Paul Lauterbur and the Invention of MRI

by M. Joan Dawson

  Paul tried to stress that the invention of MRI was not really about machinery at all. He put MRI into historical context, with an emphasis on how it drew from so many concepts buried in several different disciplines. Imaging became possible, he said, when the nature of matter became understood.

  Paul’s and Peter Mansfield’s official Nobel lectures were on Monday afternoon at the Karolinska Institute, the medical school and research facility that is one of the prize-awarding bodies. Student doorkeepers and ushers in traditional Swedish dress greeted us. Peter talked about his newest work on noise reduction during MRI examinations, and Paul gave a philosophical and historical account of how MRI came to be.

  The festivities took a week, with the ceremony being held on December 10, the anniversary of Alfred Nobel’s death.

  I had always imagined the Nobel ceremony to be an impressively gorgeous and grand affair. And so it is. We were all dressed in our finest and looking as elegant as we possibly could. Being basically not so very sophisticated and elegant people, we couldn’t always pull it off. But it didn’t matter. Everything was beautiful. It was the holiday season, the St. Lucia season, and we had all come together for the well-deserved honors to the laureates. Most of the men rented their tuxes. Many of the women, including my daughter and myself, had to quickly find the three evening gowns required, since we rarely have occasion for such finery. I was surprised and delighted by how well my eighteen-year-old daughter, ordinarily a Birkenstock type, took to elegance. She was just the right age to appreciate the fairy-tale experience of festivities in a medieval court, wearing her first off-the-shoulder long gown, dining with the king and queen, prince and princesses, dancing the night away at a royal palace ball, sipping champagne.

  In the magnificent hall, thousands of extraordinarily beautiful flowers lined the railings, the podium, and the staircases. The official tally is six thousand flowers and four thousand leaves of greenery sent by the city of San Remo, Italy, where Alfred Nobel spent his final years. The laureates descended the grand staircase to fanfare and took their seats. More fanfare and the royal family appeared. Then Professor Hans Ringertz, chairman of the Nobel Assembly at the Karolinska Institute, presented Paul. “Your discoveries of imaging with magnetic resonance have played a seminal role in the development of one of the most useful imaging modalities in medicine today. All indications are that it will be even more important in the future of both medical practice and research and, above all, for the patient.”

  Paul received his medal from the king, bowed, turned and bowed to the laureates, and then faced the audience for long applause. I thought it was exactly as it should be. And I thought about the hours and hours of hard work, the struggles, the setbacks and disappointments. I was glad he was still alive to see this day. I also wondered about the histories of the other seven laureates, who surely had overcome great hurdles as well.

  Figure 10.1

  The Nobel ceremony. Paul receiving his award from the king of Sweden.

  Paul explained in his official Nobel interview that the strongest memory he would take home with him from the Nobel festivities was the great pleasure he had in the dozen guests he had been able to invite, people whom, in some cases, he had not seen in many years, who had been very important in his early work, making it possible, encouraging him, collaborating with him. For me the best part of the whole Nobel experience was all the old friends who got in touch, some lost for years.

  The Medal

  From that 3:30 a.m. phone call in October, and continuing for some weeks after our return from Stockholm, we lived in mild euphoria, at least I did, and most of our activities related in some way to the Nobel Prize.

  When we returned home, everyone needed to see the medal and its inscription to Paul, which was in my keeping. Thinking that nothing much could hurt gold, I tossed it to many shocked and frightened family members and friends. I carried it with us to Paul’s birthplace, Sidney, Ohio, when they held a Lauterbur Day and tossed it to the high school students who had gathered around Paul after his lecture to them. I was playing with our great awe and respect for Nobel Prizes and emphasizing that this medal, symbolically so important, was really only a little bit of gold. The Nobel Foundation gave Paul three bronze replicas that look almost identical to the real one. Ake Alteus, deputy executive director for finance and accounting of the Nobel Foundation, put the real medal and a copy side by side and asked me if I could tell the difference. After much fussing and prompting I realized that the gold medal was the heavier one. So I played that game too, especially with children.

  One day I lost it. The medal, I mean. Very early, too. When we arrived home from Stockholm I did not immediately put Paul’s medal in the safe deposit box because I knew there would be many, many requests to see it. For some reason, I worried about theft. I decided to put the medal on a shelf, as a platform for displaying a small geode. Any thief, I reasoned, would not realize the value of something lying under a geode. When Elise’s friends visited one day and wanted to see the medal I retrieved it from under the geode, then went back to my cooking. A week later there was another request, I went to the geode and . . . no medal! I searched everywhere. I practically accused the girls of theft. I couldn’t sleep. I cried on the shoulders of friends to whom I confessed my guilt. I didn’t tell Paul for fear of his reaction and because I knew it had to be in the house.

  It was. On that busy day with guests for dinner I had not had time to replace the medal in its usual place and had shoved it under some work papers for safekeeping. I eventually found it when I got to work on that pile of papers, and breathed a huge sigh of relief. Paul never knew about my little drama.

  Richard Feynman considered refusing the Nobel Prize because the whole concept of prizes lacks purity. This is not a solitary story. The prizewinner in economics in 2003 told us that when his wife called his mother to tell her the news, the response was, “Don’t let it go to his head!” They were trying hard to avoid what the novelist John Gardner called the “suckerdom of fame.”2 And thus it passed with Paul. “I knew I was a celebrity,” he quipped, “when I began getting more real email than spam.” An interviewer reported, “Asking Lauterbur to talk about winning a Nobel Prize, and the work that led up to it, is not unlike asking a new grandparent to see the latest photos.”3 “What is next for you?” asked Marsha Lynn Bragg of Case Magazine. “I’m trying to keep my head amidst the temptations of empty celebrity and getting on with life.”4 He asked me to remove all honors and awards from his office. He would not think of himself in the past tense. What mattered was the work he was doing now.

  Figure 10.2

  Paul at work.

  In the days following the Nobel, even more than before, Paul was asked to describe the next big thing in MRI. His inevitable answer was to quote Niels Bohr: “Prediction is very difficult, especially about the future.” In one such lecture he pointed to his only slide, a blank screen. “This is what I know about the future,” he observed. But then he went on, in his naughty way, to describe a science fiction scenario in which NMR spectrometers learn to adjust their interrogation methods based on the differential diagnosis to be made and on the results of their initial findings.5

  Booting up the Biosphere

  Paul opened the last of his publications with this declaration:“We cannot understand biology if we do not understand how it could have begun. We cannot truly know chemistry if we cannot imagine how it could give rise to biology.”6 There are a few precedents for physicists or chemists turning to the question of life’s origin at the end of their careers. Physicist Erwin Schrödinger’s late-life monograph, What Is Life?, is one of them. Another was Linus Pauling. Where did they find the courage? It may help to be a Nobel laureate, as all three of these scientists were. Only life’s known existence makes it seem possible.

  Greg Girolami, then head of chemistry at the University of Illinois, noted about Paul, “He’s become interested in the chemistry behind the origin of life. Here is a person with a very successful caree
r who has decided in his mid-70s to change completely the research that he’s doing. That takes courage—that takes a lot of courage to do. But it also takes someone who’s amazingly creative, and that’s Paul.”7

  Paul had first asked himself questions about how the exuberance of life was set in motion before he was in middle school, maybe twelve years old. This led to his high school interest in carbon chemistry, and in silicon as an alternative to carbon in forming the building blocks of life. Many people believe we will never understand how the transition of biology from inanimate matter occurred (or could have occurred). Some, for philosophical or religious reasons, object to any attempt to understand those events in scientific terms. On the contrary, Paul always believed that the topic is suitable for ordinary scientific investigation. How could polymers have formed on the early Earth? How could the formation and chemistry of polymers have led to the organic polymers of life?

  Figure 10.3

  Paul used this cartoon in his talks on the origin of life. © ScienceCartoonsPlus.com. Reproduced by permission.

  Years earlier, at Stony Brook, Paul had taught a laboratory curriculum that touched on this subject. Everyone gets a little bored and weary toward the ragged end of the spring semester, and that is when his students repeated the exciting “Miller experiments.” Dr. Stanley Miller and Harold Urey made miniature thunderstorms. They pumped methane, ammonia and hydrogen, compounds that are known to have been present in the early atmosphere, before life began, in water vapor in a flask, to which they attached two electrodes. The electricity simulated lightning. After several days of lightning strikes, Miller and Urey analyzed the solution and found that the flask now contained small molecules that are fundamental to life, including amino acids and sugars. The world now knew how the small organic building blocks of life might have been formed on the prebiotic Earth.

  And Here a Miracle Happens

  Paul had been stewing about the so-called prebiotic stew for some time when he finally got the chance to fully explain his theories to me. We were sitting on a cushy sofa in the lobby of a hotel in Washington, D.C., having cocktails. The occasion was a meeting of the heads of the NSF Centers. Here we were often interrupted, as we so often were, by friends, acquaintances and various people who simply wanted to chatter at Paul. Paul enjoyed these pleasant greetings, but it made serious talk difficult. While recreating the Miller experiment with his Stony Brook students thirty years ago, Paul told me, he was struck by the amount of polymorphous material, gunk that had come out of the solution and adhered to the walls of the flask. At the end of a Miller experiment, only about 15% of the original carbon and nitrogen remains in the solution, so the gunk is 85% of the starting material. This had been pointed out in the original Miller-Urey paper as some kind of waste product, and nothing was made of it, not by Miller or by anyone since. Paul wondered what information might be hidden in the gunk.

  “Matter has a compulsive tendency to organize itself into complex structures” was Paul’s theme that evening. The universe, galaxies, stars, and planets were created out of uniformity. Atmospheres, seas, crusts and cores, scums and cruds, ores and layers condensed from planetary gasses. Purity is rare in nature. From simple molecules, as in the Miller experiments, to vesicles and membrane-bound structures, to entire planets and biospheres, uniformity and randomness are the exception rather than the rule. “It is hard to imagine that life would not originate under these circumstances!” said he. “Life may be a nearly inevitable stage in the maturing of chemistry on Earth and probably elsewhere as well.”

  The ideas Paul was explaining that evening were elegant (the highest praise a scientist can give an idea) and awe-inspiring. Paul had come across a reference in Chemical & Engineering News to the use of imprinted chemically active sites in surfaces of long polymers. These imprints are made when impurities in a matrix diffuse out, leaving behind sites with specific binding and catalytic properties. Chemists were now studying these “molecular imprint sites,” but had not linked them to the origin of biology. In an “aha” moment, Paul realized that molecular imprints offer an ideal mechanism for building the reproducing polymeric precursors of life step by step from small molecules.

  He had identified a role for the Miller gunk.

  Figure 10.4

  Paul always liked this cartoon. He referred to the miracle as people’s attitudes toward the origin of life. © ScienceCartoonsPlus.com. Reproduced by permission.

  Paul told me that in current studies of the origins of life, an assumption seemed to be made that biology began as a self-perpetuating system of molecules. “But what came before?” he asked. “Was it originally a protein world? An RNA world? Where did the first self-replicating macromolecules originate? As an uneaten sandwich from outer space? Or was there some unnamed supernatural influence that cannot be studied?” The key to biology, Paul amplified in a published paper, is that solid usually condenses not in crystalline form but as an amorphous substance, sometimes called a multimer, that traps impurities.8 These multimers are usually regarded as uninteresting and intractable by-products, and not well characterized if even analyzed.

  But the multimers contain reversible binding sites, tiny cavities into which molecules in a solution nicely fit, a large percentage of which are near the surface. Molecules make burrows in this stuff, and then wiggle out and other, similar molecules can wiggle in. This is the same process used by thin-layer chromatography, which separates, or unmixes, specific molecules. And because the multimers are not crystalline, molecules from solution find themselves absorbed into hospitable sites, and the conformation of the surface around them changes, sometimes to fit and catalyze the formation dimers. And from dimers the process advances, to produce trimers, quatromers, and so on.

  These imprint sites act as “nanoreactors.” And all of these molecules could self-replicate on appropriate molecular imprint sites, and could become themselves imprint sites, similar to but far less efficient than modern RNA and DNA. Membranes tend to form spontaneously and to trap large molecules within self-formed vesicles. From this physics and chemistry and eons of time, a self-replicating cellular protolife would be built and, by Darwinian-like selection, refined into life as we know it today. With the addition of a proto-evolution—that is, survival of those molecules most fit to self-replicate—they become self-reproductive. This begins to look a lot like life.

  Paul went on to develop an overall model for “the spontaneous development of biology from chemistry.”9 And it is very simple, just as MRI is very simple once explained. It is elegant and efficient, with no more than it needs to do its job. It is testable; it confronts life’s strangeness.

  One never knows, Paul said, but I feel that I’ve now got the right approach. In a grant application, “Fire, Ice and Life: Spontaneous Transformations of Chemistry,” whose poetry must have confounded reviewers, Paul wrote,

  Fire, ignited by a sufficient spark, proceeds spontaneously but irreversibly. Ice, nucleated by a particle or a bubble, can reversibly solidify a whole mass below its melting point. Life, perhaps starting from a matrix defect, can generate a biology by molecular replication. All express, not a unique force, but the full development of one of the innate tendencies of molecular matter, and an aspect of thermodynamics and kinetics rooted in the atomic nature of matter, with structure arising from atomic repulsions and directed bonds, and powered by the rearrangement of the matrix and of the reactant molecules.10

  The End

  But just as Paul’s new research into these questions was beginning in earnest, his illnesses worsened. We both knew he didn’t have much time left. In the summer of 2004, when Paul was seventy-five, we made a trip to Germany to take part in the centennial celebration of Einstein’s annus mirabilis, and then on to a Nobel conference in Lindeau, on the shores of der Boden See. Paul always recovered remarkably well from jet lag after long travel. This time he did not. He was not well in Berlin. A wheelchair was needed to get Paul to the beautiful summer home that Einstein had designed for his
family. By the time we reached Lindeau, Paul could hardly leave this chair. He insisted on taking part in the meeting and giving his talk, although he could not stand up for its delivery. I wondered what this strange illness was, and when he would recover. A local doctor was not very helpful.

  When we returned home I called Paul’s physician, and Paul was hospitalized that day. His kidneys were failing, and we were told he needed dialysis. Paul said no. I studied and found the latest methods, which looked to me relatively easy. I was persuaded that this treatment was not one of the heroic measures that Paul had always refused. Paul disagreed. I tried logic; Paul wouldn’t accept its validity. I tried tears. He was moved, but unmoving. I got angry. “Why are you leaving me! Don’t you care about me?” He didn’t listen. Then I brought out the big guns, his children. All three did what they could to change his mind. Elise cried. Paul had never before refused her anything.

  When they failed, I surrendered. We would enjoy what time was remaining to us. It was far longer than predicted, another two years and nine months. We had good times, we watched with pleasure our daughter’s maturation, and Paul continued to be scientifically productive. He occasionally reviewed his decision about dialysis and each time came to the same conclusion.