Paul Lauterbur and the Invention of MRI

by M. Joan Dawson

  Figure 3.4

  In the early days, Dow Corning’s product development was somewhat similar to this. © 1984 The New Yorker Magazine, Inc. Reproduced by permission.

  Paul says he learned many useful things during his army career, such as how to capture goats in a field when they didn’t want to be captured, how to weigh pigs without being bitten, and how to negotiate army red tape. But as a scientist, he was on his own. “Some [of us] had been drafted in the middle of graduate school, so we worked in the army laboratories where our nominal superiors were civil servants who in general did not have modern training and experience because they had been hired some years before.”17

  Soon after he arrived, Paul learned from another soldier that a nearby laboratory was to acquire an NMR spectrometer, although no one in that unit knew anything about operating one. Apparently the laboratory happened to have unspent in the budget at the end of the fiscal year just enough money to buy one. “Having leftover money in a Government budget is not something to be taken lightly, as generally you will have that much cut out of next year’s budget. So there was an urgent need to spend it in a hurry, and they spent it all on an NMR machine.”18 Paul was able to wangle a transfer to this unit on the strength of his knowledge of NMR (“I could actually pronounce ‘nuclear magnetic resonance’ so I became the base expert.”)

  Francis Bonner, later Paul’s department chairman, tells the story this way: “He was in the Army when an NMR instrument arrived on base. Nobody knew anything about it, so he and another Army chemist opened it up and figured how it worked.”19 Officially certified an expert on the subject, Paul hastily studied up. He helped set up the new lab, and, when part of the equipment turned out to be defective and had to be sent back to the manufacturer, Paul went to the Johns Hopkins University library to read all of the NMR literature, “at that time consisting almost entirely of work by physicists on the magnetic moments of nuclei and adding up to perhaps 400 references on punch cards.”20 He enjoyed this project very much, both for the new knowledge and because “in those days the technology of needles and punch cards was fascinating.”

  Paul spent the remainder of his army duty cohabitating with that NMR machine. This was larger, noisier, hotter, and heavier than the current sleek machines and used a big rack of vacuum tubes. He was among a small number of scientists who had access to NMR equipment, and the army had purchased the very best new machine (costing the equivalent of $10 million or more in today’s dollars).21 Paul was able to get his old high school buddy, Marlan Shepard, who had also just been drafted, into the unit as well, so they could work together. Norbert Muller, a Harvard PhD in physical chemistry and later a professor at Purdue for many years, was part of the group. Paul regards the second-hand scraps of a Harvard education, especially the attitudes, that he received from Muller to be an important part of his own education. After setting up the new instrument, Paul and his young colleagues had the unusual opportunity to carry out some publishable work. In addition to the regulation shaved head and classified work on biological testing of chemical warfare agents and studies on aerosols, Paul was co-author on four basic scientific papers (“which is more than you usually get out of service in the Army”), all published after he was mustered out of the military service but reporting experimental work he had done during that period.22 These papers pioneered the use of NMR to study chemical problems and are of some historical interest.

  With five other soldier buddies Paul bought an old forty-three-foot fishing boat and moored her on the Gunpowder River that opens into Chesapeake Bay. Her name was Oriole. They went out on weekends, fishing a little and drinking beer a lot. She cost each of the guys three months’ salary plus the costs of refurbishing her. One time their helmsman lost attention and nearly collided with a large sailboat. “All I can see is sails!” he yelled. (Imagine what the true sailors had to say about a motorboat nearly running them down!) They were jubilant when they brought Oriole safely through a wild hailstorm that blew buildings naked of roof and window and boats off the water. Playtime ended when the gallant Oriole sank in Hurricane Hazel.

  In time, Paul became the expert in NMR that he’d been taken for in the beginning. He was one of the very few people who could use the newfangled NMR technique at all, giving him a great advantage over more conventionally trained chemists. In the early 1950s, most chemists didn’t know much about what could be done with NMR. It would be another decade before books appeared showing how NMR could be used for studying molecular structure. A new scientific field was birthing, and with it, Paul’s career.

  4

  Early Breakthroughs

  The works of God are not like the Tricks of Jugglers or the Pageants that entertain Princes.

  —Robert Boyle

  Over the years, Paul received many awards and honors for his scientific work, almost all of them for his invention of magnetic resonance imaging in 1971. But some awards cite much earlier work, calling him “truly the father of heteronuclear NMR.” These were especially gratifying, because they acknowledge Paul’s early and lasting accomplishments in pure chemical sciences, the field of his training, allegiance, and the first twenty-odd years of his scientific career. Though indirect, this work may have been even more important than MRI.

  Why? NMR signals, the “Hello, I’m here!” resonance responses to electromagnetic interrogation, are especially large for hydrogen and fluorine, and most scientists believed that only these could yield useful chemical data. The NMR technologies of this world, including almost all MRI, use hydrogen, or proton NMR. (The two terms are interchangeable for the simple reason that the nucleus of the abundant hydrogen atom is a single proton.) Nearly all the world’s NMR expertise to this day is grounded in proton NMR. Almost all of the hardware, software, and ancillary technologies are geared to this nucleus. The reason is simple: protons, the tiniest of nuclei, have the largest NMR signals, and are the easiest to find and measure. But the signals from other nuclei have a great deal to tell us. And it was Paul, looking for problems at the fringes no one had associated with magnetic probes, who led the way.

  During the 1950s and 1960s, Paul and others showed that meaningful heteronuclei, those with “I am here” signals much smaller than those of 1H and 19F, could be studied. Modern analytic chemistry and biology would be dwarfed and deformed without heteronuclear NMR. The benefits to medicine are growing. Signals from these nuclei vary from being just a little smaller than that of hydrogen (e.g., 31P at 6.6%) to being a very tiny fraction of it (57Fe has a relative sensitivity of 3.4 × 10–5, or 0.0034%). In addition to this relative sensitivity of a nucleus, its ease of detection depends on its natural abundance, the percentage of all the atoms of a particular element that can produce NMR signals. All fluorine is 19F, so all fluorine atoms in the universe have magnetic signals. Only about 2% of the iron on Earth is 57Fe; the other isotopes of iron are invisible to magnetic resonance techniques. The multiplication of sensitivity and abundance causes huge differences in the detectability of different elements.1 The smaller the signal, the harder to locate, so signals from non-hydrogen nuclei are slightly to extremely more difficult to find and measure than hydrogen.

  There is a big reward for capturing heteronuclear signals. Deducing the character of a molecule from its NMR signals is like doing a jigsaw puzzle, except in NMR you have to create as well as arrange the pieces. Hydrogen NMR gives you a lot of the pieces, but still leaves great holes in the puzzle. Often the larger nuclei are the backbone, and the hydrogen is the decoration of a molecule. So a view of a molecule from the perspective of these larger and less sensitive nuclei can fill in a lot of the picture. The writers of the citations designating Paul as the “father of heteronuclear NMR” were knowledgeable chemists who understood the impact of Paul’s early research. The citations acknowledged Paul for showing that NMR signals could be obtained from nuclei that were previously thought—assumed, really—to be just too small and too difficult. It’s the kind of thing Paul liked to do. He did the calculations, com
pared the theoretical size of signals to the capability of the NMR instruments, saw that it was a stretch but not impossible to detect and measure some of the weaker heteronuclei, and did the experiments. He was positively gleeful to find a project that was very important and challenging, and theoretically possible, but feasible only with cleverness.

  To be picky, there are many fathers (no mothers that I know of) of heteronuclear NMR, including the first physicists who used NMR to probe atomic structure. So Paul may have been the father of heteronuclear NMR in chemistry. Other NMR spectroscopists quickly caught the challenge and were not far behind him. As always, illumination of one scientist’s success leaves the work of others in darkness. But Paul was certainly the single person who did the most, on the most nuclei, of the early heteronuclear NMR. In doing so, he showed to other chemists that a small number of parameters define the NMR spectrum of a molecule and, as the physicist Charlie Slichter said, “There is a law involved.”

  “My Own PhD Adviser”

  One might predict the direction of the next two decades of Paul’s work by looking at what he and his colleagues accomplished while in the army: all that heteronuclear work, isotope exchange, and analysis of complex data. But the really exciting stuff was launched when he was discharged, in 1955. He was twenty-six years old. He needed first to decide whether to return to the Mellon Institute or to enter a full-time graduate school. Paul thought seriously of applying to the University of Illinois, where Herb Gutowsky, whose seminar had impressed him so much, was creating excitement in molecular NMR. But when Paul’s old group (Dow Corning) at the Mellon Institute offered to buy an NMR spectrometer for his use, Paul’s decision became easy.

  Herb Gutowsky worked with and mentored many excellent scientists, but Paul was not one of them. Would their different kinds of creativity have gotten in each other’s way, or would a synergy have developed, leading to even greater scientific progress? Charlie Slichter thinks it could have been pretty exciting if they had worked together. Paul told me he didn’t think it would have gone too well. After spending years in the army directing his own research he might not have taken well to supervision and to carrying out someone else’s research plans. Paul had never had a mentor and wasn’t about to need one now. As he put it, “At that time you could throw a dart at the periodic table and find an interesting problem to study.” He figured he could do attractive things on his own.

  So Paul rejoined his old group at the Mellon and signed up for PhD studies at the University of Pittsburgh. At UP, he joined the laboratory of Christopher Dean, a physics PhD from Harvard, to study a new NMR method as a potential probe of molecular structure.2 It didn’t go well because of their different styles, but Paul learned a lot about tricky electronic equipment. Dean soon lost interest and left the university. By this time Paul had developed other research interests as well. He said in interviews, “Since no one else was interested in the work I was doing, there I was, cast on my own.” Henry Frank, then head of the Department of Chemistry and an expert in the molecular structure of water, agreed to serve as the adviser of record and allow Paul to continue his studies without an active mentor. “I was my own PhD adviser,” Paul said. During this important professional period, Paul’s personal life was also taking shape.

  Rose Mary’s Story

  Garry Barnes didn’t know he would be a matchmaker that day. Garry was Paul’s friend at Case and, like Paul, began his first job at the Mellon Institute. Garry belonged to a singles social group, the Jefferson Club, at the Unitarian Church, and invited his friend to accompany him on one of the club’s camping trips. He also gave a lift to Rose Mary Caputo, a continuity writer and traffic manager at a local television station. Paul and Rose Mary rode a long way sitting next to each other. Rose Mary was smitten by Paul’s entertaining wit and by his character; he was obviously a polite and gracious man, he would be kind. (Twenty-odd years later, my first impressions would be much the same.)

  Rose Mary was supposed to be with another man that weekend and, as a young single woman must do, was carefully arranging her activities to be unobtrusively near Paul as much as possible. The second date was a hayride, and Rose Mary kidded that she wanted a ham sandwich. Out from the hay came a ham sandwich. The courtship was charmed.

  Soon, with old-fashioned gallantry, Paul asked Rose Mary’s father for her hand in marriage. Dad said no, this is the modern world and the kids decide. They were married in the Unitarian minister’s study in 1959 with twelve people in attendance, including Garry and his wife, who was maid of honor. No one from Paul’s family was there, since marriage outside the Catholic Church was not legitimate. His parents disowned him for this transgression in a letter that began, “When Joe died we pinned all of our hopes on you.” Rose Mary’s father commented that Paul must be very sad that his family was not present. Paul responded, “We will make our own family.”

  The wedding pictures tell their stories. Paul is strong, Germanic, and masculine, looking even a bit dour as they cut the wedding cake. Rose Mary is beautifully feminine and Italian, laughing with voluble joy. They looked as much alike as a kitten and a great black bear. Marriage changed neither of them. Paul was always quiet, even taciturn. Rose Mary was garrulous. Paul was a scientist and science was his life. Rose Mary knew nothing about science. “I used to type his papers,” she says. “All I could understand were the ifs, ands, and commas.” Her mind ran to the arts, especially theater. Rose Mary believed that their individual differences were complementary and would make a strong marriage bond. And anyway, she thought she could change him into a more open and demonstrative person. (Not so, she mused years later; she became more like him.)

  They settled down in a student-rented apartment, where they decorated one wall with burlap to cover the hole in the plaster. There had been no honeymoon vacation, but they continued their romantic love affair. Paul always kept 3 × 5 cards in his shirt pocket for hurried notes. He wrote loving messages to Rose Mary on those cards nearly every day.

  Rose Mary was involved in the community theater when they met, and she continued her thespian interest after their marriage. Paul encouraged her and tried to share in this side of her life. The theater company was liberal and progressive, attitudes Paul shared. It was interracial in the 1950s, well before the changes wrought by the civil rights movement. Paul went to rehearsals and he enjoyed the company’s cast parties. But while Paul found Rose Mary’s actor friends interesting, it was clear that he could not be a part of their social circle. He was entertained, but tended to watch and study more than be involved. Paul never learned to share their camaraderie. Rose Mary’s friends found Paul to be polite but a spirit from another world, ghostly and unfathomable. He was uncomfortable, and they decided he was stuck up. Paul may have been just a mite intimidating, with his educational and scientific credentials, his commanding vocabulary and apparent erudition. They didn’t get his jokes.

  Rose Mary knew from the beginning that his work was important. She knew this because people kept calling Paul “Doctor Lauterbur” even before he had a PhD. And he was, more than anything else, a conscientious scientist. He would come home from work, have dinner, and go straight to his study for the evening. She could not even begin to attempt to share this part of his existence. In fact, she could hardly guess at its meaning. She tried to accommodate herself to this solitary aspect of her husband but, nevertheless, began to feel neglected. Because Paul was away even when he was at home, Rose Mary looked to the theater more and more for her social interactions. She told the director that she saw more of him than of her husband. She marveled that “he would tell me these things” when they were lying in bed, he with his 3 × 5 cards. He might shout out “I’ve got it!,” and she would know there had been a creative breakthrough.

  Their first child, Danny, was born in 1961. Sharyn followed two years later. The rupture between Paul and his own parents was mended temporarily with the birth of the children. They sent a wedding gift two years late. From then on, Rose Mary says, “Gertrude
was wonderful to me.” They were in constant correspondence. There were yearly trips west, to visit Rose Mary’s family and on to Ohio to visit Paul’s. For Paul these family duties were not much fun, although he did get along well with Rose Mary’s father, who much admired the “brilliant scientist.” There are lovely pictures of Dan and Sharyn with their stately Lauterbur grandmother and dignified grandfather. The grandparents secretly whisked the children away for baptism in the Catholic Church, so their souls could be saved.

  The Battle of the Technologies

  All NMR spectroscopists of the 1950s (the “magnetic resonators”) were scientific pioneers, who plunged off the established and familiar course to break new ground. Established and familiar at the time were infrared (IR) spectroscopy and mass spectrometry. IR spectroscopy was the technique that could most directly examine molecular structure.3 It had become the organic chemist’s most important tool. The Dow Corning scientists were aware of the few chemists, including the young and successful Herb Gutowsky of the University of Illinois and the highly respected Rex Richards of Oxford University. who turned from IR to NMR at this time. Both Gutowsky and Richards entered the NMR field fresh from PhD studies using IR spectroscopy. They bet their careers on the magnificent new opportunities in NMR.

  Soon other scientists saw the value of NMR. Russell Varian founded the first NMR company to manufacture commercial spectrometers. Varian Associates was an original Silicon Valley start-up, one of a few new little companies just poking up on the Camino Real. There, Jim Schoolery worked to provide exactly the tools that would make NMR the new IR. The world was moving on, and Dow Corning wanted to be in on the ride. Bill Collings, director of silicon research and development at Dow Corning, had been deeply involved in making IR what it had become. Earl Warrick, Paul’s immediate supervisor, had spent a lifetime synthesizing silicon compounds and studying them using IR spectroscopy. Both Earl and Bill had made much of their scientific reputation using IR, and they had no intention of being left behind by NMR.