn, plus half a dozen who remained in Sheffield, where I spent minimally one day a week. The Corporate Laboratory, situated on The Heath at Runcorn, was probably the closest one could get to a Bell Laboratories experience in the UK. It was in this setting that I quickly struck up a highly productive collaboration with a brilliant young chemist, Howard Colquhoun, who had only recently joined the laboratory. Following some discussions about what different kinds of complexes could be formed with crown ethers, we came to the conclusion that, as far as we knew, transition metal ammines had not been put to the test. We were fortunate insofar as there was a treasure trove of these ammines down in the basement of the laboratory that had been prepared by Joseph Chatt when he was an employee of ICI during the 1950s. I could not believe our luck. Before long we had lots of crystals of adducts of transition metal ammines with crown ethers, whose solid-state superstructures were solved at the drop of a hat by David Williams, X-ray crystallographer extraordinaire, down in London at Imperial College.

Amidst all these many superstructures, one caught our attention. It was  the 1:1 adduct in which dibenzo[30]crown-10 (DB30C10) wraps itself round  a dicationic platinum complex, carrying a 2,2′-bipyridyl ligand in addition to  a couple of cis-diammine ligands, in such a manner that the ammine ligands form hydrogen bonds with the polyether loops of the crown ether, while the two π-electron rich catechol units sandwich the π-electron deficient bipyridyl ligand in a stacking manner. The structural similarities between this bipyridyl ligand and the bipyridinium herbicide Diquat (DQT) was pointed out to us by former ICI research scientist Eric Goodings. Sure enough, when the transition metal complex was replaced by DQT we obtained deep orange crystals of a 1:1 complex with DB30C10, as revealed yet again by its solid-state superstructure. Both the adduct and the complex, when associated with soft counterions, are reasonably stable in acetonitrile solution, as indicated by the presence of diagnostic charge-transfer bands that render the solutions light yellow and bright orange, respectively.

We had injected new life into Alfred Werner’s concept of second-sphere coordination in the process of establishing donor-acceptor interactions as a force to be reckoned with in molecular recognition processes. They would ultimately serve as the sources of templation in the making of molecules with mechanical bonds. Although we had still to address the need to form complexes between crown ethers and Paraquat (PQT) – the other component of the wipe-out weed-killer that ICI marketed worldwide for many years – we had given the search for the ‘big problem’ an enormous fillip from an unlikely starting point. If I had not spent those years at ICI’s Corporate Laboratory, my role in the development of mechanically interlocked molecules, that has led to designing and synthesizing molecular machines, would either not have happened or would have taken a very different course. All of what I was subsequently to achieve in research can be traced back to these three years.

Left: With Norma outside our third Sheffield home in Bradway c. 1982. Right: After graduating from Edinburgh in 1980 with a DSc degree.

Figure 5. Left: With Norma outside our third Sheffield home in Bradway c. 1982. Right: After graduating from Edinburgh in 1980 with a DSc degree.

I left Runcorn in the late summer of 1981 with a heavy heart, but there was no option. My three-year secondment was coming to a close and, more disturbingly, the writing was on the wall for the Corporate Laboratory. Norma and the girls had come to enjoy life in Chester and it was going to be challenging for all of us to return to Sheffield. Once again, the transfer was staged by my acquiring a small semi-detached home in Bradway, from which we were able to purchase the ideal family home in the shape of an Edwardian house on Dore Road.

Sheffield in the eighties

My situation at Sheffield had been strengthened by my industrial experience and I was promoted to a Readership in Chemistry in 1982. Although many of the same issues still existed in the chemistry department at Sheffield, I was much more able to handle the slings and arrows of outrageous fortune. With growing confidence, I became quite vocal at the national level about the weaknesses, as I saw them, in the British academic system. My pronouncements and my writings – often to the British national newspapers – did not win me many friends, but at the same time they served to define where I stood on a wide range of issues. Eventually those in influential positions started to notice and take note.

At this time, I struck up another important relationship that not only turned out to be of immense value in the promotion of my research as it developed during the 1980s, but also helped me launch some university-wide initiatives, such as the Sheffield Industrial Forum in 1986. That relationship was with Roger Allum, the Press Officer for the University. He was extremely supportive and would always seek to make our research intelligible to the wider public. If I ever felt a little depressed from working in a department that was brim full of politics, I could take a walk up to the Edgar Allen Building and have a reassuring chat with Roger. He always had time for me, no matter how busy he was tending to other university business. I would leave his office with my spirits lifted and ready to take on the world.

As I moved from one university to another, the importance of maintaining good and close relationships with the talented individuals in media relations remained with me. Martin Hicks at Birmingham continued in the footsteps of Roger and once I reached the University of California, Los Angeles (UCLA), I was to learn a lot from Stuart Wolpert on how to handle live and recorded interviews for radio and television. At Northwestern University (NU) I have been blessed many times over to have Megan Fellman working closely with myself and members of my research group in getting story after story out into the public domain. More recently, I have discovered a soulmate in Stephanie Russell, Editor of the Northwestern magazine, who has gone to considerable lengths, and well beyond the call of duty, in presenting me and my research to the alumni and friends of NU, following my award of the Nobel Prize in Chemistry.

On the scientific front, after some wasted effort and unproductive years, we were able to demonstrate quite simply that a constitutional isomer of DB30C10, namely bis-para-phenylene[34]crown-10 (BPP34C10), forms a strong 1:1 complex with PQT. The fact that the solid-state superstructure of this complex was ‘rotaxane-like’ in its appearance led me to suggest that it be called a [2]pseudorotaxane, a name which eventually transmogrified into meaning a template that could subsequently be converted into a catenane as well as a rotaxane. We had established that we could thread a p-acceptor through a ring containing two laterally disposed π-donor units. Our next challenge was to reverse this recognition motif by making a cyclophane in the form of cyclobis(paraquat-p-phenylene) and containing a couple of parallely disposed bipyridinium units held rigidly apart at a plane-to-plane separation of approximately 7 Å by two para-xylylene units, through which π-donors of many different persuasions could thread. In the first instance, Mark Reddington was able to prepare this cyclophane starting from 4,4′-bipyridine and xylylene dibromide in a 12% yield.

During our efforts to publish the synthesis and full characterization of   this cyclophane in Angewandte Chemie, I received a curt letter from Siegfried Hünig at the University of Würzburg, explaining that one of his students had synthesized a whole range of very similar cyclophanes and studied their ability to complex aromatic hydrocarbons, a piece of information that was available, but overlooked by me, in Dissertation Abstracts. I wrote back to Professor Hünig, who had clearly been one of the reviewers of our communications, and suggested that he write up a communication on his work while we delayed the publication of our communications so that all three could appear in the journal in a row. Thereafter, Siegfried and I became close friends, to the extent that he and his wife invited Norma and myself to Würzburg to help celebrate his 80th birthday in 2001. The publication of our two communications coincided with the beginnings of my use of color – red for π-donors and blue for π-acceptors – so that the cyclophane soon became known in the literature as the ‘little blue box’ and was to gain considerable notoriety as a promiscuous host for a wide range of π-donors, including benzidine and tetrathiafulvalene. Subsequently, employing both templates and catalysts – and some other tricks – we have been able to prepare the little blue box in all but quantitative yield.

The stage was now set to carry out the template-directed synthesis of the first donor-acceptor [2]catenane in a remarkable 70% yield, by very simply employing the ingredients used in the preparation of the little blue box in acetonitrile at room temperature in the presence of three molar equivalent of BPP34C10. This experiment, which was carried out by Cristina Vicent and Neil Spencer, was one of the most memorable as we all gathered to watch the reaction mixture turn orange and crystals start growing on the side of the reaction flask within 10 minutes. I realized there and then that we were sitting at the entrance of a gold mine as we prepared the manuscript for publication in AngewandteChemie in October of 1989. While the manuscript was out for review, I received a phone call from Jean-Pierre Sauvage in Strasbourg saying how impressed he was by the contents and offering me his congratulations. He was obviously one of the reviewers. The 1980s represented a sea change for my group, as I began to realize that our level of research performance could be raised out of all recognition by welcoming postgraduate students and postdoctoral fellows from overseas. The arrival of Franz Kohnke from the University of Messina, not to mention the short visit of Cristina Vicent from Madrid, had a profound effect on the group culture as we became increasingly international in our composition. The cultural change also encouraged home-grown PhD students to raise their sights. Following graduation with their PhD degrees, David Leigh went to Ottawa in search of postdoctoral experience with David Bundle, while John Mathias, equipped with a postdoctoral fellowship, was invited by George Whitesides to go to Harvard.

Pier Lucio Anelli, who came to Sheffield as a postdoctoral researcher from the University of Milan, was another of a growing number of makers and shakers. Employing a pre-prepared dumbbell-shaped molecule as a template, he synthesized by templation a degenerate [2]rotaxane with two π-donating, hydroquinone-based, recognition sites for encirclement by one little blue box, which could be shown by dynamic NMR spectroscopy to be darting back and forth between the recognition sites at around 2000 times per second. I called it a molecular shuttle and concluded in a 1991 JACS communication that it was “the prototype for the construction of more intricate molecular assemblies where the components will be designed to record, store, transfer and transmit information in a highly controllable manner following their spontaneous self-assembly at the supramolecular level.” The development of this next step in the research program had to wait until a move to the University of Birmingham had been planned and executed.

Birmingham

I had been approached in 1991 by the then Vice-Chancellor of the University of Birmingham, Sir Michael Thompson, to consider moving to Birmingham as the Professor of Organic Chemistry. He had been attracted by my refusal to join the large group of whingers in British academia at that time. The Department of Chemistry was in a badly run-down state and morale was low to say the least. After much discussion and an undertaking by the Vice-Chancellor to implement a staged refurbishment of the Haworth Building and invest in some key state-of-the-art equipment, including NMR and mass spectrometers, I accepted the chair and started a phased move of my research group, now growing in size, from Sheffield to Birmingham. Norma remained in Sheffield to look after the everyday needs of the group members there, while I oversaw the revamping of the top (seventh) floor of the building and prepared for the new spectrometers to arrive on the scene. While Neil Spencer accepted the challenge of establishing the new NMR facility, I managed to persuade the highly gifted senior technician, Peter Ashton, to also make the move from Sheffield to Birmingham and establish a mass spectrometry facility that was second to none in the country. I commuted between Birmingham and Sheffield for more than a year, given the added responsibility of being one of the organizers, along with Norma and David Fenton, of the 1991 International Symposium on Macrocyclic Chemistry, at which both Donald Cram and Jean-Marie Lehn received Honorary Degrees in Science from Sheffield University. It was also the occasion when the first International Izatt-Christensen Award was presented to Jean-Pierre Sauvage.

With Don and Jane Cram at the 16th International Symposium on Macrocyclic Chemistry held at Sheffield University in September 1991.

Figure 6. With Don and Jane Cram at the 16th International Symposium on Macrocyclic Chemistry held at Sheffield University in September 1991.

A life-changing event was to occur in February 1992 when I took an early morning phone call in my Birmingham office from Alison, her first words being, “Something terrible has happened, Daddy.” She went on to explain that her mother was in hospital, having suffered a brain hemorrhage overnight. I wasted no time in jumping into my car and driving up to Sheffield, only to be told by the surgeon in charge of her case that he was going to have to operate and that there was no better than a 50% chance that Norma would survive the surgery. It was a long day that was to take a turn for the better when the surgeon informed me in the early evening that the artery in Norma’s brain had self-healed and he would not need to operate. Relief all round! We moved from our Edwardian home in Sheffield to a 1930s home in Edgbaston, close to the campus of the University of Birmingham, on 1st April. With Norma still very much in a convalescent state, I was approached by Ken Houk at UCLA, who asked me if I would consider moving to UCLA to assume occupancy of the Winstein Chair on the impending retirement of Don Cram. My reply – with mixed emotions – was an easy one. Norma was too ill for me even to share this news with her and I was in the throes of a complicated relocation. I assumed that my message to Ken declining his offer would be the last I would hear of the Winstein Chair at UCLA and that this tantalizing prospect had slipped out of my grasp. This assumption proved to be incorrect.

As far as research was concerned, my seven years at Birmingham were to exceed my wildest dreams. Our first bistable [2]rotaxane, that could be switched both chemically and electrochemically, reached the literature in 1994, following a sojourn by Richard Bissell at the University of Miami with Angel Kaifer. Olympiadane was self-assembed by David Amabilino, while Gunter Mattersteig synthesized the first bistable [2]catenane, in which the two π-donating hydroquinone recognition sites in the degenerate [2]catenane were replaced with tetrathiafulvalene and dioxynaphthalene recognition sites. A highly fruitful collaboration, in which this catenane and many other bistable MIMs were switched chemically, electrochemically and photochemically, was struck with Vincenzo Balzani and Alberto Credi at the University of Bologna. Jon Preece spent time in the laboratory of Helmut Ringsdorf at the University of Mainz learning how to produce Langmuir monolayers and films of both degenerate and bistable [2]catenanes and preparing the way for device fabrication when we reached UCLA in 1997.

Douglas Philp was a major intellectual driving force in the group during its early days in Birmingham. Aside from his high level of productivity that matched his creativity every inch of the way, he left a considerable legacy by writing a much-cited review on “Self-Assembly in Natural and Unnatural Systems” that was published in Angewandte Chemie in 1996. While Peter Glink established hydrogen bond templation (known within the group as ‘ammonium binding’) as a means of templating the synthesis of MIMs, Narayanaswamy Jayaraman and Sergey Nepogodiev launched ambitious programs of research into glycodendrimers and the synthesis of cyclic oligosaccharides related to the cyclodextrins. Steven Langford and Matthew Fyfe took over where Douglas Philp left off by bringing their keen intellects and dedicated commitment to the development of MIMs to a highly sophisticated level in relation to their physical organic chemistry.

The research group at Birmingham c. 1995.

Figure 7. The research group at Birmingham c. 1995.

Unwelcome news kept breaking in 1992. In August, Norma was diagnosed with breast cancer and underwent surgery in the form of a lumpectomy, followed by radiation and chemotherapy. The cancer recurred two years later in 1994, resulting in a mastectomy and yet more of the inevitable back-up treatment. This did not halt the progress of the disease, which was diagnosed as having become metastatic in 1996. During a visit to UCLA in 1994 to participate in a symposium to mark Don Cram’s 75th birthday, Ken Houk raised once again the availability of the Winstein Chair, reiterating the interest of the Department of Chemistry and Biochemistry in my coming to occupy it at UCLA. My feeling that Norma was not receiving the best of medical care in Birmingham was accepted by her in early 1997 and so we decided to go on a trip to the US, visiting the M. D. Anderson Clinic in Houston and the Jonsson Comprehensive Cancer Center at UCLA, where Norma was told by the oncologists we met that, while she had a chronic disease, they had 50 different ways of treating it. At this point it was decided that I would step down from being the Head of the School of Chemistry at the end of June and formally move to Los Angeles to take up the Winstein Chair on 1st July 1997. Some 15 members – including first-year graduate students Stuart Cantrill, David Fulton, Sarah Hickingbottom, James Lowe and Anthony (Ant) Pease – of my research group made the transition from the middle of England to the West Coast of America, with postdoctoral fellow Françisco Raymo acting out the role of the scout. Coming to grips with the very different way American academia operates compared with that in the UK, together with getting my mind round the funding system from the federal agencies and beyond, constituted a baptism of fire for a 55-year-old. We simply rolled up our sleeves and got on with it. Norma, for the first time gainfully employed as a research assistant to my group by UCLA, helped in all this.

University of California Los Angeles (UCLA)

In just over a decade at UCLA, from 1997 to 2008, we broadened the scope of our template-directed approaches to mechanically interlocked molecules (MIMs) by appealing to both hydrogen-bond and metal templation, as well as developing donor-acceptor templation to cover the production of a wide range of molecular switches. Stuart Rowan joined my research group in 1998, with the intention of establishing his own independent academic career in the United States, after having played a major role in the furtherance of dynamic covalent chemistry (DCC) at the University of Cambridge with Jeremy Sanders. This thermodynamically controlled approach to the template-directed synthesis of MIMs can be extraordinarily powerful. It eventually led to high-yielding syntheses of molecular Borromean rings and Solomon knots. Template-directed approaches under kinetic control to MIMs began to rely more and more on the use of ‘click chemistry’, as popularized by Barry Sharpless. Amongst the ring leaders during this period – in addition to Stuart Rowan (University of Chicago) – were Ivan Aprahamian (Dartmouth College), Adam Braunschweig (Hunter College), Sheng-Hsien Chin (National Taiwan University), William Dichtel (Northwestern University), Amar Flood (Indiana University), David Fulton (University  of Newcastle), Jan Jeppesen (University of Southern Denmark), Steve Joiner (Moorpark College), Ken Leung (Hong Kong Baptist University), Cari Meyer (Pierce College), Ognjen Miljanić (University of Houston), Al Nelson (University of Washington), Brian Northrop (Wesleyan University), Hsian-Rong Tseng (University of California, Los Angeles), Bruce Turnbull (University of Leeds), Sebastian Vidal (University of Lyon), Scott Vignon (Washington DC) and Jishan Wu (National University of Singapore).

Norma and I with David Leigh, Stuart Rowan and Stuart Cantrill after the International Symposium on Macrocyclic Chemistry held at St Andrews University in July 2000.

Figure 8. Norma and I with David Leigh, Stuart Rowan and Stuart Cantrill after the International Symposium on Macrocyclic Chemistry held at St Andrews University in July 2000.

The UCLA era was characterized by numerous efforts to uncover applications for molecular switches, both the non-degenerate catenated and rotaxanated varieties. One of the most rewarding and fulfilling collaborations was with Jim Heath in the field of molecular electronics. The marriage between molecular switches and electrodes is far from being an easy one, and I have to say that Jim picked his way through what turned out to be a bit of a minefield with the greatest of ease. By employing crossbar devices, he and his highly skilled team of graduate students and postdoctoral fellows were able, using the LB technique established during the Birmingham days, to lay down monolayers of switchable catenanes and rotaxanes between parallel wires of polysilicon (bottom electrodes) and orthogonally disposed parallel wires of titanium capped with aluminum. By 2007, using an amphiphilic bistable [2]rotaxane, a 160,000-bit molecular electronic memory circuit had been fabricated at a density of 100,000,000,000 bits per square centimeter. The entire 160-kbit crossbar device was smaller than the cross-section of a white blood cell. It transpired that there is one fatal weakness with the crossbar devices, and that is their lack of robustness. When Omar Yaghi arrived at UCLA in 2006 we started a joint program of research, whereby bistable MIMs are being incorporated inside metal-organic frameworks – and it continues today at Northwestern University (NU) in collaboration with Joe Hupp and Omar Farha.

For a time Norma’s oncologists kept her cancer at bay, chiefly by moving in the face of resistance to treatment from one anticancer drug to another, and subsequently to a cocktail of two or three or more of them. She and I were able to travel the world together for a while, visiting many cities, including Paris, Stockholm and Vienna in Europe and Kyoto and Nara in Japan. Slowly and perceptibly, Norma’s state of health started to wane as the side effects of the drugs began to sap her energy, causing her to seek refuge in our small Santa Monica townhouse, assisted by a kind and marvelous caregiver, Sylvia Mena, and no end of material and psychological support from Alice Jung, wife of my colleague Mike Jung, who was a dab hand at making Norma laugh and in so doing lifting my spirits. She referred to Mike’s other half as ‘Alice the Angel’. By late November 2003, the 25th to be precise, Norma’s head oncologist, John Glaspy, told me what I had already guessed: it was that the disease had reached her brain and that it was only a matter of time, a few weeks at most, before a battle that had occupied a fifth of her life and demanded our attention for a third of our married lives was about to end. Norma always insisted that her brain was her last refuge: if and when  it was invaded by the “little buggers,” she would throw in the towel. Her final foray into the outside world was a sight to behold. It was an excursion to Gap in Santa Monica to purchase a large selection of garments for her grandson, only a few weeks away from being born to Fiona and Quentin McCubbin, yet she was not going to set eyes upon James Fraser (the Second!). Norma’s shopping sprees were legendary, but this one stole the show. For the first time since 1966, she was oblivious to the spirit and trappings of Christmas as she prepared to make a dignified exit, simply commenting that she had drawn the short straw. During the final days of her life she communicated with me using a pencil and writing pad, being too weak to speak. Her last comment, written the night before she passed away on 12th January 2004, was, “Am I dead yet?” She sank into oblivion as I was struggling to decipher her question and so I was not able to provide her with an answer. In the last few weeks of her life she was insistent that her main legacy were ‘her girls’ and there is no arguing with that statement to this day. She had every right to feel proud of Fiona and Alison.

The departure in 2003 of Jim Heath to the California Institute of Technology (CALTECH) signaled two changes in my professional life. One was the taking over of the Directorship of the California NanoSystems Institute (CNSI) from Jim, the founding director, first of all in an acting capacity and then subsequently for real. Despite these developments, Jim and I maintained our collaboration in the realm of molecular electronics, aided and abetted by Bill Goddard’s entry into the program. Through his impressive computational investigations, he did much to vindicate our proposed switching mechanism exhibited by monolayers of bistable rotaxanes in crossbar devices. I became a great admirer of Bill’s command of his science and the fearless manner in which he tackles large and complicated problems, a trait that continues to this day. No one knows and understands our donor-acceptor catenanes and rotaxanes all the way from bistable molecules through to devices better than Bill: this belief is supported by arguments presented in more than 30 joint publications. Another positive change that occurred around 2003 was the forging of a close and equally fruitful collaboration at UCLA with Jeff Zink, whose knowledge and practical expertise in relation to the preparation of mesoporous silica nanoparticles led to the covering of the surfaces of these 100–200 nanometer diameter particles with both bistable/switchable rotaxanes (nanovalves) and their supramolecular counterparts, which we called snap-tops, as a sophisticated means of controlling the release of small molecules, such as anticancer drugs. My foray into drug delivery systems was undoubtedly influenced by my day-to-day experiences of living for 12 years with a cancer patient. I have to admit, however, that I am coming to the opinion, after having co-authored more than 30 articles with Jeff, that, while more and more sophisticated ways of delivering drugs to patients suffering from degenerative diseases can prolong their lives, they are probably never going to provide the cures that many people would like to think are just around the corner.

After graduating with his PhD from UCLA in 2001, Stuart Cantrill spent a couple of years at CALTECH as a postdoctoral scholar with Bob Grubbs, one of the 2005 Nobel Laureates in Chemistry. The outcome of this association was yet another collaboration, in which Grubbs-catalyzed olefin metathesis in many of its different manifestations was introduced into the thermodynamically controlled syntheses of MIMs using hydrogen bonding as the source of templation.

Stuart returned to UCLA in 2003 to take on my undergraduate teaching responsibilities and to assist me in the running of my research group while I was CNSI Director. During what turned out to be a three-year sojourn, he also became the de facto Associate Editor of Organic Letters. It was during this time that he not only made sure that the research he had initiated in relation to the dynamic synthesis of the molecular Borromean rings reached the light of day in the literature, but he was also to discover that his own future lay in scientific publishing. On his return to the UK in 2005 he found employment with the Nature Publishing Group, first of all as an Associate/Senior Editor with Nature Nanotechnology, before being given the responsibility in 2008 to launch Nature Chemistry as its Founding Chief Editor. It is this kind of career progression by my students that I look back upon with immense pride.

Left: Three peas in a pod. With Alison and Fiona at Fiona's wedding in June 2000. Right: Outside Buckingham Palace with Alison and Fiona in June 2007 after being knighted by HM Queen Elizabeth.

Figure 9. Left: Three peas in a pod. With Alison and Fiona at Fiona’s wedding in June 2000. Right: Outside Buckingham Palace with Alison and Fiona in June 2007 after being knighted by HM Queen Elizabeth.

Two bolts appeared out of the blue in late 2006 and early 2007 that could be considered as serious game-changers. The first one arrived in the context of a phone call on 13th November 2006 from Bob Pierce, the British Consul General in Los Angeles. To my consternation, Bob asked me if I would be prepared to accept an appointment to Her Majesty the Queen as a Knight Bachelor. My acceptance, under a cloak of secrecy, became public knowledge in the 2007 New Year Honours List. It led to my attending an investiture in June 2007, accompanied by David Leigh, a 1987 PhD graduate from my Sheffield days, along with Fiona and Alison. The second great surprise came in the form of a call to my cell phone from my assistant, Christina Oliver, while I was attending the Third Annual FENA Review Meeting at the LUXE Hotel in Los Angeles. On this occasion, the message, which encroached upon a conversation I was having with Youssry Botros (Intel), who was appointed as a consultant from industry to the Center for Functional Engineered Architectonics (FENA) directed by Kang Wang at UCLA, was from the King Faisal Foundation in Riyadh to say that I had been selected to receive the 2007 King Faisal International Prize (KFIP) in Science. Youssry, who was born and brought up in Egypt, was immediately raised to a highly excited state on learning the news from me. In the event, I invited Youssry, a fluent Arabic speaker, to accompany Alison, her then fiancé Mikey Ho, and myself on our first trip to Saudi Arabia to receive the Prize from the King in the middle of April. During a week-long visit, Youssry and I had our first meeting with Prince Turki Al-Saud who was then Vice-President of the King Abdulaziz City for Science and Technology (KACST), and he is now the President of KACST. Following this meeting, KACST has generously funded six projects at Northwestern University related to energy storage, energy harvesting, molecular electronics, porous materials, membrane technology and drug delivery, under the auspices of a Joint Center of Integrated Nanosystems (JCIN). Managing JCIN along with my highly supportive co-Director Majed Nassar, has been aided and abetted in a big way by Alyssa Avestro, Ashish Basuray, Tracy Chen and Mark Lipke.

Meeting President Obama in the Oval Oce along with Fiona and Alison.

Figure 10. Meeting President Obama in the Oval Oce along with Fiona and Alison on 30 November 2016.

It became clear towards the end of 2006 that the fortunes of the CNSI were set to suffer as a result of a change in the State of California Administration in Sacramento. Although buildings were nearing completion at both UCLA and the University of California, Santa Barbara (UCSB), it was apparent that there would be next to no funds made available from the State to equip the two buildings. I had little desire to find myself in charge of two white elephants.

I had tried to interest Chad Mirkin at Northwestern University in moving to UCLA to take over the Directorship of the CNSI from me. He was not interested but then turned the tables on me by inviting me to move to NU. Negotiations with the then President Henry Bienen at NU began in February 2007 and proceeded at such a pace that an announcement of my move could be made in August of that same year, allowing a few members of my group to start relocating a month later into newly refurbished laboratories in the Technological Institute. Although it was to take until August 2014 for a brand-new building, sanctioned and supported on my advice by the President, to house some of the major items of departmental equipment (spectrometers and diffractometers) to materialize, it was well worth the wait. I moved up to Evanston on 1st January 2008 amidst a spate of gong-collecting. It seems that awards and prizes feed off one another to a considerable extent. In January 2010 my research group, under the guidance of Doug Friedman, moved with military-like precision from the Tech building into the newly opened Silverman Hall to occupy research space second to none in our previous 40-year history. It did not take long for it to be called the Research Palace – or RP for short.

Nortwestern University

At Northwestern, a decade of broadly based activity in research relating to supramolecular chemistry, as well as mechanostereochemistry, has relied heavily on simply allowing a team of extremely creative graduate students and postdoctoral scholars free rein within the remit of the grants that support their research. This approach to invention and innovation in research has been highly successful, leading to a host of serendipitous events. One of these accidental discoveries, by Ron Smaldone – who was joined on its realization by Jeremiah Gassensmith and Ross Forgan – relates to the unexpected ability of γ-cyclodextrin to form highly porous extended structures with Group IA metal cations, particularly potassium, rubidium and cesium ions. This discovery in turn has led to the establishment of a start-up company, PanaceaNano, in 2010 with Youssry Botros as its Chairman and Chief Executive Officer (CEO). The company has developed several Organic Nano-Cube (ONC) based materials that are completely safe for use in many industries, such as cosmetics, home and personal care, health and medicine, chemical, environment, food and beverage, and agriculture. In less than one and a half years, the company has developed and shipped many prototypes for testing by collaborators and distributors in the cosmetics, fragrances and drugs areas. The other chance discovery, by Zhichang Liu, relates to a remarkable lock-and-key fit between α-cyclodextrin and potassium tetrabromoaurate in a 2:1 ratio within a linear and rigid supramolecular polymer, which aggregates in its thousands – like drinking straws in a box – to form needle-like crystals within minutes in aqueous solutions. A start-up company, Cycladex, was launched in 2014 with Roger Pettman, one of my early postgraduate students from my Sheffield days, as its CEO. The company is offering the opportunity to the goldmining industry to abandon the use of cyanide and mercury in the isolation of gold from ore and to adopt a much less expensive environmentally friendly way of achieving a better outcome.

The research group beside the Northwestern Arch.

The front of the American Chemical Society Building in Washington, DC.

Figure 11. Signage. Top: The research group beside the Northwestern Arch in October 2016. Bottom: The front of the American Chemical Society Building in Washington, DC. In an e-mail received on 3 November 2016, Stu Borman of C&E News comments that ‘all I can see out my window now is “RAS” and “DDA.”

In the realm of supramolecular chemistry, the trio of Michal Juríček, Jonathan Barnes and Edward Dale devised much more user-friendly and efficient approaches to the synthesis of the little blue box, before going on to expand the dimensions of this tetracationic cyclophane to yield much larger receptors they called ExBox and ExCage, which turned out to be ideal for complexing polycyclic aromatic hydrocarbons. An intellectually satisfying piece of research carried out in collaboration with Jay Siegel at Tianjin University was the induced-fit catalysis of corannulene bowl-to-bowl inversion, which illustrates very nicely the principles of enzyme catalysis. In what is a simple textbook example, catalysis of the inversion process in corannulene, induced by its stereoelectronic binding inside ExBox, can be followed along a single ‘reaction’ coordinate, where the reactant and product are the same. A full paper published in the Journal of the American Chemical Society, “ExCage” – one of the shortest titles ever for an article on chemistry – amounts to a tour de force in contemporary physical organic chemistry enacted by the ExBox/ExCage trio.

Family gathered together at the Nordic Museum in Stockholm.

In the midst of some young budding scientists at a party in the Grand Hotel in Stockholm.

Figure 12. Top: Family gathered together at the Nordic Museum in Stockholm, 2016. Bottom: In the midst of some young budding scientists at a party in the Grand Hotel in Stockholm, 2016.

The reason that the laissez-faire approach to supervising graduate students and postdoctoral scholars in the Northwestern chemistry department thrives so well is because it is an approach that is endorsed to the full by the vast majority of the faculty. The experimentally and computationally active members in different research groups interact with each other so well − more often than not from the bottom up − that it has led to the comment that we hunt in packs in the Department of Chemistry at Northwestern. Allowing these interactions to take their own course without meddling or interference is an extremely effective dynamic when it comes to the attainment of high-quality research. It is a dynamic that, is by and large, lost on university administrators and the regulatory authorities, who are much attracted and enamored by the concept of research being performed in silos. The fact that the laissez-faire approach is the dominant practice in the Northwestern Chemistry Department despite the presence of rules and regulations that would dictate otherwise, has rendered it possible for my research group personnel – Gokhan Barin, Ali Coskun, Marco Frasconi, Sergio Grunder, Chenfeng Ke, Severin Schneebeli, Cory Valente and many others, to collaborate with their counterparts in the groups led by Mike Wasielewski, Joe Hupp, Omar Farha, Bartosz Grzybowski, Emily Weiss, Chad Mirkin, Mark Ratner, George Schatz and Lin Chen, while maintaining active collaborations with Bill Goddard’s group at CALTECH and Omar Yaghi’s group at UC Berkeley. Add to this list the name of my fellow Nobel Laureate Jean-Pierre Sauvage, who spent a couple of years (2010–2012) coming from Strasbourg to Evanston from time to time as a visiting professor, and you have yet another source of intellectual stimulation par excellence. His overarching presence encouraged us all to spend a considerable amount of time thinking deeply, practicing painstakingly and writing wisely about chemical topology, a subject area that will surely come into its own right in years to come.

Breakdown of Stoddart group members.

Figure 13. Breakdown of Stoddart group members during the past 45 years from 43 different countries. Those group members (a few) who have changed their nationality are counted twice, reflecting both their original and present nationalities, leading to a total number of entries of 417 on the pie charts. I thank Carson Bruns for producing this illustration at the drop of a hat!

Two additional developments at Northwestern deserve special recognition. One was the demonstration in 2010 by Ali Trabolsi, and followed through by Albert Fahrenbach, of the strong 1:1 complex formed between viologen radical cations and the bisradical dicationic cyclophane, obtained on reduction of the little blue box in the presence of methyl viologen or its derivatives. It was somewhat counterintuitive that three ‘free’ electrons would hold a complex together in the face of substantial Coulombic repulsion, but it is a fact! This discovery led to the template-directed synthesis of catenanes and rotaxanes. While Jonathan Barnes set about making the homo[2]catenane of the little blue box – an achievement which Diego Benítez described as being intellectually disruptive – Hao Li employed radical templation to make rotaxanes that have been introduced subsequently into the design and synthesis of a rapidly growing range of artificial molecular pumps by Chuyang Cheng, Paul McGonigal and Cristian Pezzato. This story is featured in my Nobel Lecture – produced, as in the case of hundreds of other presentations, with the help and expertise of graphic artist Alex Bosoy.

Meeting Chinese Premier Li Keqiang in the Great Hall of the People.

Figure 14. Meeting Chinese Premier Li Keqiang in the Great Hall of the People on 20 January 2017.

The other development worthy of special mention was the writing, along with Carson Bruns, of a major treatise on MIMs. In every respect – both words and pictures – the heavy lifting was done by Carson during a 30-month period that spilled over into some of his time as a Miller Research Fellow at Berkeley. It was quite fortuitous that Wiley ended up introducing the work to the world at large in the early part of November last year, halfway between the announcement of the 2016 Nobel Prize in Chemistry on 5th October and the prize-giving in Stockholm on 10th December. The manuscript was reviewed critically by many colleagues and the production of its six chapters, along with all the necessary components that go into the making of any book, were orchestrated by two people in particular. One was Xirui Gong, who read the proofs sentence-by-sentence, word-by-word, letter-by-letter, and number-by-number. The other was Margaret (Peggy) Schott, who assisted me in the demanding task of quality control as well as assuming responsibility for the production of the index in a highly effi cient manner. Over the past 10 years at Northwestern University, Peggy has helped me, day-in and day-out, to guide a team of highly talented, yet often quite demanding, young researchers, from the day of their arrival to that of their departure and beyond into their own independent careers. These activities reflect only the tip of the iceberg when it comes to hailing the support Peggy – a PhD chemist and Northwestern alumna – provides to so many in the chemical community – locally, nationally and internationally.

Epilogue

In reflecting upon my peripatetic journey, which started with my valuable early experiences at the ‘University of Life’ on the farm, I can look back with feelings of pleasure interspersed with times of personal and professional hardships. There have been occasions marked by joy and others by sorrow. There have been periods that were characterized by success and others by failure, which I did my best to mitigate. Through all my life’s experiences, the aim has always been the same: to emerge from life’s roller coaster better informed and more knowledgeable about the ways of the world.

Putting all the ups and downs aside, I have been immensely privileged to be able to practice my hobby almost every day of my life in the presence of highly intelligent and outstandingly gifted young people, roughly aged between 18 and 32 drawn from nearly all quarters of the globe – and to do the things I love doing with them as a result of the generosity of those institutions and people, often without my being able to put a label or face to them, who have lent their support to my vision and mission from the Athens of the North (Edinburgh University) to the Windy City beside Lake Michigan (Northwestern University) with interludes on the edge of the Canadian Shield beside Lake Ontario (Queen’s University), in the Socialist Republic of Yorkshire (University of Sheffield), on the Plains of Cheshire beside the Wirral (ICI Corporate Laboratory), in the Heartland of Albion (University of Birmingham and in the City of Angels alongside the Peaceful Sea (University of California, Los Angeles). My journey is far from over: it will continue as long as family and friends fail to raise a red card telling me that I have reached my sell-by date.

Science is global and there’s no going back: scientists the world over live in a global village. There are no better words to catch this sentiment than those of the Scottish poet Robert Burns. In an epic poem, he emphasizes that “we’re all the same under the skin.” It is a statement of egalitarian sentiments. The poem reads –

Then let us pray that come it may
(As come it will for all that)
That Sense and Worth over all the earth
Shall have pre-eminence and all that
For all that, and all that,
It’s coming yet for all that
That man to man the world over
Shall be brothers for all that.

Oh, that people who exercise power and influence in the world over we ordinary mortals might be guided by these sentiments. What a wonderful world it would be for all humankind if there were no borders – and rejoice at the thought, no countries.

From The Nobel Prizes 2016. Published on behalf of The Nobel Foundation by Science History Publications/USA, division Watson Publishing International LLC, Sagamore Beach, 2017

This autobiography/biography was written at the time of the award and later published in the book series Les Prix Nobel/ Nobel Lectures/The Nobel Prizes. The information is sometimes updated with an addendum submitted by the Laureate.

Copyright © The Nobel Foundation 2016

James E. Rothman – Biographical

This autobiographical sketch of a life in science mainly focuses on a question I am now often asked – when and how did you know you wanted to be a scientist, and how did you become one? I am also asked by young scientists for advice I could impart from my own experiences and observations. With this in mind, this essay essentially provides bookends of my life until now, and I hope it may be of interest less from the particulars and more from generalizations that may emerge in the eyes of a reader, especially a young scientist. My Nobel lecture complements this essay, focusing mainly on what happened in between the bookends.

Childhood

From the earliest time I can remember I wanted to be a scientist, especially a physicist. I am not entirely sure where this came from, but at least in part it must have come from my parents (Fig. 1) who deeply valued education, especially in science and medicine. I was really fortunate and owe my parents a lot – they made me feel that I could do anything, and they provided the resources to enable me a privileged education unencumbered by financial needs.

My parents Gloria and Martin Rothman bringing me to Yale as a freshman (1967). Photograph taken in front of Branford College, where I lived as an upper classman, and where my wife Joy Hirsch and I now live as Resident Fellows. Our children Matthew and Lisa both lived in Branford College, graduating from Yale in 2000 and 2004, respectively.

Figure 1. My parents Gloria and Martin Rothman bringing me to Yale as a freshman (1967). Photograph taken in front of Branford College, where I lived as an upper classman, and where my wife Joy Hirsch and I now live as Resident Fellows. Our children Matthew and Lisa both lived in Branford College, graduating from Yale in 2000 and 2004, respectively.

My mother Gloria, with her enormous focus and drive, would in today’s world have been a high-powered executive. But she grew up in an earlier era where women had far fewer options. She ran the home and my Dad’s pediatric practice and taught me how to organize and manage. My father Martin was an intellectually oriented small-town physician who had wanted to do medical research as a young man, but had graduated in the Great Depression and then been caught up in World War II. He was always keen to involve me in the things he did. At perhaps the age of eight (Figure 2, left), I remember accompanying him on nocturnal house calls, at other times to the hospital; assisting him at home by measuring the intervals in his patients’ electrocardiograms; and helping him perform blood analyses in the small lab behind his office.

Photographs of the author in 1958 (age 8) and much later in 1984 in my laboratory at Stanford University, the same month that our three pivotal papers appeared in 'Cell' describing cell-free transport between Golgi stacks.

Figure 2. Photographs of the author in 1958 (age 8) and much later in 1984 in my laboratory at Stanford University, the same month that our three pivotal papers appeared in Cell describing cell-free transport between Golgi stacks.

But I believe that my focus on science came at least as much from the times during which I grew up, and the values that I and other Americans internalized from the society around us. In the 1950s and 1960s science and technology were viscerally understood and applauded by most Americans as mainstays of economic and political power following the victories of World War II. This era began with the polio vaccine eradicating a dread disease and with atomic energy (for better and for worse). It ended with the transistor, the digital computer, and the first men on the Moon.

In such an environment, and with my supportive family, and with an abundance of curiosity and a natural talent for mathematics, it is not surprising that I was designing and building electronics and launching rockets while still in elementary school. Rockets were a big thing for me as a boy (Figure 3). I taught myself basic trigonometry in 7th grade so I could triangulate the height of the rockets, and then calculus two years later so I could better understand the physics involved. As I began to study more advanced physics and mathematics formally in high school, I devoured the subject and challenged myself far outside the excellent curriculum at my secondary school (Pomfret School), so much so that I was graduated after my junior year. Entering Yale College in 1967, I was absolutely committed to theoretical physics.

The author, second from the right, preparing to launch a model rocket, age 12. I was entranced by mathematics, physics, and technology.

Figure 3. The author, second from the right, preparing to launch a model rocket, age 12. I was entranced by mathematics, physics, and technology.

Yale

Yale provided the perfect environment in which a committed young scientist could develop while also immersed in the broader culture. Yale was big enough to provide every opportunity, yet organized into relatively intimate units (Colleges) small enough to foster the individual. The students had all varieties of interests, and my friends were drawn largely from outside the sciences, providing breadth to complement my personal scientific focus (these friendships continue today with annual summer reunions of the “812 Club,” named after a room in Branford College). I also studied and especially internalized from my friends a great deal about art, philosophy, and history.

As an entering freshman, I was accepted into an “Early Concentration” program which rapidly enabled me to focus deeply on mathematics and physics at an advanced level. Physics taught me how to rigorously analyze the components of a problem by first imagining the form a solution would take. This can be a useful approach when engulfed in the fog that envelopes the uncharted waters of biology.

As I began my junior year, perhaps with fatherly concerns about the poor employment prospects for physicists at that time, my Dad strongly encouraged me to at least give biology a try. I was not especially open-minded, as there was a well-understood intellectual pecking order that every budding physicist was soon informed of. Theoretical physicists were the brightest. Experimental physicists were failed theoreticians, but nonetheless useful for confirming theories. Chemists were not so bright, but still socially acceptable. Biologists were said to be even less bright, and generally not worth mentioning. But, even at the very first lecture in the general biology course, I was amazed that (in contrast to the highly structured field of physics) the research frontier in molecular biology seemed instantly accessible, and yet could be equally rigorous and structure-based.

Thus began a multi-year process in which I gradually learned to think like a biologist, while still retaining the orthogonal way of thinking like a physicist. I believe this mindset was critical not only in my choice of the problem whose solution was recognized by this Nobel Prize, but also in providing me the means to solve it (as elaborated in my Nobel lecture). Therefore, I will devote some detail here to this process of transition from physics towards biology.

The transition came in stages, initially via self-taught physical chemistry (though I never formally studied this subject or many others – in fact, I have completed only one term of college chemistry and biology and most of what I have learned in science and medicine has been self-directed). In physics, I had gravitated to statistical mechanics, probably because unlike quantum mechanics you can visualize it in simple terms. Statistical mechanics served as my intellectual bridge to biology. For example, consider that the three dimensional conformations of polymers (a classic problem in statistical physics and thermodynamics) such as polypeptides are a fundamental determinant of their biochemical mechanisms. A term of research (junior year) with the theoretical chemist Marshall Fixman on the statistical mechanics of polymers equipped me with a fluid way of visualizing individual versus ensemble behavior of molecules that to this day guides my thinking in biochemistry and cell biology.

The next stage in my transition (also junior year) came via Harold Morowitz, introduced by Fixman, a theoretical biophysicist with equal interest in science as in philosophy. Harold was a broad intellectual who has had many interests, but just then he was especially interested in the hotly debated question of the basic structure of biological membranes. His laboratory had just done some influential experiments demonstrating thermal phase transitions in the membrane of microorganisms mimicking the behavior of isolated lipid bilayers. In retrospect, I was attracted by a combination of the familiar (thermal physics and conformational changes of a polymer [fatty acid chain] in the phase transition) and Harold’s personal warmth and charm. Soon I was working in his lab with a postdoctoral fellow, designing and building an instrument to measure the phase transitions, and was deeply engaged.

Harold had a way of collecting interesting people around him, including his former PhD student Donald Engelman. Harold advised me to go to the research seminar that Engelman was to give during an upcoming visit to Yale. This was the first seminar I had ever attended, and as it turned out it was a “job seminar” resulting in Don joining the faculty of Molecular Biophysics and Biochemistry soon thereafter. He spoke about his now classic experiments with Maurice Wilkins (Nobel Prize, 1962) demonstrating the lipid bilayer in biological membranes using an elegant combination of microbiology and X-ray diffraction. I think Harold asked Don to take me under his wing, where in a sense I have been ever since (Don remains one of my closest friends and happily we are both now at Yale). We took on the problem of how cholesterol buffers the fluidity of the lipid bilayer, extinguishing the thermal phase transitions, and my earliest publications came from this. Don taught me by his example how to dissect each morsel of data to get the most from it.

In doing this, I learned another important lesson – the central importance of numbers. My students sometimes seem surprised that there are a lot of numbers that I have at my disposal whenever I may need them; this is true, and it is no accident. From Yale onwards, I have always made a point of remembering key numbers, and I have learned to do this automatically every time I hear a new one. For example, π and e in mathematics; Boltzmann’s constant in physics; absolute zero temperature, the diameter of a hydrogen atom, and the density of various materials in chemistry; the size of proteins and their secondary structure motifs, and the sizes of viruses, organelles and so on in biology; and the rates of fundamental processes (for example, diffusion in water, lipid bilayers; the rate of cell locomotion and so on). Ready knowledge of scale and rates allows one to quickly see if a hypothesis or a result or an experimental design is reasonable.

At that time Yale had an unusual program for a dozen or so seniors called Scholar of the House (sadly this wonderful program has been discontinued). This program allowed me to spend senior year fully in research (with Harold and Don) with no formal course work, and to graduate solely on the strength of a thesis, if it was accepted (if it was not I would need to repeat senior year conventionally). The thesis was evaluated by a committee of Yale’s most eminent scholars drawn mainly from the humanities. With so much riding on this, I was mortified when Harold playfully showed me the evaluation of my work he had written fully in limericks – I was sure I was doomed; but apparently it was just right for the humanists, and I was graduated (with the award for the best thesis).

During that last year at Yale I became a scientist.

Harvard

My father had cnvinced me that I should go to a medical school rather than directly to a PhD program. At that point my knowledge of biology was as narrow as my knowledge of physics was deep, and it would have been impossible to make an informed choice of which discipline in biology to focus on. Therefore, I entered Harvard Medical School (in 1971) with the idea of learning biology and then doing research, rather than ever practicing. I succeeded in the former, ultimately leaving the MD program more or less after the basic sciences (but with enough clinical exposure to gain a lifetime of respect for clinical medicine).

The first year at Harvard Medical School easily proved to be the greatest didactic experience of my life because HMS offered an unencumbered platform for self-directed learning with wonderful access to first-class research professors built on a broad and well-organized curriculum. I still rely on the many things I learned in that first year or so.

In particular, it was as a first year medical student in histology that I first learned about the secretory pathway, at a time when the discoveries of George Palade (Nobel Prize, 1974) were still fresh and remarkable. What an astonishing process – how could cells make vesicles from membranes? How could each vesicle know where to go? How could it fuse? It was particularly amazing because at the time it was not even possible to begin to imagine the form a molecular solution might take. This captured my imagination, but not enough was known to productively take up the problem then. But it would ultimately become a lifelong focus when I started my own laboratory at Stanford in 1978.

My PhD thesis (initially as part of Harvard’s MD-PhD program) was with Eugene Kennedy, a master of membrane biochemistry. Kennedy, who was a brilliant intellectual and an original thinker, taught me how to formulate a complex problem in biochemical terms. Some of this work was in collaboration with John Lenard, whom I will soon mention. We established how lipid bilayers in cell membranes are formed by asymmetric biosynthesis, following on the PhD thesis work of Roger Kornberg (Nobel Prize, 2006), which had at that time just established the basics of the physical dynamics of lipids in membranes.

Harvard, therefore, is where I became an experimentalist and in particular a professional biochemist. Everything that happened afterwards followed from that.

Deep and enduring scientific friendships

A life in research provides many opportunities to meet remarkable people as a student and afterwards around the world. It is hard to over-emphasize the importance of several formative, warm and enduring friendships for my development and success as a scientist. Some evolved from what we would today call mentoring relationships, initially with somewhat older (but still young) scientists who were nonetheless more established than me. Th s group included (in the order of our fi st acquaintance) Donald Engelman, John Lenard, Qais Al-Awqati, Roger Kornberg and Per Peterson. I fi st met each of these extraordinary individuals essentially as teachers. I have already mentioned Engelman.

John Lenard was a young full professor at Rutgers when we met in 1974. He took me into his lab (and his home) while I was still a graduate student so we could understand the topology of lipids in viral envelopes. We worked day and night together and we soon bonded personally. Though we never collaborated experimentally again, many ideas and personal decisions have been subject to John’s wise counsel. We wrote several review articles together over the decades, and in each case he taught me how to improve the framing of ideas and my writing style. Happily, we see each other regularly for dinners, museums, and theatre in Manhattan.

Qais Al-Awqati was my teacher in renal physiology when I was a second year medical student (1972) and he was junior faculty at Mass General. We met again much later (1986) when coincidently we both were at Cold Spring Harbor Laboratory summer lab courses, and we had many lovely evening walks together discussing books and occasionally science. We have been close ever since. Qais is not only one of the world’s best physicians and cell biologists, but without doubt one of the most intelligent and cultured people I have ever met. What a privilege it is to continue to learn from and enjoy him, whether we talk about science or he guides me through the Metropolitan (be it the art museum or the opera).

Roger was an assistant professor in the department of Biological Chemistry at Harvard Medical School and I met him as a PhD student. We had a common interest in membranes, but soon we were discussing ever-widening scientific terrain because of his deep and penetrating mind. He broadened and sharpened my perspective on biochemistry, first as a student and then soon as faculty colleague at Stanford. At Stanford we met many times a week, and I turned to him for criticism and inspiration. After I left Stanford (1988) this of course diminished in frequency, but never in intensity. I also suspect that Roger’s endorsement after “road-testing” me at Harvard somehow figured importantly in the job offer from his father Arthur Kornberg (Nobel Prize, 1959) and the other faculty to join their Biochemistry department, which came while I was still in the MD-PhD program in 1976.

Per Peterson, as he puts it, “discovered me” at a membrane meeting in Heidelberg (1980). Per is a cellular immunologist, and was at that time the director of the Wallenberg Laboratory in Uppsala (Sweden). As he told me, my findings were good raw material, but needed polishing. Of course, he was correct. He has been trying, with occasional modest success, to improve me ever since. Per has a rare combination of great analytical power with a genuinely sympathetic understanding of human nature. This has enabled him both to contribute centrally to science, and to build and run large and successful organizations, most recently as the Chairman of Research and Development at Johnson & Johnson. During his evolution Per has kept me at his side, and taught me a tremendous amount about the dynamics of industry and approaches to management that have proven very useful to me. He continues to inspire me and help me focus on what really matters.

Other important friendships started on more personal terms but soon evolved into long-term informal intellectual or actual collaborations where new ideas could be debated with absolute intellectual honesty in friendly ways and often in nice settings as well. I met Graham Warren (Figure 4, top) in 1976 when he was a postdoctoral fellow at Cambridge (UK) on an extended visit to Harvard, and we immediately hit it off, his reserve a complement to my exuberance, Graham harboring a well-known (merciless) intellectual rigor salved by his gracious humor. Graham and his family spent a summer at Stanford in 1978, so we could work together (actually starting my lab jointly) on what turned out to be a bold but ultimately ill-conceived hypothesis that we had convinced ourselves was the key to the sorting problem. Although in the past few years, with his responsibilities directing the Max Perutz Institute in Vienna, and mine at Yale, our contact has been less, we have seen each other numerous times every year and many of my best ideas have often drawn on our discussions.

Top: the author with Graham Warren in 1976, photographed in Haverhill, Massachusetts, my home town shortly after we first met when he was visiting Harvard and I was still a PhD student there. Many of my formative ideas took shape in discussions with Graham, and later ones as well. Bottom: with Felix Wieland in 1987, photographed in Half Moon Bay, California, taken during the period of his pivotal sabbatical in my Stanford laboratory. Felix is a consummate enzymologist and taught me much.

Figure 4. Top: the author with Graham Warren in 1976, photographed in Haverhill, Massachusetts, my home town shortly after we first met when he was visiting Harvard and I was still a PhD student there. Many of my formative ideas took shape in discussions with Graham, and later ones as well. Bottom: with Felix Wieland in 1987, photographed in Half Moon Bay, California, taken during the period of his pivotal sabbatical in my Stanford laboratory. Felix is a consummate enzymologist and taught me much.

I met Felix Wieland (Figure 4, bottom) in 1985 at Regensburg (Germany) where he was then an assistant professor. He came up to me after my lecture on cell-free reconstitution with the idea of spending two years at Stanford trying to figure out how membrane fusion worked. As with Graham, we also immediately hit it off, though in Felix’s case it was his contagious Bavarian exuberance and humor synergizing with mine. Soon, he was in Palo Alto. Wieland was a real enzymologist who taught me (and the rest of my lab) how the business is really done, having himself learned at the hands of a master (his uncle) Fyodor Lynen (Nobel Prize, 1964). Without Felix, I doubt there would have been NSF, SNAP, SNAREs or coatomer, and even if there were they would not have been as much fun. By 1987 Felix moved back to Germany (at Heidelberg) but we still see each other frequently. I look forward to our annual escapes with our wives to Bad Drei Kirchen (Bolzano), and the Rothman and Wieland children continue their childhood friendships to this day.

With my wife, Joy Hirsch, in the lobby of the Four Seasons Hotel in Washington D.C. on November 19, 2013, just after the meeting of the American Nobel laureates and spouses with President Obama, en route to the dinner at the Swedish Embassy.

Figure 5. With my wife, Joy Hirsch, in the lobby of the Four Seasons Hotel in Washington D.C. on November 19, 2013, just after the meeting of the American Nobel Laureates and spouses with President Obama, en route to the dinner at the Swedish Embassy.

Without a doubt the most important, deepest, and most vital relationship is of course with my wife, Joy Hirsch (Figure 5). In addition to the personal side, Joy is also my scientific partner. She is my sounding board on every subject, and has been my critic and supporter through the many early years when my work was not accepted as it is now. Joy comes from a successful farming family in Salem, Oregon and from this very American background is imbued with the Yankee attitude that every problem can be solved if you think about it enough and try hard enough. Joy also lives by this belief in her research. She is also a Professor at Yale, and is gifted scientist who is renowned for her fundamental studies of human cognitive processes and related diseases.

Observations on style from a life in science

As a closing bookend, I will offer some observations that may be of interest to others, especially younger scientists. This is not necessarily to impart specific advice, which would be disingenuous as I rarely followed the advice I was given as a young man; it is more to offer the use of some of my personal experiences as a springboard for generalizations that may apply to the reader. Some of these thoughts will be familiar to several generations of my students, who may recall having heard one or another as a frequently trodden-out aphorism. Some are from my own teachers.

Science and art. Science at the edge is an art form as much as a strictly logical development of ideas. The rare artists and the rare scientists capable of performing at the edge have a lot in common. They both have an intuitive vision carrying strong emotional content. Neither is easily discouraged from their work, even with strong obstacles in their path. These are essential traits.

Choosing a problem. As a new junior faculty member at Stanford, I asked Arthur Kornberg why he chose to understand DNA synthesis in the early 1950s. He said that the problem was of the greatest importance; that everyone else assumed it could not be done; but that he thought it could be. I listened very carefully when he said this.

The importance of a clear hypothesis. I often tell people in my lab “if you want to hit a home run, you have to be in the ball park. If you are outside the ball park you can swing all day but you will never hit a home run.” This idea comes from physics where computationally complex problems are approached by making simplifying “ball park” assumptions so that the main variables can be identified. To do this in biology, you imagine you are designing the system and therefore how you would design it for the required function. This provides a model – a hypothesis – of the form that a likely solution will take. You are now in the ball park, because you can now design specific tests of the model. Your exact model is almost certain to be wrong in detail (evolution rarely works by Cartesian rules) but is likely to be correct in spirit, and this will allow you to get to the truth faster. This process is very basic to my approach to science, as I described in my Nobel Lecture (Figure 9 in the published lecture).

Troubles Are Good For You (TAGFY). The “TAGFY Philosophy” was first enunciated by the master enzymologist Ephraim Racker, and I pass it on. TAGFY has proven true for me over and over again. For example, after Erik Fries and I first published cell-free transport, we had great difficulty repeating our exact results, and it would have been easy to be discouraged. But TAGFY meant that we were really about to discover something basic that we had no idea about. Indeed, in resolving the “trouble” we found that we had reconstituted intra-Golgi vesicular transport, a process not previously known to exist (as documented in the Nobel Lecture). TAGFY can give you strength in hard times.

If you are hitting your head against a brick wall, find a new wall. It is so human to try that experiment one more time hoping for a better result. It almost never pays. Try a new approach. Remarkably, most people don’t.

It is much harder to stop a project than to start one. To do so takes real intellectual honesty and a complete disregard of ego. Worse, stopping involves a huge sunk cost of time and emotion, but if you don’t, then the next phase (which may hold success) will be only further away.

Don’t be afraid to be “stupid.” If you don’t understand it, it is probably unclear. If you don’t know how to do something, ask. It is far better than losing days in the lab because you didn’t. It is amazing how many people don’t ask. I always did and it made a difference.

Smart is good; lucky is better. Eugene Kennedy always said this, and he was right. In other words, in spite of any and all, don’t over-think and be open to chance.

Additional personal history

In addition to me (1950) my parents Gloria Rothman (née Hartnick, born 1923) and Martin Rothman (1915–2005) had two children, Richard (1953) and John (1955). My brother Richard is an MD-PhD who recently retired from the NIH after many years as a leading researcher in neuropharmacology, and is now in practice in Psychiatry. John is a successful attorney specializing in mediation. I am married to Joy Hirsch (Figure 5) who is an eminent professor at Yale in Neurobiology and Psychiatry. She is a graduate of the University of Oregon (BS) and Columbia (PhD). We reside in New York and New Haven. I am always dazzled by her beauty and elegance but equally by her brilliance and compassion. Joy is the glue that holds together our wide circle of personal and scientific friends, and our extended family. She has also been an exceptional stepmother to our children, and we are very proud of their accomplishments. Matthew (1977; Figure 6) graduated from Yale (BA) and Columbia (MBA) and is a senior executive in a major investment firm. He is married to the former Sarah Levinson, a senior executive in a national public relations firm. Sarah and Matthew are superb parents to our two delightful grandchildren, Alexandra (2010) and George (2012). Lisa (1982; Figure 6) graduated from Yale (BA) and Columbia (MD) and soon will start her residency in Dermatology at NYU. She is married to the former Jeannie Chung, an attorney in a major Manhattan law firm.

With my children, Lisa and Matthew on the stage in the Concert Hall in Stockholm, immediately after the conclusion of the Nobel Prize Ceremony, December 10, 2013. (Courtesy of Alexander Mahmoud and the Nobel Foundation).

Figure 6. With my children, Lisa and Matthew on the stage in the Concert Hall in Stockholm, immediately after the conclusion of the Nobel Prize Ceremony, December 10, 2013. (Courtesy of Alexander Mahmoud and the Nobel Foundation).

Curriculum vitae

James Edward Rothman was born on November 3, 1950 in Haverhill, Massachusetts (U.S.A.). He went to public schools in Haverhill, Massachusetts for elementary school through 8th grade, and then to Pomfret School (Pomfret, Connecticut) in 1964, from which he graduated in 1967. He then matriculated at Yale College, graduating summa cum laude in 1971 with a B.A. in Physics, having been Scholar of the House. Rothman then matriculated at the Harvard Medical School as an MD student, then joined the MD.-PhD program there. Ultimately, he graduated with a PhD in Biological Chemistry (thesis advisor, Eugene P. Kennedy) in 1976. He then joined the laboratory of Harvey F. Lodish in the Department of Biology at M.I.T. as a Damon Runyan postdoctoral fellow (1976–1978). In 1978 he joined the Department of Biochemistry at Stanford University as an assistant professor, and was promoted to associate professor with tenure (1981) and then full professor (1984). Rothman moved in 1988 to Princeton University in the Department of Molecular Biology where he held the E. R. Squib Chair of Molecular Biology. In 1991 he moved to the Memorial Sloan-Kettering Cancer Center where he founded and chaired the Cellular Biophysics and Biochemistry department, served as a Vice-Chairman of the Sloan-Kettering Institute for Cancer Research, and held the Paul Marks Chair. In 2004, Rothman joined the Columbia University College of Physicians and Surgeons as a professor in the Department of Physiology and Cellular Biophysics, where he also directed the Columbia Genome Center and held the Clyde and Helen Wu Chair of Chemical Biology. Then, in 2008 he returned to Yale and at the time of this writing is the Wallace Professor of Biomedical Sciences and Chair of the Department of Cell Biology and a Professor of Chemistry.

Prior to the Nobel Prize, Rothman’s contributions to cell biology, biochemistry, and neuroscience were recognized by numerous prizes and honors. These include: the Eli Lilly Award for Fundamental Research in Biological Chemistry, U.S.A. (1986); the Passano Young Scientist Award, U.S.A. (1986); the Alexander Von Humboldt Award, Germany (1989); the Heinrich Wieland Prize, Germany (1990); election as Member, U.S. National Academy of Sciences (1993); the Rosenstiel Award in Biomedical Sciences, U.S.A. (1994); election as Fellow, American Academy of Arts and Sciences (1994); the Fritz Lipmann Award, U.S.A. (1995); elected as Member, Institute of Medicine, National Academy of Sciences, U.S.A. (1995); Honorary Degree, University of Regensburg, Germany (1995); elected as Foreign Associate, European Molecular Biology Organization (1995); the Gairdner Foundation International Award, Canada (1996); the King Faisal International Prize in Science, Saudi Arabia (1996); the Harden Medal of the British Biochemical Society, U.K. (1997); the Lounsbery Award, National Academy of Sciences, U.S.A. (1997); the Feodor Lynen Award, U.S.A. (1997); honorary MD and PhD degrees, University of Geneva (1997); the Jacobæus Prize, Denmark (1999); the Heineken Prize for Biochemistry, The Netherlands (2000); the Otto-Warburg Medal, German Biochemical Society, Germany (2001); the Louisa Gross Horwitz Prize, U.S.A. (2002); the Lasker Basic Research Award, U.S.A. (2002); elected as Honorary Member, Japanese Biochemical Society (2005); the Beering Award U.S.A. (2005); elected as Fellow, American Association for the Advancement of Science (2007); the E.B. Wilson Medal, American Society for Cell Biology (2010); the Kavli Prize in Neuroscience, Norway (2010); and the Massry Prize. U.S.A.

From The Nobel Prizes 2013. Published on behalf of The Nobel Foundation by Science History Publications/USA, division Watson Publishing International LLC, Sagamore Beach, 2014

This autobiography/biography was written at the time of the award and later published in the book series Les Prix Nobel/ Nobel Lectures/The Nobel Prizes. The information is sometimes updated with an addendum submitted by the Laureate.

Copyright © The Nobel Foundation 2013

Robert W. Fogel – Biographical

I was born in New York City in 1926, four years after my parents and my brother migrated to the United States from the city of Odessa in Russia. Although they arrived in New York penniless, my parents scraped together enough savings to establish the first of several small businesses just after I was born. Despite the hard times of the Great Depression and the modest financial circumstances in which we lived, they created a joyful household and they encouraged my brother and me to be optimistic about the future.

My parents’ reverence for learning encouraged both my brother and me toward academic pursuits. In many ways, however, it was my brother who was the main intellectual influence on me until he joined the armed forces in 1941. Almost six years my senior in age and nine years ahead of me in school, he inspired me with his intellectual brilliance. I still remember the intense discussions by my brother and his college classmates about the social and economic issues of the Depression that I overheard as I lay in my bed, supposedly asleep, in the next room.

My education in the public schools of New York City between 1932 and 1944 was an excellent preparation for a life in science. Because of the Depression, these schools were able to attract a remarkably talented and dedicated collection of teachers who encouraged their students to strive for the highest levels of accomplishment. That environment led me to aspire to a career in science, and also kindled my love for literature and history.

My professional training began at Cornell University (BA 1948) and continued at Columbia University where I obtained my MA (1960), and at Johns Hopkins University, where I obtained my Ph.D. (1963). It was at Cornell that my scientific interests shifted from physics and chemistry to economics and history. The switch in focus was precipitated by the widespread pessimism about the future of the economy during the second half of the 1940s, when forecasts about the imminent return to the massive unemployment of the Great Depression were rife.

I began my graduate training with the naive belief that by combining the study of history and economics I would quickly discover the fundamental forces that had determined technological and institutional changes over the ages and that such knowledge would point to solutions to the current problems of economic instability and inequity. As I became aware of how little was actually known about these large processes and their interconnections, I began to focus on more discrete issues: What did we really know about the role of the factory system in economic and institutional change during the nineteenth century? What was the nature and the magnitude of the contribution of particular new technologies, such as railroads or steel mills, to economic growth? I also concluded that to answer such questions, much greater use had to be made of quantitative evidence, so I set out to master the most advanced analytical and statistical methods that were then taught in the economics department. It was only later that I discovered that the training program I had worked out for myself was unorthodox for an economic historian.

The two teachers who influenced me the most during my year at Columbia were George J. Stigler, who taught the graduate microeconomics sequence, and Carter Goodrich, who taught the sequence in American economic history. Stigler made microeconomic theory come alive. He emphasized not its elegance but its applicability to a wide range of issues in economic policy. He continually moved between theory and evidence, carefully considering the empirical validity for the assumptions that theorists made about the slope or other aspects of the shape of key functions. He often considered when, with what model, and under what implicit assumptions one could draw a particular inference from a given body of data.

Goodrich impressed me not only with his knowledge of the literature of American economic history, but with his willingness to identify the gaps in the profession’s collective knowledge of key issues. By the end of the course one not only had a good grasp of what was known about the process of American economic growth, but a list of potential projects. It was to Goodrich that I turned for advice on my master’s thesis. He was then engaged in research for his book, Government Promotion of Canals and Railroads and raised a number of issues that puzzled him about the financing, riskiness, and benefits of the Union Pacific Railroad. These questions became the subject matter of my master’s thesis, which was also my first published book. Although Goodrich did not himself make use of the new mathematical and statistical methods of economics, he encouraged me to do so. He also suggested that, given my substantial interests and quantitative approaches to economic history, Simon Kuznets at Johns Hopkins was probably the best economist to guide my future training.

The teachers who taught me the most at Johns Hopkins, aside from Simon Kuznets, were Abba Lerner and Fritz Machlup in microeconomic theory; Evsey Domar in macroeconomic theory and the theory of economic growth; T.C. Liu in mathematical economics, and two teachers of mathematical statistics and of sampling design in the School of Public Health.

Simon Kuznets, who supervised my doctoral dissertation, was by far the most influential figure in my graduate training. Soft spoken and of moderate stature, one did not have to be in his class very long to discover that he was a towering intellect, erudite not only in economics, but also in history, demography, statistics, and the natural sciences. His course in economic growth covered the history of technological change during the modern era, demography and population theory, and the use of national income aggregates for the comparative study of economic growth and of the size distribution of income. It was not until some years later that I realized the course presented the substance of the research that later appeared in a series of 10 supplements to Economic Development and Cultural Change, and in his 1966 monograph, Modern Economic Growth: Rate, Structure, and Spread – the work for which he was awarded the third Nobel Prize in economics. Kuznets’s course was valuable not only for the substance of the material but also for the way that he used the material to transmit the art of measurement. He repeatedly demonstrated that the central statistical problem in economics was not random error but systematic biases in the data, and he conveyed a number of powerful approaches to coping with that problem, particularly emphasizing the role of sensitivity analysis.

By the time I left residence at Johns Hopkins, I had worked out a two-pronged research strategy that I thought could keep me going for a decade or more. The first was to measure the impact of key scientific and technological innovations, key governmental policies, and key environmental and institutional changes on the course of economic growth. The second was to promote the wider use of the mathematical models and statistical methods of economics in studying the complex, long-term processes that were the focus of economic historians. In my mind these two objectives were closely interrelated. The best argument for the new methods was the demonstration that in the study of particular issues, such as the contribution of railroads to economic growth, these methods were superior to traditional approaches. The new methods made it possible to lay out the key analytical issues in a manner that made them amenable to measurement, to identify the categories of evidence needed to resolve the points at issue, to develop techniques of measurement that were suitable for both the issues and the available evidence, and to assess the robustness of the results.

Several factors made the realization of my research program possible. One was the willingness of university administrators to provide me with a generous share of the limited research funds at their disposal, a sine qua non for work that was both labor and computer intensive. Even when I was still an unproven new assistant professor at Rochester, Lionel W. McKenzie provided several research assistants, a computer programmer, and all of the computer time I could use. Deans D. Gale Johnson and Robert McC. Adams made similar investments in my research at Chicago during the 1960s and early 1970s at levels that reflected as much their estimates of my promise as of accomplishments. This type of support was continued at Harvard by Henry Rosovsky during the last half of the 1970s.

Except for a small grant from the Social Science Research Council (SSRC) when I was still a student at Johns Hopkins, my work on railroads was supported exclusively from university funds. Since my later projects were based on ever-larger data sets, obtained primarily from manuscript sources at archives, these projects could not have been carried out without the generous support of foundations, particularly the National Science Foundation (NSF) and the National Institutes of Health (NIH), but to a significant degree also such private foundations as the Ford Foundation, the Exxon Educational Foundation, and the Walgreen Foundation Endowment Fund. University funding still remained crucial since it took considerable outlays of funds to bring a large project to a point that could win approval from peer review committees.

Another key factor was the plunging cost of data processing made possible by rapid advances in computer hardware and software. These technological developments made it feasible to work with ever-larger data sets. By linking together the data on individuals and households from a wide range of archival sources, data sets could be customized for particular economic issues. The sources include the manuscript schedules of decennial censuses, probate records, military and pension records, genealogies, tax rolls, death certificates, and public health records.

Still another important factor in making such research feasible was the cooperation of offcials at the U.S. National Archives and of the Genealogical Library of the Church of Jesus Christ of Latter-Day Saints in Salt Lake City. The Genealogical Library is especially valuable because it is a depository for vast quantities of records from all over the United States, and from many other countries, relevant to economic, social, and biomedical research. Although collected for religious reasons, officials of the Library have made their holdings available to the scientific community, providing a resource that would otherwise have required enormous sums of money to reproduce.

No single organization has contributed more to the study of long-term economic growth than the National Bureau of Economic Research (NBER). The long-term approach figured prominently in NBER research programs conducted between the late 1930s and the late 1960s. That work, which was conducted mainly at the macro level, was a continuation of the Bureau’s pioneering work in the development of national income accounts and related measures of macroeconomic behavior. However, during the 1970s the Bureau’s work on long-term growth processes had waned. When Martin Feldstein became President of the NBER in 1977 he decided to undertake a new program on the long-term Development of the American Economy (DAE), and asked me to be its program director.

I appointed an executive committee consisting of Lance E. Davis, Stanley L. Engerman, Robert M. Gallman, Claudia D. Goldin, Clayne L. Pope, and myself to chart the direction of the new program. After reviewing the Bureau’s past work, and the new direction it was taking under Feldstein’s leadership, the committee sought to identify a set of current policy issues to which the DAE could contribute. In the course of this review we consulted with Simon Kuznets, Douglass C. North, Richard A. Easterlin, and Moses Abramovitz, among others.

After more than a year of investigation, we concluded that to understand the sources of the long-term decline in saving and investment rates, the factors influencing the rate of technological change, or the long-term shifts in the demographic structure of the population and the labor force, we needed to know much more about microeconomic behavior than was known at the time. Research at the microeconomic level, however, had been inhibited by the absence of suitable data. The DAE, therefore, turned its attention to the problem of constructing new data sets capable of illuminating the relationship between the current and the past behavior of families and firms.

The executive committee launched a series of pilot projects investigating the feasibility of creating several representative data sets consisting of intergenerationally linked families. Such data sets would open up entirely new possibilities for examining the interaction of economic and cultural factors and their mutual influence on such variables as the saving rate, the rate of female entry into the labor force, fertility and mortality rates, the inequality of the wealth distribution, migration rates, and rates of economic and social mobility. These data sets could not be created from a single set of records but required the linking of several different types of archival records. The executive committee also began a pilot study on the feasibility of constructing data sets based on firm records that would permit the analysis of the way that firms respond to the changing technological opportunities that are open to them, as well as to the changing institutional and legal environment in which they must operate. Dealing with such issues required the development of representative sets of firm records stretching over long periods of time that not only contained information on the decision-making processes of these firms, but also on the economic consequences of the decisions.

The DAE’s review of the pilot projects concluded that the design of portable computers for data retrieval, and of software to manipulate large files, had developed to the point where the creation of such microeconomic data sets was feasible. A score of projects were set out by 1980 and investigators to lead them were chosen. Claudia Goldin, who became the director of the DAE in 1991, reported that there are now some forty DAE research associates. Since the start of the DAE, they have created over fifty longitudinal and cross-sectional data sets that span the period from the late 1700s to the present. These data sets have formed the basis for scores of papers, several conference volumes and a number of monographs.

My ability to work on the problem of creating and studying large lifecycle and intergenerational data sets reached a new level in 1981 when Richard N. Rosett, then Dean of the Graduate School of Business at The University of Chicago, invited me to succeed George J. Stigler as the Charles R. Walgreen Professor of American Institutions. In addition to the unusual research fund endowed by Walgreen, Rosett offered to establish a Center for Population Economics (CPE) that would focus on the interaction of economic, demographic, and biological processes over life-cycles and generations. The invitation was enthusiastically supported by Hanna Gray, who was then the President of The University of Chicago. The generous support of the CPE has been continued by John P. Gould, who succeeded Rosett as Dean, by Robert S. Hamada, the current Dean, and by Hugo F. Sonnenschein, President of The University of Chicago.

Without the resources of the Walgreen Chair and the CPE the current research projects on which I reported in the Prize Lecture would not have been possible. The data on health conditions, for example, comes from a project called Early Indicators of Later Work Levels, Disease, & Death which is tracing nearly 40,000 Union Army men from the cradle to the grave. It takes over 15,000 variables to describe the life-cycle history of one of these men. These life-cycle histories are created by linking about a score of data sets. It took more than half a decade of work to investigate the potential of these data sets, work out procedures for data retrieval and file management, and to establish the feasibility of the enterprise in our own minds.

The site committee of the National Institutes of Health which reviewed the original project proposal in 1986 agreed that such a project could in principle make a significant contribution to an understanding of the process of aging, but they were skeptical about the quality of some of the data, about whether the software and programming procedures we had developed by that time were adequate for the management of such a large data set, and about whether the project could be completed within the proposed budget. To resolve these doubts it was necessary to draw a six percent subsample which linked together all of the separate sources and which demonstrated the effectiveness of the software by analyzing the information in the subsample. It took an additional four years to complete the second phase of the justification of the project. Thus nearly a decade of preliminary research, much of it funded by Walgreen and the CPE, was required before the project was accepted by the peer reviewers of NIH and NSF.

No individual has done more to help me pursue a career in science than my wife of forty-five years. I met Enid Cassandra Morgan during the election campaign of 1948 when she was a Sunday school teacher, a leader of the youth organizations of St. Phillips Episcopal Church, and the head of Harlem Youth for the election of Henry Wallace. Over the years Enid has been both my most confident supporter and my keenest critic. During my graduate training her earnings contributed significantly to the income of our family. When I was an assistant professor she combined care of the children with many hours of unpaid labor as a research assistant in library archives. She helped boost my self-confidence when my unorthodox findings provoked controversy and criticisms, and she often provided insightful suggestions for the improvement of my lectures, papers, books, letters, and research proposals.

Throughout the years she has been the overseer of my social conscience, pulling me back to reality when she saw that my preoccupation with the abstract aspects of scientific issues had led me to extenuate their deeply human aspects. I also benefitted greatly from her experiences as Student Counselor, Dean of Students, and Director of Student Life at Rochester, Harvard, and Chicago. She has helped me to understand the administrator’s point of view and to improve what she and my sons refer to as “people skills”.

My sons, Michael and Steven, have shared in the joys and the tribulations of being raised by academic parents. They have encouraged me to adhere steadfastly to scholarly principles in the face of unfair criticisms. They have read my papers and books, offered helpful suggestions, and sometimes helped substantially in the process of editing, teaching me how to say more with fewer words.

One aspect of the plunging cost of data processing has been the emergence of large-scale collaborative projects in economic history. Such projects have been promoted partly by economies of scale in the retrieval and cleaning of the data sets and partly by the wide range of skills required to manipulate, analyze and interpret the data. There were, for example, thirty five contributors to the three technical volumes of Without Consent or Contract, many of them former students who are now distinguished senior investigators. The research team for the Early Indicators project is even larger. It has been my good fortune to have had access not only to the pool of talented students at Chicago, but also to those at Harvard and Rochester. In both the slavery and aging projects these students were often far ahead of the senior investigators in recognizing major unanticipated findings, in proposing novel approaches to the analysis of the data, in discovering new data sets, and in offering probing criticisms.

It is known far and wide among economic historians that much of the credit for the success of my research enterprises goes to Marilyn Coopersmith who has worked with me for more than a quarter of a century. She was the administrative assistant of the DAE program from its inception until 1991, and she has been the associate director of the CPE since 1981. She is not only an effective coordinator but has been a diligent researcher and a friend to a legion of graduate research assistants, who often turned to her for help in overcoming bureaucratic obstacles.

The companionship of scholars and the thrill of continuous learning are two wonderful aspects of a life in science. When one is engaged with students who are both very curious and very bright, it is never quite clear who is teaching whom. I have also had the good fortune of collaborating with senior investigators who are all exceptional teachers with enthusiasm for their work and with great patience for the bewilderment of novices. Their guidance greatly facilitated my efforts to train myself for research involving the interconnections between economics, demography, and the biomedical sciences. James Trussell tutored me as I tried to master the mathematical models of demography and the art of applying them to incomplete data. J.M. Tanner has spent numerous hours teaching me the fundamentals of the branch of medicine called auxology (the study of human growth), looking at our data and helping to interpret them, guiding me through basic texts, calling my attention to the latest relevant papers, and reading and criticizing my work. I received a similar education from Nevin S. Scrimshaw in epidemiology (particularly of infectious diseases), in nutrition, and in some aspects of both physiology and clinical medicine.

From Les Prix Nobel. The Nobel Prizes 1993, Editor Tore Frängsmyr, [Nobel Foundation], Stockholm, 1994

This autobiography/biography was written at the time of the award and later published in the book series Les Prix Nobel/ Nobel Lectures/The Nobel Prizes. The information is sometimes updated with an addendum submitted by the Laureate.