Paul Lauterbur and the Invention of MRI

by M. Joan Dawson

  At first only specialists who could master the idiosyncrasies of the large and complicated instruments could do NMR. Commercial spectrometers, even with major improvements, were still large and unwieldy. The most significant obstacle to a real widespread acceptance of NMR was the fact that each spectrum had to be individually calibrated and even then was not very reliable, making duplication of data difficult. The now fabled Varian A-60, a spectrometer introduced in 1961, not only gave larger signals than previous systems but also benefited from many technological innovations.25 Paul’s original spectrometer, the one on which he had done most of his breakthrough early work, was obsolete. And the A-60 was the first system robust and easy enough for people outside a small NMR coterie to use. Now the whole chemical community woke up to the possibilities NMR created. The A-60 became the workhorse of organic chemistry laboratories around the world. Old-timers nostalgically reminisce about its virtues; they love the A-60 the way some people do their first car. Everyone who used the machine speaks of “the old A-60,” kind of saying, “This is what made me what I am.” Paul did his first MRI study using an A-60 spectrometer that is now on display in the lobby of the chemistry building at Stony Brook University.

  What Next?

  Paul chose his early projects based on what he found “fun and interesting.” He proved to be an outstanding young scientist and a sought-after speaker at conferences and as a faculty member. In one case, he gave a seminar at a university, only later realizing that it had been intended as a way to evaluate him as a candidate for a faculty position. As the senior faculty put together their offer to him they learned, with much embarrassment, that he had not yet obtained his PhD and was therefore not technically eligible for the position.

  That incident was something of a wake-up call. In 1962 Paul interrupted his fast-paced scientific achievement long enough to write and defend a dissertation. It had taken nine years. Now an earnest search for a new position took on new importance. Earl Warrick hoped to arrange a position for Paul at the Dow Corning Company’s headquarters in Midland, Michigan, since Dow Corning had decided in 1956 to consolidate all research and development in Midland. “You’ll get a nice fat industrial salary,” Earl argued, “and a chance to do some interesting stuff.” Paul never considered this seriously. He had often visited Midland and found a very controlled, tight little culture of time clocks and belly to the bench. He said, “There was a general understanding that reading and going off to the library were slacking,” and “The bosses maintained that if you work overtime it means that you aren’t efficient enough to get your work done during working hours, like trying to work overtime on an assembly line and mucking it up.” There were union matters that Paul despised. Even top managers had to punch time clocks when they went to meetings, a humiliation that Paul claimed made the union guys feel better. Earl was shocked when Paul chose academia. Not only were the wages lower but also, in Earl’s opinion, industrial research was the only place to be.

  For the first time in Paul’s life, his working relationships, not with his close colleagues but with the guys who called the shots in Midland, began to go dramatically wrong. And he did not understand why. He asked to go to an American Chemical Society meeting. A student should not do this; the initiative for such a privilege should come from above. He sat in on sales pitches for an NMR magnet—unusual for a student, he later realized, but it never occurred to him that he should not. He had some good reasons to think that life in an industrial laboratory would not suit him in the long run: “Misfits are less tolerated in industry than in academia. I knew I would be a misfit.”

  Clearly, Paul was never meant to be an industrial scientist. He just couldn’t take it seriously. He had always wanted to understand the depth of things, so at heart he was a basic and not an applied scientist. Although the industrial laboratory was good fun and an important part of Paul’s education, it could never have sustained him intellectually. The “academic” style of science, of basic, pure research, was frowned on in the Dow Corning research laboratories, Paul said. For example, he once tried to convince Earl Warrick to use statistical methods in designing experiments in order to obtain data more efficiently. Earl was more bemused than anything else. Paul called the methods then in use at the lab “catch as catch can.” Statistical methods were a hard sell because they might entail using combinations of reagents that one would not ordinarily put together, that could never result directly in a product. Art Berry, then assistant director of research at Dow Corning in Midland, once remarked to Paul, “That’s a very nice piece of academic-style research.” This was not intended, Paul perceived, as a compliment.

  There was tension between Paul’s instinct to learn the science of the systems he studied and the need of his company to develop commercial products. It is possible that his bosses considered the internationally renowned young scientist to be a cuckoo in their nest. The problems certainly lay in Paul’s orientation toward basic research in a lab where product development was paramount. And there was a certain churlishness; he did not take for granted what everyone else knew to be true.

  Inevitably, there was a showdown.

  Paul received an invitation to speak at a Faraday Society meeting in England. This is a very prestigious society and attendance is limited to invitees only, typically Nobel Prize winners and other scientists of their caliber. Graduate students are most definitely not ordinarily speakers at the Faraday Society meetings, and to Paul the honor was exceedingly exciting. But when he applied for permission to go, the company denied it. Maybe there were concerns about leak of proprietary information, but the issue ended as one of prideful, vengeful heavy-handedness. Knowing how ungracious it would appear for an American to turn down the invitation, Aksel Bothner-By, a respected NMR spectroscopist who worked for the administration of the Mellon Institute, intervened with his organization to arrange partial support for Paul. But Dow Corning still refused. Finally, Paul said he would take vacation time to make the trip and would pay his own expenses. This time he was told “No, and if you go it is insubordination and grounds for dismissal!” The big shots were making it clear that Dow Corning didn’t have the same values in science that Paul had. “Maybe I should move to a university,” thought he.

  Years later Paul remarked, “Imagine me trying to develop magnetic resonance imaging on the side while I worked in this kind of environment.” He settled on a position at the new State University of New York at Stony Brook (SUNY, now Stony Brook University). Francis Bonner, founding head of the Chemistry Department at Stony Brook, was after the best young chemists rather than following the more usual practice of trying to fill a particular niche within the study of chemistry. (“I just wanted the strongest department I could make.”) Bonner asked Paul, “Would you be content with an assistant professorship or do you demand associate professor? Thinking quickly, Paul replied, “associate.” Francis then used this demand to get him an associate professorship, and tenure soon after. At about this time, 1963, C. N. Yang, a Nobel laureate in physics from the Princeton Institute (where he had been a colleague of Albert Einstein), was recruited with great fanfare to the Physics Department at Stony Brook. So, in the traditional rivalry between the Departments of Physics and Chemistry, Bonner was often asked when Chemistry would get its own Nobel Prize winner. “We are growing them in situ,” he replied.

  And Paul said, “Off I went to do my silly things.”

  5

  The 1960s: Stony Brook, Stanford, and Spectrometers

  Scientific research is a very odd occupation.

  —John Rowan Wilson

  Paul left Pittsburgh in 1963 for the nascent chemistry faculty of Stony Brook. Shortly after Rose Mary followed, and their marriage ran into trouble. Rose Mary and Paul’s fifth wedding anniversary took place the day President Kennedy was shot. Rose Mary dates the beginning of her marriage problems and her illness from that time. Paul told her he had found a job on a new campus of the State University of New York, or SUNY, then located in Oyster Bay. S
he looked on the map: well, Oyster Bay was not Manhattan, where as a city girl she would have liked to live, but it was reasonably close to civilization. Then Paul said they would be going to Stony Brook because a new campus was being built there. She looked at the map again. Her finger kept moving east and east and east, past all the little towns and out into nothing. There she found Stony Brook.

  Rural life simply did not suit her. Paul tried to help. He called the Drama Department at Stony Brook and said he noticed they were doing Jean-Paul Sartre’s No Exit in the new community theater. His wife had just finished working on a production of No Exit in Pittsburgh. Did they need help? Yes, they did need someone with her experience.

  Rose Mary began to feel that Paul was married to his work and not to her. From their earliest times together, when Paul was working at the Mellon Institute, she was lonely for his company. This feeling was only magnified after the move to Stony Brook. They were living in parallel worlds, she thought. She had always known that they were “opposites,” but hoped that they would balance in some way. It never happened. They would go out to dinner, and she would expect to then take in a movie or some other entertainment. But no: Paul would drop her off and go back to the laboratory. Looking back, she feels she should have known much earlier that the marriage could not work. Did Paul love his lab more than his family? How could a man care more about incomprehensible science than about his family? And then the illness began to manifest.

  Rose Mary still had wonderful times during which she felt like superwoman. She was the life of the party; she could do no wrong; she needed no sleep. “I still miss my highs,” she told me years later. At first the cycles were more an inconvenience than anything else. But she became less and less able to function in the times between those glorious, exuberant dancing moods. And during the highs, she gradually found herself “doing crazy things.” She was diagnosed as having manic-depression, what we now call bipolar disorder. In the beginning the cycles were absolutely predictable: two weeks high, two weeks low, almost like a menstrual cycle. Maybe, she and her husband figured, she was suffering from postpartum depression. Rose Mary and Paul went first to an internist, then to an endocrinologist, and then to a psychiatrist. Because the cycles were monthly, the first efforts at treatment were hormonal. This strategy proved ineffective. The psychiatrist was not encouraging. He told Paul that people with such behavioral patterns wear out their caregivers. There were three periods of major illness, 1963–64, 1966–67, and 1970–72. At first Paul was very attentive and solicitous. He would look after the kids during her depressive episodes and make her breakfast.

  The second wave of severe illness was even worse than the first. A manic phase resulted in a full ninety days of sleeplessness. In the following depression she could not eat, had no appetite for food or life, and couldn’t get out of bed. Paul was again the perfect attendant, but while he cared for her tenderly, he just could not deal with her manic crises. At one point, without telling her husband, she went off to a conference in Allentown, Pennsylvania. “I was dancing and singing,” she said, “and people called Paul because I was acting so strangely.” Paul retrieved her and “I hid in a closet because I didn’t want to be with him. I went to N. Nassau Psychiatric hospital within a couple of days.” The family was in crisis, and Paul took the two children to his sister, who had five children of her own. To the end of his days, Paul felt guilty and embarrassed that he needed to impose on Margaret this way.

  Rose Mary’s doctor recommended shock therapy. She was frightened but desperate to get well, and agreed. Treatment began March 20, 1967. She remained two months in the hospital and underwent another thirteen shock treatments as an outpatient. She waited in a dreary, windowless room with a dozen other patients as, one by one, they disappeared into the treatment room. In the short term the treatments did clear her head and calm her. Either because of or in spite of her treatments, the disease went into remission later that year.

  Berkeley of the East

  Stony Brook University is now a world-class institution with a beautiful campus, but its birth pangs, dating from 1957, were severe. Things were still pretty chaotic when Paul arrived. On the north shore of Long Island, the charming seaside village of Stony Brook is set in a landscape of great natural beauty. This stood in stark contrast to the campuses of SUNY, of which Stony Brook as well as other public universities was a part. It was one of the largest public higher education systems in the country. At one point, SUNY had sixty-one separate units. Out of this gigantic organization, run by a gigantic state, often came gigantic mayhem. Yet, although much younger than universities such as Yale, Stanford, and Cornell, Stony Brook would be ranked among them by the time of its twenty-fifth anniversary in 1983. The phrase “Berkeley of the East” was an expression of the aspirations for Stony Brook.

  Figure 5.1

  View of the Stony Brook campus, 1964. Courtesy of the University Archives, Stony Brook University.

  Figure 5.2

  The new chemistry building at Stony Brook under construction. Courtesy of the University Archives, Stony Brook University.

  SUNY had a reputation for being stubborn and inflexible; or rather, the problems arose with the state legislature in Albany. Paul complained that negotiations with Hewlett Packard to provide Stony Brook with frequency counters took months. In the meantime, Hewlett Packard had begun to produce its next generation of frequency counters, which had advanced solid-state electronics in place of vacuum tubes. The new ones were less expensive to buy and maintain, but Albany dictated the old clunky ones, and Hewlett Packard had to reopen its old assembly line! Paul’s favorite story of a bureaucracy tying its own shoelaces together was the year when new calendars couldn’t be issued in January because the state government had been slow, very slow, to produce a new state budget. The calendars had to be stored in a warehouse until March, when they could be released.

  There was always an aura of learning around Paul, and always a stream of fresh ideas, an endless supply of intellectual questions. While at Stony Brook he continued to publish papers on aromatic and other classes of organic compounds. He continued his interest in heteronuclear NMR as the field grew, and continued to develop useful insights. He carried on studies of 13C, its chemical shift, and chemical shift anisotropies; these remained interesting and useful challenges. And he carried out studies of unusual inorganic complexes, and described a unique approach to dynamic nuclear measurements.

  A new excitement grew up around the way different isotopes of nuclei with different atomic weights would affect an NMR spectrum; so much might be learned from this about the structure of molecules. Paul began a series of studies of isotope effects on the spectra of nearby nuclei, first on 59Co (cobalt), then on a number of other nuclei in aqueous solutions. He said he was simply curious about what the spectrum of 59Co would look like because it was spread out over such a wide range. “It was a luxury I allowed myself at that time,” he told me, “doing stuff that wouldn’t get an instant IPO or grant funding. . . . I did a lot of other things in those days just for myself, just out of curiosity and not especially for publication.” He was able to overcome the broadening of 59Co resonances by clever choice of the cobalt compounds that were highly symmetrical, so field gradients canceled.

  Paul had created the spectrum of crystals of calcite while still at the Mellon Institute, measuring the effect of crystal orientation on the NMR signal.1 A magnetic resonator of the time informed me, “everyone knew about Paul’s calcite study.”

  Following the calcite study, Paul looked for other suitable nuclei. “Lead just kind of presented itself,” Doug Morris, a later student of Paul’s, remembers being told.2 207Pb has a relatively strong signal, and the dipolar broadening could be kept within bounds by using such compounds as wulfenite (PbMoO4), cerussite (PbCO3), and anglesite (PbSO4) because their naturally narrow lines, a result of their dilute lattices, were exactly what was needed to get a spectrum from a solid object. At first he tried to grow the crystals, but couldn’t get
enough material on which to do the NMR. So he went out and got a piece of wulfenite, familiar to geologists, and it worked very well.3 This was the first study of hydrogen chemical shift anisotropy of a single crystal.

  As so often happened to Paul’s imaginative ideas, the work was never properly published. Paul was dependent on two collaborators. One, the graduate student on the project, died of kidney disease before the work was completed. The other, an x-ray crystallographer from nearby Brookhaven National Laboratories, was working out the absolute crystallographic orientation, since the NMR data could not reveal the orientation of the hydroxyl groups with respect to the rest of the crystal. He died of cancer. As a result of these tragedies, Paul and his colleagues were never really given full credit.

  Figure 5.3

  The chemistry faculty at Stony Brook. Left to right: Professors Lauterbur, Friedman, Bonner, Haim, Wolfsberg, and Kosower. Courtesy of the University Archives, Stony Brook University.

  Studying the Molecules of Life

  “This guy works smart,” Doug Morris a young colleague of Paul’s, remembers being told by his PhD mentor, “and he has done a lot of things he doesn’t talk about.” New areas began to interest Paul during the mid-sixties, the most profound being the application of NMR to the structure and function of large biomolecules. The computer revolution was just beginning, packing power for signal analysis. Paul recognized that 13C NMR studies of the structure of biopolymers were becoming possible, and he began a series of 13C NMR spectroscopy of peptides and proteins.4 Paul eventually applied his skills to the use of 13C as a probe of the accessibility to solvent of various molecular groups in proteins, a technique that continues to be used for understanding their functions.5