The Nobel Prize in Physiology or Medicine 2003
Paul C. Lauterbur, Sir Peter Mansfield
Paul Lauterbur's quest to develop a medical imaging tool that worked using magnetism succeeded through a mixture of accidental meetings, detours and dogged persistence.
"All detours should be so productive!" cried Paul Lauterbur at the end of his Nobel Lecture. Lauterbur found himself changing course from chemistry to medical imaging, but thanks to a series of unexpected events the detour was one that lasted almost thirty years, and culminated in a Nobel Prize in Medicine for his discovery of magnetic resonance imaging, or MRI.
In May 1971, Lauterbur was a professor of chemistry at the State University of New York in Stony Brook. Some years before, Lauterbur had joined the board of directors of a company based near Pittsburgh called NMR Specialties that sold and leased state-of-the-art nucleic magnetic resonance (NMR) spectrometers to academic institutions and companies. The company suddenly found itself facing bankruptcy because of some very dubious business practices, and during a hastily arranged Board meeting the firm's bank denied any further support unless a trusted person could lead the company out of the crisis.
Lauterbur was offered the position because, as he later revealed: "I was the only academic on the Board, the semester had just ended, and the others believed that I was free for the summer." This explanation belied the fact that Lauterbur was one of the foremost specialists in NMR spectroscopy. NMR spectroscopy, discovered by Felix Bloch and Edward Purcell, and for which they received a Nobel Prize in 1952, can identify the composition of chemicals in liquids and solids by virtue of the fact that the nuclei of atoms behave like spinning gyroscopes and are weakly magnetic. Bloch and Purcell discovered that when these subatomic spinning tops are exposed to a strong magnetic field and are bombarded by radio waves, the nuclei emit radio waves in a manner that reveals their identity.
A chance encounter in 1971 set off a chain of experiments that would move NMR spectroscopy from a tool chemists use to solve structures to one that doctors could use to create detailed images of internal organs. Leon Saryan, a post-doc from Johns Hopkins University, was visiting the company while Lauterbur happened to be on site. Saryan was looking to reproduce some exciting data that Raymond Damadian had collected at NMR Specialties the year before.
Damadian, a medical doctor from the State University of New York in Brooklyn, had published studies in the journal Science showing that the NMR signals from cancerous rat tissues are significantly different than the signals from healthy rat tissues. NMR spectroscopy is used mainly to detect hydrogen atoms in a molecule, and because cells contain a high proportion of water Damadian was investigating whether the technique could detect tumours, by virtue of the fact that the water content in tumour cells is different from normal cells.
Lauterbur was impressed by Saryan's successful reproduction of Damadian's data. The way in which Saryan had to get this data, however, shocked Lauterbur. As a chemist he was not used to seeing animal experiments, and he found the way in which the rats were sacrificed and dissected to study their tissues by NMR "rather distasteful". It should be possible to get the same information non-invasively from outside a living body, thought Lauterbur.
Lauterbur pondered this question as he walked out of the company premises that evening to have a hamburger at a nearby stand. He started thinking step-by-step about how he could create images using NMR.
Images require spatial resolution, so there needs to be a distinguishable difference between neighbouring elements of an object to make them visible. Normally chemists go to great pains to create as uniform a magnetic field as they possibly can, as this produces the clearest, sharpest NMR signal from their samples. But the animal experiments showed that different tissues turn uniform magnetic fields into a number of different local fields, which consequently fire out radio signals at different frequencies. So why not use a variable or non-uniform magnetic field from the start? After all, researchers knew the frequency at which nuclei resonate with radio waves is directly proportional to the strength of the applied magnetic field, and this strength determines the resulting NMR signal. Why not introduce variations, or gradients, into the magnetic field to tag each hydrogen nucleus with its own magnetic coordinates? Different parts of an object would emit radio waves of different frequencies, and somehow tracking and measuring this could provide positional information that could be used to build an image of the way in which the molecules are arranged.
In other words Lauterbur realized that the blurry signals from non-uniform magnetic fields that chemists normally try to avoid could contain hidden and valuable information about the spatial distribution of molecules. On a paper napkin, he scribbled down some notes, and these ideas, conceived between bites of a hamburger, enabled the birth of magnetic resonance imaging.
Lauterbur returned to his university for the fall semester, as a colleague took over company responsibilities, and he began to test his ideas. At night time, Lauterbur would use the best NMR machine on the campus, located in the chemistry department, and carefully restore the settings each time before he left.
The system Lauterbur created seems far removed from the sleek, automated MRI scanners that we are used to seeing today. In 1971 computer power was not advanced enough, so Lauterbur had to invent a hand-written procedure that could convert the NMR signals into a magnetic resonance image. Slowly but surely, Lauterbur arrived at a solution he called "back-projection imaging", which allowed him to introduce variations, or gradients, into the magnetic field. In the back-projection technique, a magnetic field gradient is applied at several defined angles around an object, and the NMR spectrum recorded. A second set of signals are then recorded at specific variations to the original angles. Superimposing the data from these multiple projections on paper with the help of algorithms allowed Lauterbur to reconstruct the image in the form of two-dimensional ‘slices'.
Today, back-projection imaging has been superseded by the two-dimensional Fourier transformations that Richard Ernst (Nobel Laureate 1991) introduced into NMR later in the 1970s, but at the time Lauterbur's method was the key to solving the imaging problem. Among the first images that Lauterbur made using this method were of tubes of heavy water in a beaker of ordinary water. No other imaging technique at the time could distinguish heavy water, which contains deuterium atoms – that is hydrogen atoms with an extra neutron – from the normal version of water.
Lauterbur submitted a paper to the journal Nature outlining his discovery – which he gave the rather grand name of zeumatography, from the Greek word zeugma, or yoke, to signify the fact that the technique links chemical and spatial information. The paper was rejected by the editors, mainly because they were unconvinced by the fuzziness of the images. Lauterbur, convinced of his concept, appealed to the editors, who eventually accepted a revised version of the paper, which included references to cancer and other potential medical applications.
"Almost thirty years later Nature publicly celebrated its appearance there," said Lauterbur, who would also later remark that "You could write the entire history of science in the last 50 years in terms of papers rejected by Science or Nature."
Nature's hesitance in publishing Lauterbur's breakthrough results may seem baffling in retrospect, but when put in context is perhaps not that surprising. In the mid 1970s, radiologists were feverishly embracing another imaging tool that they had also been sceptical of at first, computed tomography, which combines multiple X-ray images to produce two-dimensional images of the body's organs. The idea that a tool used to identify the chemical structures of compounds in solution could also create similar images to CT scans was met with scepticism by radiologists and with indifference by most NMR researchers.
One laboratory that thought otherwise was based at the University of Nottingham in England. From there came the second cornerstone to build the edifice of modern MRI. Peter Mansfield, a professor of physics at the university, developed new techniques to speed up the way in which the radio signals from nuclei are acquired and images formed. Mansfield's methods, known as echo-planar imaging and active magnetic screening, helped reduce the time taken to generate MRI scans from minutes, and often hours, to less than a second, and these advancements still form an integral part of all scanners used today.
Thanks to Mansfield's methods, not to mention improvements in computer capacity, MRI was successfully introduced into practical medicine in the 1980s, and is increasingly proving to be an invaluable diagnostic tool. Today, more than 20,000 MRI scanners are in use worldwide and more than 60 million examinations are conducted annually. Despite chance playing an important part in his success, there was one opportunity that Lauterbur missed out on. Lauterbur could not get a patent on his basic discovery. Officials from the State University of New York rejected Lauterbur's application, saying that "the applications of his discovery would not cover the expense of securing a patent."
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