Paul Lauterbur and the Invention of MRI

by M. Joan Dawson

  18. Paul C. Lauterbur, “Nuclear Magnetic Resonance Spectra of Elements Other than Hydrogen and Fluorine,” in Determination of Organic Structures by Physical Methods, vol. 2, ed. Frederick C. Nachod and W. D. Phillips (New York: Academic Press, 1962), 465–536.

  19. John J. Burke and Paul C. Lauterbur,“Sn119 Nuclear Magnetic Resonance Spectra,” Journal of the American Chemical Society 83, no. 2 (January 1961): 326–331.

  20. The Burke-Lauterbur paper was the first study of 119Sn in a wide variety of compounds, most containing halogens. They found a very large range of chemical shifts that correlated with molecular structure and observed several mixed tin halides that formed in the sample tube in slow exchange reactions.

  21. Paul C. Lauterbur and R. J. Kurland, “On the Signs of CH and HH Coupling Constants,” Journal of the American Chemical Society 84, no. 17 (September 1962): 3405.

  22. Paul C. Lauterbur, “Anisotropy of the C13 Chemical Shift in Calcite,” Physical Review Letters 1, no. 9 (November 1958): 343–344.

  23. One major controversy involved the basic chemical shift scale. Should it be the long-used δ scale, with the reference (tetramethylsilane—TMS—for proton NMR) at 0, or a scale favored by many organic chemists, the τ scale, with TMS at 10? To complicate matters, the scales ran in opposite directions. Books of data were published using each scale. Although the committee successfully reached agreement in many other areas, this one was solved only in 1972 with a firm recommendation from the International Union of Pure and Applied Chemistry to use the δ scale.

  24. Edwin D. Becker, Cherie L. Fisk, and C. L. Khetrapal, “The Development of NMR from the Early Beginnings to the Early 1990s,” in Encyclopedia of Nuclear Magnetic Resonance, vol. 1, ed. David M. Grant and Robin K. Harris (Chichester, UK: John Wiley and Sons, 1996), 1–158.

  25. For example, the A-60 was the first commercial instrument to use a field/frequency lock.

  Chapter 5

  1. Paul C. Lauterbur, “Anisotropy of the C 13 Chemical Shifts in Calcite,” Physical Review Letters 1 (1958): 343.

  2. Doug Morris, comments made at a memorial symposium, Experimental NMR Conference, Daytona Beach, FL, April 2007.

  3. Paul C. Lauterbur and John J. Burke, “Anisotropic 207Pb Magnetic Shielding in a Single Crystal of Wulfenite, PbMoO4,” Journal of Chemical Physics 42 (1965): 439–440.

  4. Paul C. Lauterbur,“C Nuclear Magnetic Resonance Spectra of Proteins,” Applied Spectroscopy 24, no. 4 (July–August 1970): 450–452.

  5. Paul C. Lauterbur, Elden J. Runde, and B. L. Blitzer, “13C NMR Spectroscopy of Biopolymers,” in Magnetic Resonances in Biological Research, ed. Cafiero Franconi (London: Gordon and Breach, 1971), 355–364.

  6. These first experiments were done using double resonance techniques on an early superconducting spectrometer at Varian.

  7. Paul first attempted the enrichment using 13C-enriched methyl iodine, which reacts with the methionines of RNAase B, using decoupling to find the four methionines at this protein’s active site.

  8. It is well known that bromoacetic acid, a halogen, reacts with sulfur in the methionine, and this could be a pathway to enrichment. But C bromoacetic acid was unavailable. So Paul had to start with 13C-enriched glycine and reconvert it to the halogen amino acid.

  9. Paul had a similar problem with his 3H studies—the label was not where it was supposed to be.

  10. Lauterbur, “13C Nuclear Magnetic Resonance Spectra of Proteins.” The 25 MHz spectrum was obtained by Roy Johnson in the Varian Applications Laboratory using a 25% aqueous solution of the protein in an 8 mm sample tube containing a 2 mm tube of 13C-enriched CH2I2 for a field-frequency lock signal.

  11. Richard R. Ernst and Wesley A. Anderson, “Application of Fourier Transform Spectroscopy to Magnetic Resonance,” Review of Scientific Instruments 37, no. 1 (January 1966): 93–102.

  12. The method used by Monsanto entailed an isotope effect on chemical reaction rates and equilibria.

  13. Of these four men, Baldeschwieler was to gather venture capital from Silicon Valley friends; Shapiro, a synthetic chemist, was to take the basic enriched 13CO and make it into useful compounds; and McIntyre was to handle relations with the Los Alamos laboratory. Paul’s role, as he told it to me, was generally to pull things together.

  14. Howard Breuer, “Lauterbur to Garner Award for Research,” Stony Brook Statesman, November 14, 1984.

  15. Internal company documents, now in the Paul C. Lauterbur Collection, Chemical Heritage Foundation Archives, Philadelphia, PA.

  Chapter 6

  1. Christine Des Garennes, “2003 Nobel Laureate Dies at Urbana Home,” The News-Gazette, March 28, 2007.

  2. Paul C. Lauterbur, “Take-home Lessons for Life,” Commencement address, Pitt Chronicle (University of Pittsburgh), May 3, 2004.

  3. Ibid.

  4. Paul C. Lauterbur, “One Path Out of Many: How MRI Actually Began,” in Encyclopedia of Magnetic Resonance, vol. 1, ed. David M. Grant and Robin K. Harris (Chichester, UK: John Wiley and Sons, 1996), 445–449.

  5. Continuous functions can be represented by a grid or network of points, as obtained by MRI, and can be solved by iterative techniques. The image is constructed from the one-center harmonic representations in the shape of the field variation because of the shim coils. Paul also had vague ideas that the object or gradient center could be moved to generate more functions, but all those musings were never written down. Instead, he pursued a much simpler idea. Sets of linear gradients oriented in different directions could uniquely encode each of a finite number of points representing the object, and Paul thought that an iterative comparison of the projections thus generated with those from images, progressively refined to minimize the differences, could converge on a correct solution. His consultants disagreed on whether it would work, so he tried.

  6. Richard Gordon and Gabor T. Herman, “Reconstruction of Pictures from Their Projections,” Communications of the Association for Computing Machinery 14, no. 12 (December 1971): 759–768.

  7. Proceedings of an International Workshop Held at Brookhaven National Laboratory, Upton, New York, July 16–19, 1974, ed. Robert B. Marr. The workshop was sponsored by the Applied Mathematics Department, Brookhaven National Laboratory.

  8. Lauterbur, “Take-home Lessons for Life.”

  9. Ibid.

  10. Paul C. Lauterbur, Helena Mendonça-Dias, and Andrew M. Rudin, “Augmentation of Tissue Proton Spin-Lattice Relaxation Rates by in vivo Addition of Paramagnetic Ions,” in Frontiers of Biological Engergetics, ed. P. Leslie Dutton, Jack S. Leigh, and Antonio Scarpa (New York: Academic Press, 1978), 752–759.

  11. Hal Swartz, “Some of My Interactions with Paul C. Lauterbur,” EPR News Letter: The Publication of the International EPR (ESR) Society, vol. 14, nos. 1–2, 200e.

  12. Research notes, Paul C. Lauterbur Collection, Chemical Heritage Foundation, Philadelphia PA; Paul C. Lauterbur, “Cardiovascular NMR Zeugmatography,” grant application to the National Institutes of Health, submitted in 1977.

  13. Austin Elliott, “Interview with Paul Lauterbur, December 2003,” Physiology News, Summer 2004, 12–15.

  14. Research note, Paul C. Lauterbur Collection, Chemical Heritage Foundation Archives, Philadelphia, PA.

  15. Paul C. Lauterbur, “Stable Isotope Distributions by NMR Zeugmatography,” in Proceedings of the First International Conference on Stable Isotopes in Chemistry, Biology, and Medicine, Argonne National Laboratory (Argonne, IL: U.S. Atomic Energy Commission, Office of Information Services, 1973), 255–260. The coconut is in the Paul C. Lauterbur Collection, Chemical Heritage Foundation Archives, Philadelphia, PA.

  16. In a true three-dimensional image, the information is obtained simultaneously in three dimensions. Pseudo-three-dimensional images are made by obtaining a series of slices and stacking them to derive a third dimension.

  17. Marcelino L. Bernado and Paul C. Lauterbur, “Rapid Medium-Resolution 3-D NMR Zeugmatographic Imaging of the Head, ” European Journal of Radiology 3, suppl. 1 (Au
gust 1983): 286–290.

  18. Gabor T. Herman, Jayaram K. Udupa, David M. Kramer, Paul C. Lauterbur, Andrew M. Rudin, and Jochen M. Schneider, “Three-dimensional Display of Nuclear Magnetic Resonance Images,” Optical Engineering 21, no. 5 (September– October 1982): 923–926.

  19. Paul was a New York State employee, and had he used state facilities in developing his invention, any patent would belong to SUNY. But at the time of his invention Paul was in New Kensington, Pennsylvania, and without a summer salary.

  20. Elliott, “Interview with Paul Lauterbur.”

  21. Kettering Prize news release, General Motors Cancer Research Prizes, 1985.

  22. Greg Kline, “UI’s Lauterbur Paved Way for Imaging of Body,” The News-Gazette, December 7, 2003.

  23. Paul C. Lauterbur, “Image Formation by Induced Local Interactions: Examples Employing Nuclear Magnetic Resonance,” Nature 242, no. 5394 (March 1973): 190–191.

  24. Paul’s letter to Nature, Paul C. Lauterbur Collection, Chemical Heritage Foundation Archives, Philadelphia, PA.

  25. Reviewer’s comment: Paul C. Lauterbur Collection, Chemical Heritage Foundation Archives, Philadelphia, PA.

  26. Laura Garwin and Tim Lincoln, eds., A Century of Nature: Twenty-One Discoveries That Changed Science and the World (Chicago: University of Chicago Press, 2003).

  27. Kettering Prize news release.

  28. Greg Kline, “Profs Receive Awards,” The News-Gazette, December 10, 2003.

  29. Lauterbur, “Stable Isotope Distributions by NMR Zeugmatography.”

  30. Research notes, Paul C. Lauterbur Collection, Chemical Heritage Foundation Archives, Philadelphia, PA.

  31. Paul C. Lauterbur, letter to Dr. A. Berson, May 4, 1990. Original in the Paul C. Lauterbur Collection, Chemical Heritage Foundation Archives, Philadelphia, PA.

  32. Elliott, “Interview with Paul Lauterbur.”

  Chapter 7

  1. Sonny Kleinfield, A Machine Called Indomitable (New York: Times Books / Random House, 1985), 61.

  2. Raymond Damadian, “Apparatus and Method for Detecting Cancer in Tissue,” U.S. Patent 3,789,832, issued February 5, 1974. The patent was controversial in many ways.

  3. Edward Edleson, “Basic Research Leads to Radio Signals from Cancer Tissue,” Downstate Reporter, Spring 1971.

  4. One of the issues that really bothered Raymond Damadian was that Paul had not cited his paper. Paul told me, “For Nature you have to limit the citations. I cited the technical references that seemed more important.”

  5. Kleinfield, A Machine Called Indomitable, 63.

  6. Ian R. Young, “Significant Events in the Development of MRI,” Journal of Magnetic Resonance Imaging 20, no. 2 (August 2004): 183–186; and John R. Mallard, “Magnetic Resonance Imaging: The Aberdeen Perspective on Developments in the Early Years,” Physics in Medicine and Biology 51, no. 13 (July 2006): R45–R60.

  7. Kleinfield, A Machine Called Indomitable, 137.

  8. Kleinfield, A Machine Called Indomitable, 123.

  9. Ibid.

  10. Howard Breuer, “Lauterbur to Garner Lasker Award for Research,” Stony Brook Statesman, November 14, 1984.

  11. Paul C. Lauterbur, C.-M. Lai, Joseph A. Frank, and Charles S. Dulcey, Jr. “In Vivo Zeugmatographic Imaging of Tumors,” Physics in Canada 32, special issue (July 1976), “Digest of the Fourth International Conference on Medical Physics,” abstract 33.11.

  12. Raymond Damadian, “Tumor Detection by Nuclear Magnetic Resonance,” Science 171, no. 3976 (March 1971): 1151–1153.

  13. Paul C. Lauterbur, Joseph A. Frank, and M. J. Jacobson, “Water Proton Spin-Lattice Relaxation Times in Normal and Edematous Dog Lungs,” Physics in Canada 32, special issue (July 1976), “Digest of the Fourth International Conference on Medical Physics,” abstract 33.

  14. Joseph A. Frank, Michael A. Feiler, Waylon V. House, Paul C. Lauterbur, and M. J. Jacobson, “Measurement of Proton Nuclear Magnetic Longitudinal Relaxation Times and Water Content in Infarcted Canine Myocardium and Induced Pulmonary Injury,” Clinical Research 24, no. 3 (1976): 217.

  15. Paul C. Lauterbur, “Flow Measurements by NMR Zeugmatography,” manuscript dated October 24, 1973. Paul C. Lauterbur Collection, Chemical Heritage Foundation Archives, Philadelphia, PA.

  16. Pixels are small two-dimensional regions of homogeneous intensity. The contrast in the image is produced by the different intensities among the pixels in the array.

  17. Similar to multiplicative ART, described by Richard Gordon and Gabor T. Herman, “Reconstruction of Pictures from Their Projections,” Communications of the Association for Computing Machinery 14, no. 12 (December 1971): 759–768.

  18. The department was very proud of creating this innovative facility, which used an IBM 1800, but its time was short because computers quickly fell in price, making it possible for every lab to have one or more.

  19. Personal communication, Charles Dulcey, May 2005.

  20. Paul C. Lauterbur, “Reconstruction in Zeugmatography: The Spatial Resolution of Magnetic Resonance Signals,” in Techniques of Three-Dimensional Reconstruction: Proceedings of an International Workshop Held at Brookhaven National Laboratory, Upton, New York, July 16–19, 1974, ed. Robert B. Marr. The workshop was sponsored by the Applied Mathematics Department, Brookhaven National Laboratory.

  21. Now in the Paul C. Lauterbur Collection, Chemical Heritage Foundation Archives, Philadelphia, PA.

  22. Fremey’s salt is a nitroylsulfonate with an unpaired electron (therefore a free radical) that is unusually stable and water-soluble. Fremey’s salt also has unusually narrow resonance lines, which makes them easy to detect.

  23. Paul C. Lauterbur, “Cancer Detection by Nuclear Magnetic Resonance Zeugmatographic Imaging,” Cancer 57, no. 10 (May 1986): 1899–1904.

  24. Edward Heidelberger, Steffen B. Petersen, and Paul C. Lauterbur, “Aspects of Cardiac Diagnosis Using Synchronized NMR Imaging,” European Journal of Radiology 3, suppl. 1 (August 1983): 281–285.

  25. Randy Lauffer, expert testimony in Bayer Schering Pharma AG v. Bracco S.p.A., Bracco International B.V., and Bracco Imaging S.p.A. Patent dispute, 2010.

  26. Waldo Hinshaw, Paul A. Bottomley, and G. Neil Holland, “Radiographic Thin-Section Image of the Human Wrist by Nuclear Magnetic Resonance,” Nature 270, no. 5639 (December 1977): 722–723.

  Chapter 8

  1. Although Paul explored a method of slice selection, he generally used the geometry of the transmitting coil to define a two-dimensional plane.

  2. The sensitive point method entails applying three oscillating gradients in three orthogonal directions such that their values match at one single point, which will give rise to the NMR signal. That sensitive point is then moved electronically through the sample in a raster pattern. Hinshaw, Moore, and Andrew later produced a “sensitive line” method along the same principles.

  3. John R. Mallard, “Magnetic Resonance Imaging: The Aberdeen Perspective on Developments in the Early Years,” Physics in Medicine and Biology 51, no. 13 (July 2006): R45–R60.

  4. The method was patented.

  5. Paul had anticipated the spin-echo experiment in a memorandum of October 1971 and in his draft patent application of August 1972.

  6. Many believe that EPI is the reason Mansfield shared the Nobel Prize with Lauterbur in 2003.

  7. Paul C. Lauterbur, “Magnetic Resonance Zeugmatography,” Pure & Applied Chemistry 40, nos. 1–2 (January 1974): 149–157.

  8. Waldo S. Hinshaw, Paul A. Bottomley, and G. Neil Holland, “Radiographic Thin Section Image of the Human Wrist by Nuclear Magnetic Resonance,” Nature 270, no. 5639 (December 1977): 722–723.

  9. Ian R. Young and Hugh Clow, “NMR Imaging,” New Scientist, November 11, 1978, 588.

  10. Sir Peter Mansfield, “Autobiography” (Nobel Foundation, 2003), http://www.nobelprize.org/nobel_prizes/medicine/laureates/2003/mansfield-autobio.html.

  11. T2 yields particularly good contrast between tissue and cerebrospinal fluid. T2* is a combination of the tr
ue T2 with extrinsic mechanisms for loss of signal cohesion. T2* yields information about brain activation.

  12. Mallard, “Magnetic Resonance Imaging,” R45–R60.

  13. Peter Marks, “Star Professor Has SUNY in Bidding War,” Long Island Newsday, March 15, 1985.

  14. Ibid.

  15. Elizabeth Wasserman, “Lauterbur to Resign from SB,” Stony Brook Statesman, April 17, 1985.

  16. Kettering Prize news release, General Motors Cancer Research Prizes, 1985.

  17. Hal Swartz, “Some of My Interactions with Paul C. Lauterbur,” EPR: News Letter: The Publication of the International EPR (ESR) Society, vol. 14, nos. 1–2 (2004): 7–8.

  18. Jerry Pohost, interview with author.

  Chapter 9

  1. Related by Joe Zhou (Xiaohong Zhou) at the Daytona Beach meeting of the Experimental NMR Conference, 2007.

  2. Quoted in Larry Bernard, “Lauterbur Honored for Imaging Research,” Inside Illinois, October 4, 1990.

  3. Ibid.

  4. Paul C. Lauterbur, David M. Kramer, Waylon V. House, Jr., and Ching-Nien Chen, “Zeugmatographic High Resolution Nuclear Magnetic Resonance Spectroscopy: Images of Chemical Inhomogeneity within Macroscopic Objects,” Journal of the American Chemical Society 97, no. 23 (November 1975): 6866–6868.

  5. Julie Wurth,“UI’s $6 Million Magnet of Troubles,” The News-Gazette, April 14, 1996.

  6. Minutes of the Biomedical Magnetic Resonance Laboratory Management Advisory Committee Meeting, November 4, 1993. Paul C. Lauterbur Collection, Chemical Heritage Foundation Archives, Philadelphia, PA.

  7. The Dewar vacuum.

  8. Julie Wurth, “UI Continues to Refine Techniques of Brain Scanning,” The News-Gazette, April 14, 1996.

  9. Paul was the first recipient of the Fiuggi International Prize. The award, to be presented every three years by the Fiuggi Foundation for Culture in Italy, honors a lifetime of devotion to culture, science, or art, “providing mankind with contributions worthy of a particular acknowledgement.” The 1987 prize was designated to recognize international distinctions in the field of medicine or biology.