- Email: [email protected]
The Nobel prize for MRI: a wonderful discovery and a sad controversy
CORRESPONDENCE
COMMENTARY
CORRESPONDENCE e-mail submissions to [email protected]
The Nobel prize for MRI: a wonderful discovery and a sad controversy Sir—In reporting this year’s Nobel prize for physiology or medicine to Paul Lauterbur and Peter Mansfield for work leading to magnetic resonance imaging (MRI), Stephen Pincock (Oct 11, p 1203)1 alludes to the puzzling absence of Raymond Damadian—an MD scientist at State University of New York Downstate Medical Center—from the prize and notes that the reason for his absence is now clear. But we see through a glass darkly: the real answer is murkier than ever. The discovery of MRI in medicine comprised two steps. First was Damadian’s report in 1971 of differences in tissue proton relaxation among normal tissues and between normal and cancer tissues, and proposal of external nuclear magnetic resonance (NMR) scanning of live human beings.2 Second came the development of imaging methods during 1972–80. The first methods were devised by Lauterbur—who reconstructed two-dimensional images using magnetic field gradients, imaging two capillary tubes in water3—and by Damadian, who registered a patent in 1972. During 1977–78, and using a video-like field-focusing method with a human-sized superconducting magnet built in his laboratory, Damadian and his students obtained the first wholebody MR images, including those of the chest and abdomen in healthy people and in patients with cancers.4 In 1974, Mansfield had devised a faster pulsed-sequence method which did not rely on Lauterbur’s reconstruction technique. Lauterbur, Mansfield, and Damadian’s methods were supplanted by spin-warp imaging, a gradient method developed in 1980. Spin-warp combines phase-encoding with the twodimensional Fourier MR concept of Richard Ernst, who won the Nobel prize for chemistry in 1991.5 Both steps are essential to medical MRI. In key papers, Ernst5 cites Lauterbur,3 Damadian,2 and Mansfield; the spin-warp paper cites Ernst5 and Damadian.2 For all imaging methods, tissue proton relaxation and density differences account for the contrasts and
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anatomic detail unique to MRI. This fact led the US High Court of Patents and Supreme Court in 1997 to uphold Damadian’s 1972 patent. That Damadian, Lauterbur, and Mansfield made important contributions in launching medical MRI seems unambiguous. Why, then, did the Nobel prize recognise two scientists whose contributions involved imaging techniques alone, but exclude the third scientist who conceived of whole-body NMR scanning, discovered tissue proton relaxation differences crucial to MRI’s genesis and use, and achieved the first human whole-body MR images? This question is compounded by Alfred Nobel’s will, which mandates that the physiology or medicine prize be awarded for the most important discovery; the physics and chemistry prizes include important methods. This year’s physiology or medicine prize seems to have ignored the fundamental biomedical discoveries on which imaging methods are based. Unfortunately the canon of scientific recognition might be abandonded in the real world. There is disciplinary loyalty within the NMR community, with aspersions cast about Damadian as a physician whose early contributions were inconsequential. The main controversy involves Lauterbur’s claim of exclusive primacy in the discovery of medical MRI. Although Damadian’s work directly led to Lauterbur’s, this fact was not acknowledged by Lauterbur until years later, and only after acerbic public complaints by Damadian. Also, use of field gradients for linear spatial localisation, fundamental to gradient imaging methods, was discovered by Robert Gabillard and independently by Herman Carr and Edwin Purcell in 1952, and described in classic NMR textbooks. This previous work was never acknowledged by Lauterbur, despite published reminders by Carr and others. It is sad that this important scientific discovery with direct human benefit is marred by controversy, and sadder yet that the Nobel award has exacerbated rather than settle an unnecessary controversy.
Paul Dreizen Department of Medicine, Biophysics Division, State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA (e-mail: [email protected]) 1 2
3
4
5
Pincock S. US and UK researchers share Nobel prize. Lancet 2003; 362: 1203. Damadian R. Tumor detection by nuclear magnetic resonance. Science 1971; 71: 1151–53. Lauterbur P. Image formation by induced local interactions: examples employing nuclear magnetic resonance. Nature 1973; 242: 190–91. Damadian R, Goldsmith M, Minkoff L. NMR in cancer XVI: FONAR image of the live human body. Physiol Chem Physics 1977; 9: 97–100. Kumar A, Welti D, Ernst RR. NMR Fourier zeugmatography. J Magn Res 1975; 18: 69–83.
Erythropoietin to treat anaemia in patients with head and neck cancer Sir—Michael Henke and colleagues are the first to publish a randomised trial on the use of erythropoietin as an adjuvant to radiotherapy in the treatment of cancer (Oct 18, p 1255).1 Outcome in the group treated with erythropoietin was reported to be inferior to that of the control group. We have concerns about the design, results, and interpretation of this study. A heterogeneous population was studied, which included patients who received radiotherapy primarily as well as those who received it postoperatively. Additionally, patients with recurrent tumour were entered. The microenvironment is regarded as a major factor in the oxygenation status of malignant tumours. This microenvironment and the vascular supply for microscopic residual tumours in the postoperative situation are completely different from those of the non-violated primary tumour. The presumed effects of erythropoietin on tumour oxygenation2 are therefore also likely to be different. The primary endpoint of the study was locoregional progression-free survival, with progression defined
THE LANCET • Vol 363 • January 3, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet publishing Group.
COMMENTARY
CORRESPONDENCE e-mail submissions to [email protected]
The Nobel prize for MRI: a wonderful discovery and a sad controversy Sir—In reporting this year’s Nobel prize for physiology or medicine to Paul Lauterbur and Peter Mansfield for work leading to magnetic resonance imaging (MRI), Stephen Pincock (Oct 11, p 1203)1 alludes to the puzzling absence of Raymond Damadian—an MD scientist at State University of New York Downstate Medical Center—from the prize and notes that the reason for his absence is now clear. But we see through a glass darkly: the real answer is murkier than ever. The discovery of MRI in medicine comprised two steps. First was Damadian’s report in 1971 of differences in tissue proton relaxation among normal tissues and between normal and cancer tissues, and proposal of external nuclear magnetic resonance (NMR) scanning of live human beings.2 Second came the development of imaging methods during 1972–80. The first methods were devised by Lauterbur—who reconstructed two-dimensional images using magnetic field gradients, imaging two capillary tubes in water3—and by Damadian, who registered a patent in 1972. During 1977–78, and using a video-like field-focusing method with a human-sized superconducting magnet built in his laboratory, Damadian and his students obtained the first wholebody MR images, including those of the chest and abdomen in healthy people and in patients with cancers.4 In 1974, Mansfield had devised a faster pulsed-sequence method which did not rely on Lauterbur’s reconstruction technique. Lauterbur, Mansfield, and Damadian’s methods were supplanted by spin-warp imaging, a gradient method developed in 1980. Spin-warp combines phase-encoding with the twodimensional Fourier MR concept of Richard Ernst, who won the Nobel prize for chemistry in 1991.5 Both steps are essential to medical MRI. In key papers, Ernst5 cites Lauterbur,3 Damadian,2 and Mansfield; the spin-warp paper cites Ernst5 and Damadian.2 For all imaging methods, tissue proton relaxation and density differences account for the contrasts and
78
anatomic detail unique to MRI. This fact led the US High Court of Patents and Supreme Court in 1997 to uphold Damadian’s 1972 patent. That Damadian, Lauterbur, and Mansfield made important contributions in launching medical MRI seems unambiguous. Why, then, did the Nobel prize recognise two scientists whose contributions involved imaging techniques alone, but exclude the third scientist who conceived of whole-body NMR scanning, discovered tissue proton relaxation differences crucial to MRI’s genesis and use, and achieved the first human whole-body MR images? This question is compounded by Alfred Nobel’s will, which mandates that the physiology or medicine prize be awarded for the most important discovery; the physics and chemistry prizes include important methods. This year’s physiology or medicine prize seems to have ignored the fundamental biomedical discoveries on which imaging methods are based. Unfortunately the canon of scientific recognition might be abandonded in the real world. There is disciplinary loyalty within the NMR community, with aspersions cast about Damadian as a physician whose early contributions were inconsequential. The main controversy involves Lauterbur’s claim of exclusive primacy in the discovery of medical MRI. Although Damadian’s work directly led to Lauterbur’s, this fact was not acknowledged by Lauterbur until years later, and only after acerbic public complaints by Damadian. Also, use of field gradients for linear spatial localisation, fundamental to gradient imaging methods, was discovered by Robert Gabillard and independently by Herman Carr and Edwin Purcell in 1952, and described in classic NMR textbooks. This previous work was never acknowledged by Lauterbur, despite published reminders by Carr and others. It is sad that this important scientific discovery with direct human benefit is marred by controversy, and sadder yet that the Nobel award has exacerbated rather than settle an unnecessary controversy.
Paul Dreizen Department of Medicine, Biophysics Division, State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA (e-mail: [email protected]) 1 2
3
4
5
Pincock S. US and UK researchers share Nobel prize. Lancet 2003; 362: 1203. Damadian R. Tumor detection by nuclear magnetic resonance. Science 1971; 71: 1151–53. Lauterbur P. Image formation by induced local interactions: examples employing nuclear magnetic resonance. Nature 1973; 242: 190–91. Damadian R, Goldsmith M, Minkoff L. NMR in cancer XVI: FONAR image of the live human body. Physiol Chem Physics 1977; 9: 97–100. Kumar A, Welti D, Ernst RR. NMR Fourier zeugmatography. J Magn Res 1975; 18: 69–83.
Erythropoietin to treat anaemia in patients with head and neck cancer Sir—Michael Henke and colleagues are the first to publish a randomised trial on the use of erythropoietin as an adjuvant to radiotherapy in the treatment of cancer (Oct 18, p 1255).1 Outcome in the group treated with erythropoietin was reported to be inferior to that of the control group. We have concerns about the design, results, and interpretation of this study. A heterogeneous population was studied, which included patients who received radiotherapy primarily as well as those who received it postoperatively. Additionally, patients with recurrent tumour were entered. The microenvironment is regarded as a major factor in the oxygenation status of malignant tumours. This microenvironment and the vascular supply for microscopic residual tumours in the postoperative situation are completely different from those of the non-violated primary tumour. The presumed effects of erythropoietin on tumour oxygenation2 are therefore also likely to be different. The primary endpoint of the study was locoregional progression-free survival, with progression defined
THE LANCET • Vol 363 • January 3, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet publishing Group.