Paul Lauterbur and the Invention of MRI

by M. Joan Dawson

  Earl Warrick, a fellow of long tenure, wrote:

  The Mellon system fostered excellent relationships among the fellows. No rivalries developed because no two projects in the same field were ever initiated. So productive were these relationships that in the time I was to spend at Mellon, I would learn more from my association with other fellows than in much of my laboratory work.10

  This spirit, cooperative and collaborative, made a perfectly natural habitat for Paul, one that he tried to recreate in his later academic positions. Many of his longest friendships were forged in “the Mellon days.”

  The Mellon’s longtime home (known as the new Mellon Institute), built in 1937, is an extraordinary work of art deco. Modeled on the Parthenon and rich in classical allusions, the Mellon Institute is surrounded by sixty-two Ionic columns. The sides, platform and steps are all granite. Eight monolithic marble columns support the lobby, and the ceiling is of suspended marble. The building is spacious, with high ceilings, marble floors and fine inlaid wood paneling in the vestibule and meeting rooms.

  Paul and his colleagues lived and worked as “princes of science” in this palace. The building has a large auditorium and library, and the laboratories were furnished with the most up-to-date equipment, allowing far more sophisticated research than any of the companies participating could. The general attitude of service people there was, “We are here for the researchers. Our job is to facilitate your job.” Even harder to believe is that the third floor foyer was home to a receptionist, always on the job and to whom the researchers went to have errands run. There was a run twice a day to the local premises of Fisher Scientific; the second run was to pick up orders placed earlier that day!

  Sadly, the grandeur is all gone now. When Mellon merged with Carnegie Tech, forming Carnegie Mellon University, the Mellon building was no longer seen as a temple of science. It was just another university building to be stuffed with students. The Mellon is an old and disheveled lady now, in ill health and in want of cleaning and renewal. But in the days when Paul began his career, she was a grande dame.

  Why Is Rubber Rubbery?

  Paul’s job was to figure out how fillers such as carbon black (very fine particles of carbon) increase the strength, stiffness, and hardness of natural rubber and how silicates do the same for silicone rubber. How could particles that do not form tight (covalent) bonds have such dramatic effects on rubber’s physical characteristics? No one knew whether the filler connected with weak (ionic) bonds to the polymers of rubber or whether it somehow affected their properties by physical proximity but no chemical bonds. The work involved a fascinating variety of activities. Paul wrote,

  It had long been known that carbon black dramatically improves the properties of natural or synthetic organic rubbers, and it had been found that the same was true for silicone elastomers if small particles of silica were used in place of carbon, but it was not known whether surface chemistry was involved or simply physical properties. I addressed one aspect of the problem by substituting phthalalocyanine dyes for silica, and they worked perfectly. . . . I never achieved a theoretical understanding of the effect, despite intense study of elastomer theory, but I had bright blue rubber and skin.11

  Young Lauterbur, with his typical desire to penetrate to the soul of nature, wanted to achieve a theoretical understanding of why rubber is rubber. It had been invented in the late nineteenth century by trial and error, and in the 1950s knowledge of both natural and synthetic rubber’s properties was still empirically determined. The chemical reactions of vulcanization, the process that makes latex into rubber, were not understood. For Paul, understanding the mechanism of vulcanization was the primary goal, because it could lead to greater understanding of polymer behavior in general. For his mentor, Earl Warrick, and the Dow Corning Corporation, the primary goal was practical: to improve synthetic rubbers. Although most of the results were proprietary, this early work resulted in Paul’s first publication.12

  One’s first appearance in print is a happy milestone in a scientist’s career, but Paul’s disappointment in the failure of his academic goal lies behind the lines of prosaic print. He had succeeded in providing some practical information on the reaction of fillers with polymers of synthetic rubbers, but there is no evidence that the work made much difference in the field. It did provide background information for a patent taken out by Warrick and others. (By company policy, junior members of the team were not included on a patent, even if their contributions were the key to success.) Paul was amused at the wording of the patent; it included priority rights on the platinum thiocyanine Paul had used. Given the very high price of platinum, “The tire would be more expensive than the car.” I wonder how he would have felt had he known that the problems he was working on still are not fully resolved some sixty years later.

  It was also Paul’s duty to participate in the drudgery of maintaining a high vacuum on a vacuum distillation line. (Use of a vacuum decreases the heat required for separating components of a mixture in solution.) He and his friends would joke that they were “pumping in the vacuum” to maintain the line’s subatmospheric pressure. This worried Earl Warrick, who would furrow his brow and inquire with great seriousness and some anxiety, “You do know, of course, that you are pumping gas out of the system, and not pumping a vacuum in?” Because their boss and mentor so worried about this, the young guys referred to pumping vacuums all the more. To compound their mischievousness and their boss’s anxiety, they talked about letting vacuum out of the system once the distillation was complete.

  Warrick was the father of three daughters, of whom the eldest was Nancy, who, after they moved to Midland, Michigan, was a close childhood friend of mine. Nancy and I were in Girl Scouts together, and I played and had sleepovers at her house. One evening Dr. Warrick brought home a young man whom he introduced as a colleague from Pittsburgh who was working for a short while on a project in Midland. The colleague was a rather large young man with knobby knees, wearing Bermuda shorts, sandals, and very, very thick glasses. I was a shy twelve at the time and tried to respond to the introduction in a most adult way. But the colleague made a clever and sly joke that required a witty response I could not provide, so I ran away in embarrassment. I thought he was the most special, most awesome person I had ever met; his joke showed an intelligence that I had not known existed. Both Paul and I were guests at the Warrick home often in those times. I could never have guessed that more than two decades later we would meet again and marry.

  The Ground Floor of NMR

  It’s a lot of fun being in on the beginnings of a new field of scientific research. Everything is fresh. Everything is exciting. New information comes pouring in; understanding leaps ahead. And you know that you are making history, that the work you do now will be the foundation for the work of generations into the future. As Paul began his career as a research scientist, nuclear magnetic resonance (NMR) studies of molecules were that new and exciting field.

  Here is a reminder of how NMR works: Almost since atoms were first discovered (by a long birthing that occurred mainly in the latter half of the nineteenth century and early part of the twentieth), it was known that nuclei of many kinds of atoms, commonly hydrogen, are tiny magnets. They line up to some extent in the Earth’s low magnetic field, but the effect is much stronger, and they stand seriously at attention, if they are placed in a strong magnet. “Line up” is not quite precise; what they do is spin, somewhat like the diurnal revolution of Earth on its axis. And as they revolve, they circle, like a child’s toy top when it is set spinning. It is the axis of their spins that aligns with the magnetic field.

  In 1946, Felix Bloch, of Stanford University, and Edward Purcell, of the MIT Radiation Laboratory, independently learned that this circling, or precession, could be disturbed using electromagnetic waves and that the atoms would respond (resonate) with their own tiny electromagnetic signals. Excitingly, that tiny response reveals secrets about the internal structure of the atom itself. Bloch and Purcell, quite ama
zingly and coincidentally, and by approaching the problem in quite different ways, had discovered nuclear (having to do with the atomic nucleus) magnetic (requiring a magnetic field) resonance (the responses of nuclei in a magnetic field). Much of what is now known about nuclear physics was discovered or verified using NMR technology. These formidable scientists shared the Nobel Prize in 1952 for their discoveries.

  To this day, physicists use NMR to probe the internal structure of atoms. In the early days, the physicists had the technique all to themselves, happily measuring and interpreting the atomic spins and magnetic moments, which are different for each element. Then, in 1950, they learned to their shock that the spin frequency of an atomic nucleus is not a single unique number13 but one that changes slightly according to chemical bonds. The rock of NMR, that each atom has a single, unique signal, was sundered. The physicists viewed this with the horror Newton might have felt had he found that the rate of fall depends on whether the apple is a Red Delicious or a Granny Smith.

  But then a few chemists caught on. Chemists aren’t interested in nuclear physics; when they use NMR they are taking advantage of the physicists’ deplorable finding that the magnetic signals are shifted slightly (the chemical shift) by nearby chemical bonds. The physicists’ problem was the chemists’ solution. The shift results from the proximity of other surrounding atoms, and so it can tell you, indirectly, about the structure of the molecules. This was great! Chemists now could burrow among the molecules by using magnetic fields. Lots of great new experiments were waiting, and a whole new theoretical context for NMR in chemistry had to be developed. And Paul was there, and young, as the study of molecules using NMR began to happen.

  There was an arrangement between the Mellon Institute and the University of Pittsburgh whereby fellows of the Institute had both student and faculty privileges at the university. This meant access to the library, permission to attend seminars and lectures, and use of the faculty lounges. To most people the best privilege was access to faculty-reserved football tickets. For Paul, the important thing was that he could take classes at the University of Pittsburgh for free. From Mellon, he climbed up the hill to Pitt’s Chemistry Department, where he took many, many courses. He led a double life, straddling the worlds of industry and academia; with this little extra effort he had it all. He would follow many other Mellon Institute fellows, including Earl Warrick, to earn a higher degree at the University of Pittsburgh in this way. Many student scientists more or less live in their laboratories, as Paul did at this time; it is a rite of passage. But Paul would always spend most of his time at work.

  Paul applied and was accepted to be the first student in a joint program between the Physics and Chemistry Departments at Pitt, having a mentor in physics and completing the chemistry PhD program. Paul’s interest in that program shows his early affinity for interdisciplinary research (or rather his refusal to recognize disciplinary boundaries), long before “interdisciplinary” became a scientific buzzword. He was to emphasize the importance of breaking disciplinary boundaries all of his life. As a graduate student Paul was required to give two class literature reports. As if to prove the great breadth of his intellectual awareness, one of these was on interstellar molecules (a subject that always interested him) and the other described the principles of NMR.

  Why NMR? It was something of an accident. Paul first became interested in a closely related technique, electron spin resonance (ESR). He believed that free radicals might be involved in the chemical reactions of vulcanization, just the kind of question for which ESR provides good answers. So he studied up on ESR, and while he was able to devise an appropriate ESR experiment, he had no access to ESR equipment and could not go forward. From ESR to NMR is a very small step: ESR involves magnetic resonance signals from electrons, and NMR involves magnetic resonance signals from atomic nuclei. A paper on NMR physics in polymers was published just as Paul was getting a grip on these technologies, and he realized that NMR might be even more useful than ESR in his own work on rubber, and in work on the chemistry of polymers in general. Decades later, he was to explore possibilities of using ESR, as well as NMR, in MRI.

  Fate called. During the 1952–53 academic year Herb Gutowsky, of the University of Illinois, gave a seminar at the Mellon Institute. Herb was one of the originators of molecular studies by NMR techniques, one of the handful of chemists who took up the field from its physicist founders in the late 1940s and early 1950s. He has been called the “father of NMR in chemistry.” Here is Charlie Slichter (a physicist and respected scientist in NMR) on Herb Gutowsky.

  Gutowsky and his students and collaborators made fundamental, pioneering discoveries in nuclear magnetic resonance (NMR). Their discoveries firmly established NMR as a major experimental tool in chemistry. Furthermore, Herb Gutowsky realized as early as 1950 that NMR would have a major impact in solving a wide range of structural and dynamics problems in chemistry, biochemistry, and material science. Indeed, many of the subfields of modern NMR spectroscopy can be traced to the original work by Gutowsky and coworkers.14

  At the Mellon, Gutowsky spoke about his laboratory’s efforts to measure the NMR properties of methanes. Methane is quite a simple little thing (CH4), and its hydrogen atoms can be substituted with some other atom or group. By systematically changing the substituents and looking at the chemical shift of the NMR signals of the substituted methanes, Gutowsky hoped to figure out the three-dimensional structure of the core methane itself. This was an important advance in chemistry and one of the first applications of NMR to chemical research. Here, thought Paul, was at last the ideal tool with which to develop clear insights into the difference between silicon and carbon chemistry!

  Paul wanted to know more. “I was very interested in how molecules are put together, and it looked like a much clearer way of solving chemistry problems than anything else I had heard of at that time.”15 At another time, he wrote, “Nuclear magnetic resonance fascinated me because of the clarity with which it apparently could reveal molecular structures and behaviors. And since I never cared to do things in a more complicated way than necessary, a method that presented the data in ways that seemed closely linked with a shortest possible chain of reasoning to certain features of molecular structure was extremely attractive.”16 Paul, with an audacity startling to himself (“he was a professor, and I was a mere college graduate”), suggested a collaboration to Gutowsky, in which Paul would synthesize substituted silanes (SH4) that were not available commercially, and on these Gutowsky’s laboratory would do the NMR spectroscopy. He and Gutowsky would then try to work out what the comparative data of the silicon and carbon compounds meant. Gutowsky agreed, and Paul browbeat Warrick into supporting his plans to synthesize the necessary compounds.

  Nothing came of it, however, because Paul was soon drafted. But the die was now cast, and Paul was hooked, fully appreciative of the potential usefulness of NMR in molecular studies. He was to become a member of the first cadre of chemists to use NMR for this purpose. Gutowsky’s lecture was the starter motor, or maybe the proximate trigger, for much of Paul’s future career. From 1956 to 2003, Paul published 319 papers that involved NMR techniques in one way or another. Only his first paper, on filler phenomena in silicone rubber, and his final papers, one in 2005 and a posthumous paper in 2008, relating to the origins of life, did not use, in some way, NMR technology.

  It began with the army.

  The War Machine: The NMR Spectrometer

  The United States was at war in Korea, and Paul’s time came to serve: “I continued working there at the Mellon Institute and doing a bit of work with Pitt when my draft board decided that that was enough. ‘You have been deferred as a student for long enough. If we aren’t careful, you’re going to get out of your military service.’” He had been at the Mellon Institute for two years. His first military assignment was to a tank battalion at Fort Knox, Kentucky, but, as Paul tells it, his bad eyesight and his graduate study both made him poor material for the regular army. He was then se
nt to the Scientific and Professional Personnel program at the Army Chemical Center in Edgewood, Maryland. Paul said the center was populated by misfits like himself, “including felons, illiterates, Harvard PhDs and pretty much anyone who was not fit for combat duty.” Their job was to develop the first “chemical weapons of mass destruction”—that is, chemical warfare agents that could kill rapidly and effectively by acting on the nervous system. He was sent to Fort Bragg, North Carolina, for minimal basic training, and, returning to Edgewood, began work on the development and toxicity of nerve gases.

  The army was trying to develop ways to block breathing and other muscular functions by agents (cholinesterase inhibitors) that could halt the transmission of impulses from nerve to muscle. Specifically, when Paul arrived, the Chemical Weapons Laboratory was interested in possible fluorine substitution of these ordinary organic molecules to produce more potent nerve gases—in this they were sadly mistaken. Paul and his young colleagues developed a deep disdain for the army chemists, who ordered them to put fluorine on cholinergic molecules, the molecules that transmit information from nerve to muscle. The general idea was that fluorine is nastier than other stuff, but there seemed to be no particular scientific plan. It is true that the fluorine atoms would increase the reactivity of the cholinergic molecules, but the molecules themselves were totally lacking in toxicity, and fluorine would not make them toxic. The whole project, said Paul “was irrational and silly.”

  Paul was amused by army culture. In preparation for an inspection by big brass, the scientists had to clear all lab benches of their equipment, dismantle and put away all of their working apparatus. All books were closed and put neatly onto bookshelves. Then they stood around in freshly cleaned and ironed white lab coats, supposedly examining various colored solutions, until the shining moment passed. There were not enough lab coats to go around, so a runner gathered up the coats from the floors the dignitary had passed and rushed them to the floors that were yet to be inspected.