The 2003 Nobel Prize for MRI: significance and impact.

Abstract

As this editorial was prepared on December 10, 2003, our colleagues, Paul C. Lauterbur, PhD, and Sir Peter Mansfield, both former Presidents of the International Society for Magnetic Resonance in Medicine (ISMRM), were recognized in Stockholm as co-recipients of the 2003 Nobel Prize in Physiology or Medicine. Their separate contributions in gradient imaging and echo-planar imaging are internationally recognized as seminal accomplishments in the field. In addition, each has made significant contributions to the scientific community, as evidenced by their presence as authors in the archival literature, their training of young investigators, and their support and voluntary contributions to organized medicine, including, in particular, our society. This event highlights the rapid development in the field and the truly significant impact on health care delivery that magnetic resonance imaging (MRI) and its correlative diagnostic imaging and associated therapeutic modalities have provided. In this issue, we have several invited editorial comments that focus on the excitement and energy that the Nobel Prize in Medicine for MRI has generated. First, we present laudatory remarks from Michael Moseley, PhD, President of the ISMRM, and Jörg F. Debatin, MD, Medical Director and Chief Executive Officer of the University Hospital, Hamburg, Germany, and a member of the Editorial Board of JMRI. These are followed by an editorial by Chris Boesch, MD, PhD, former President of ISMRM, in which he places the current award in a perspective of 13 Nobel Prizes directly and indirectly related to the development of MRI. Third, we have two observations on the disappointment of our colleague, Raymond Damadian, MD, in not being recognized with a share of the Nobel Prize. Presenting their views on this matter are William G. Bradley, MD, PhD, Chairman of the Department of Radiology, University of California at San Diego and JMRI Editorial Board member, and Jürgen Hennig, PhD, Universität Freiburg, Germany, past President of ISMRM and JMRI Editorial Board Member. Finally, we close with a discussion of the complex genesis of MRI that touches on all of the above issues by Ian Young, PhD, member of the Editorial Board of JMRI. It is noted that the editorial opinions expressed in the following articles are the personal opinions of the authors and not the official position of the ISMRM. Any discussion concerning the selection of Nobel Laureates could certainly benefit from the expertise of someone directly associated with that process. Hans G. Ringertz, MD, PhD, Professor and Chairman of the Department of Radiology at Karolinska Institute, is also the Chairman of the Nobel Academic Council and was kind enough to share some of the intricacies involved in awarding the Nobel Prize for Physiology or Medicine. The nomination procedure is an extensive, year-long process that invites a great number of universities and other organizations to recommend possible nominees. As has been discussed elsewhere during this year's debate, up to three individuals involved in the discovery and/or development of the specific entity being honored may receive a Nobel Prize; however, the contributions of each of the winners do not always have to correlate directly. In March, the top nominees from the previous year are re-examined, and preliminary international investigations are begun. The field is narrowed to 20-25 potential prizes by June, and experts in all of those areas are chosen to conduct more thorough investigations of the nominees. Further winnowing then occurs until the top three possibilities are chosen at the end of September. The final meeting of the Nobel Assembly occurs in October, and then that year's Nobel Laureate(s) are chosen and announced. The process then culminates in the actual awarding ceremony in Stockholm during the first half of December. This year, there is considerable debate regarding the Nobel Prize awards in Medicine for MRI, and I trust that the following editorials will contribute to that discussion. We certainly welcome editorial comments that would seek to disagree, be supportive, or correct any of the observations and conclusions mentioned in this introduction or the invited editorials that appear in this issue of JMRI. Recent editorial opinions by John Gore, PhD, Editor, Magnetic Resonance Imaging (1), and Felix W. Wehrli, PhD, Editor-in-Chief, Magnetic Resonance in Medicine (2), provide important historic perspectives describing the evolution of the science and technology of MRI. These are exciting days in our field, and it is indeed an honor to be a part of the process. Notice that I have provided brief descriptive comments, in italics, to separate sections of this collection of editorial opinions. C. Leon Partain, MD, PhD Editor-in-Chief Gore J. Out of the shadows—MRI and the Nobel Prize. N Engl J Med 2003;349:2290–2292. Wehrli FW. On the 2003 Nobel Prize in medicine or physiology awarded to Paul C. Lauterbur and Sir Peter Mansfield. Magn Res Med 2004;51:1–3. The International Society of Magnetic Resonance in Medicine fosters scientific dialogue on pertinent MR related topics for discussion, education, and documentation through the publication of enduring scholarly material. The Society speaks through its selected officials, the annual meetings, and its journals with their duly-established and broad-based editorial boards, who are accountable to the Society Board of Directors through its Publications Committee. The journals consider both invited and submitted editorial comments on appropriate topics as one of the vehicles of scientific dialogue. In that spirit, and within those guidelines, the first two invited editorial comments (below) come from the current President of the ISMRM and from a former member of the Board of Trustees of the ISMRM, respectively. These remarks illustrate the international balance that is valued at the ISMRM, with one coming from the United States and the other from Germany. Further, the balance between basic science and clinical investigators is also valued, and these two voices are representative of those two fundamental disciplines. It is also gratifying to help focus on our moral responsibility of providing the human benefits of MRI to the underserved of the world, in addition to those of us who are blessed to have more than our share of opportunity and resources. Additional commentary is invited from the members of our Society and others who read these words. They will be seriously considered for publication as part of our commitment to moderating meaningful scientific discussion. As the President of ISMRM, I would like to speak for all of our members in conveying our sincere congratulations to Professors Paul Lauterbur and Peter Mansfield on winning the 2003 Nobel Prize in Physiology or Medicine. This is the occasion that many of us have been waiting years for: the well-deserved recognition of the pioneering efforts that these two have made that has affected everything that we all do within the sphere of magnetic resonance. We are very happy that their work has finally been acknowledged with this prize. It provides the public recognition that MRI has deserved in significantly improved diagnostic imaging in many diseases for many disciplines. This award builds on the earlier Nobel Prizes given to the fundamental discoveries of the magnetic moments [Rabi, 1944], the nuclear magnetic resonance (NMR) phenomenon [Purcell and Bloch, 1952], the implementation of two-dimensional MR spectroscopy [Ernst, 1991], the development of MR spectroscopy for three-dimensional macromolecular structures [Wüthrich, 2002], and now, deservingly, for MRI. Beyond the recognition of this fact by the Nobel Academy, we should also be aware and grateful for the contributions that Drs. Lauterbur and Mansfield have made to the Society: both are members of our Society, both are past Gold Medal Winners, and both are Society Past-Presidents. To pay tribute, the Scientific Program Committees for the 2004 and 2005 Annual Meetings will be planning several Nobel celebrations for the 2004 Kyoto meeting. The ISMRM Board of Trustees has bestowed the ISMRM Honorary Membership to Drs. Lauterbur, Mansfield, Ernst, and Wüthrich. Clearly, these are momentous times for MRI. We all take pride in congratulating Drs. Lauterbur and Mansfield for their recognition by the Nobel Academy! Michael Moseley, PhD Stanford University Stanford, California The accomplishments of Paul Lauterbur and Sir Peter Mansfield have been evident long before this year's Award of the Nobel Prize in Physiology or Medicine. Millions of patients have benefited from the use of magnetic resonance in medicine over the past two decades. Awarding the Nobel Prize to Paul Lauterbur and Sir Peter Mansfield now pays tribute to the significance of their scientific contributions as the founders of modern MRI. The Nobel Prize carries another equally important message, however: MRI has entered the world stage of medicine and is here to stay. While this recognition is obvious to all those working with MRI, the benefits of this technology have remained limited to only the most developed regions of the world. A vast number of countries lack all infrastructure for MRI; and many other countries are considerably underserved. Thus, we should interpret the awarding of the prestigious Nobel Prize to the developers of MRI also as a moral obligation to widen the access to MRI technology. This will require increased research into means to reduce the cost of MRI infrastructure and new efforts to accelerate the training of staff required for operating and interpreting MRI studies. In my mind, the ISMRM, with its two journals, MRM and JMRI, seems to be an excellent vehicle to accomplish this mission. Jörg Debatin, MD University Hospital Essen Essen, Germany The next invited editorial comes from the immediate past President of the ISMRM, Dr. Chris Boesch. His overview provides a special perspective on the rapid development and application of MRI over a relatively short period of time, involving the award of 13 Nobel Prizes, including one to his own major professor. His overview of this process from his perspective as a recognized, elected ISMRM officer and as a Swiss physician- investigator follows below. The article includes 31 references that help to focus on the history of the development of MRI. Additional commentary for supportive or conflicting views is invited for consideration for publication in JMRI. Multiplied many times by emails and phone calls, a press release went around the globe in a few hours: “The Nobel Assembly at Karolinska Institutet has today decided to award The Nobel Prize in Physiology or Medicine for 2003 jointly to Paul C. Lauterbur and Peter Mansfield for their discoveries concerning magnetic resonance imaging.” The MR community was speculating for years about a Nobel Prize that would be awarded to the developers of MRI. While it has been obvious that this discovery deserves recognition, it was a question of when and how the Nobel Prize Committee would select the laureates. While many contributed to the development of MRI in the early days, Paul C. Lauterbur and Sir Peter Mansfield unquestionably are the ones who had the fundamental ideas. While we celebrate happily these most recent laureates, their merits shall be put into a historic perspective of other Nobel Prizes in the field of NMR. In particular, I want to emphasize that four prizes were awarded for NMR in little more than a decade (Tables 1 and 2). Looking at the history of NMR (1-3) and at its applications in very different fields helps to recognize the enormous versatility of this physical effect and may explain why this field is so successful. It also gives an idea of how many applications are still hidden and waiting to be discovered in the future. In this respect, looking back may help to look forward. See Table 2, Norman F. Ramsey Toronto 2003: Lecture on I. Rabi (see Table 1) There is no question that Paul C. Lauterbur's 1973 publication in Nature represents a milestone in the development of MR in medicine (4). He suggested that magnetic field gradients could be used to define the spatial distribution of protons in water by different frequencies. In this seminal paper, he showed a two-dimensional image of two tubes filled with water based on a “projection reconstruction” algorithm that was closely related to image generation by computed tomography (CT). While Lauterbur's publication was the most explicit and clear-cut suggestion of how NMR could be used to obtain images in macroscopic dimensions, Mansfield considered the use of magnetic field gradients for a spatial separation of NMR signals in a more theoretical description about “NMR diffraction in solids” (5). This approach dealt with crystals and was so sophisticated that it was overlooked for almost a decade before the MR community realized that Mansfield, in fact, had also suggested the use of gradients for spatial encoding, i.e., for imaging. While gradients had been used in earlier years to destroy spurious signals from imperfect radiofrequency pulses or as diffusion and flow sensitizing elements in a pulse sequence, Lauterbur and Mansfield introduced the unique idea to use gradients for spatial encoding, i.e., to generate a spectrum of spatially distributed frequencies. Recently, Raymond Damadian claimed, in The Washington Post, his entitlement to the prize. It is unquestioned that he deserves recognition for his observation of relaxation time differences in malignant tissue (6). His suggestion motivated the application of MR in medicine, and, in that respect, it also fostered interest for the new imaging technology. However, his US patent on an “Apparatus and method for detecting cancer in tissue” (7) failed to show a feasible method to obtain spatially selected NMR signals. The described “beam of radiofrequency waves with a narrow cross-section, generated by helically moving transmitters” has, to the best of my knowledge, not been used so far to generate two-dimensional images. In particular, the later “Topical Magnetic Resonance” (8) and “FONAR” (9) are based on a spatial variation of the static magnetic field, not of the radiofrequency field. In contrast, two other ideas had a particular impact: “echo planar imaging,” proposed again by Sir Peter Mansfield (10), and the application of Fourier techniques (11), suggested by Richard R. Ernst's group (Nobel Laureate 1991). Tables 1 and 2 show nicely how NMR evolved from a physical tool (Prizes 1944 to 1989) to applications in chemistry (Prizes 1991 and 2002) and in medicine (Prizes 2003). Following the observation of Stern and Gerlach (12) in 1921, who observed the “spin” of silver atoms, Isidor Isaac Rabi published a one-page report on “A New Method of Measuring Nuclear Magnetic Moment” (13). He used oscillating fields to re-orient the nuclear spins and was awarded the Nobel Prize in Physics in 1944. At least two scientists contributed significantly to the field but failed in one or another way. It seems that E. K. Zavoisky, a scientist in Kazan/Russia, observed an NMR effect in 1941 (2), yet was not able to reproduce it, mainly due to World War II in his home country, the USSR. He was more successful in a related field, i.e., electron spin resonance (14). Another scientist, C. J. Gorter, attempted to measure nuclear paramagnetism. However, while he failed several times with his own measurements (15), he inspired Rabi's group to conduct their successful experiment (13). In the Western hemisphere, WWII promoted the development of radar and subsequently improved radio-transmitters and amplifiers, which were necessary for the discovery of magnetic resonance. At the end of the war, in 1946, Purcell, Torrey, and Pound (16) published a report on NMR effects in solids. At the same time, Bloch, Hansen, and Packard (17, 18) made a similar and successful attempt to measure what they called “nuclear induction.” It seems that it was not immediately clear that the two independent groups described the same effect. These reports were crucial for modern applications of NMR in solution and human tissue because they transferred knowledge about Rabi's work in molecular beams into an effect that had been observed in bulk matter. Bloch and Purcell were awarded the 1952 Nobel Prize in Physics. So far, NMR contributed almost exclusively to the development of nuclear physics, and research in this field continued to concentrate on characterizing materials and measuring nuclear parameters. In his Nobel Lecture, Richard R. Ernst revealed an astonishing fact: quite a few scientists who contributed to the early development of NMR received a Noble Prize in Physics for their subsequent work in other areas. A. Kastler (Nobel Laureate 1966) was one of those who proposed the “double resonance method,” combining optical with magnetic resonance (19). J.H. Van Vleck (Nobel Laureate 1977) developed the theory of dia- and paramagnetism and also published together with C.J. Gorter (20). Nicolaas Bloembergen (Nobel Laureate 1981) worked on relaxation effects (“BPP theory”) and the influence of motion (21). K.A. Müller (Nobel Laureate 1987) contributed significantly to electron paramagnetic resonance (22). H.G. Dehmelt (Nobel Laureate 1989) developed pure nuclear quadrupole resonance (23). N.F. Ramsey (Nobel Laureate 1989) was I.I. Rabi's first graduate student and introduced the concept of the chemical shift (24) and J coupling. In the early years of NMR, a spectrum was measured by continuous irradiation with radiofrequency waves (CW). Seminal publications by H.C. Torrey (25) and E. Hahn (26, 27) showed that the signals “free induction decays” and “spin echoes” could also be detected after the excitation of the spins with a radiofrequency pulse. Ernst and Anderson (28) realized that these signals contain the whole information of a spectrum and thus introduced Fourier techniques into NMR. In the following years, the two subsequent Nobel Laureates, Richard R. Ernst (Chemistry 1991) and Kurt Wüthrich (Chemistry 2002), both worked at the ETH in Zurich, Switzerland. Amazingly, an old photograph shows two huts on the roof of the chemistry building where their offices had been installed. They used a common NMR system, and Richard R. Ernst was desperate because it was equipped for CW only, though he had just invented the much more powerful Fourier technique. In the following years, an extremely successful collaboration started between the two groups; in contrast to the offices, the NMR equipment was always brand new and powerful. After an oral presentation by Jean Jeener, Richard Ernst developed two-dimensional NMR spectroscopy (29, 30), which is also the basis for modern imaging techniques (11) in medicine. While the paper on Fourier imaging had enormous impact on the development of MRI, Richard R. Ernst received his Nobel Prize 1991 particularly for his contribution to high-resolution NMR, where multi-dimensional Fourier techniques were increasingly used. Meanwhile, Kurt Wüthrich and his group applied NMR techniques for the elucidation of three-dimensional structures of biologic macromolecules (31). After decades of continuous improvements, NMR conformation analysis of molecules in solution became an essential tool in biochemistry and biophysics. When the Nobel Committee awarded the prize to Ernst in 1991, it was not immediately clear that Kurt Wüthrich would also be awarded some years later. However, when the committee decided to assign the 2002 Prize again to the field of high-resolution NMR, the message was clear: 1) high-resolution was so powerful in chemistry that it was appropriate to select this field again and 2) even if the scientific work of Ernst and Wüthrich was closely related, both contributions were so unique that they deserved an independent recognition. As an interesting fact, the leftmost columns of Tables 1 and 2 illustrate how prophetic the ISMRM has been in selecting speakers for the opening sessions at the annual meetings. Also demonstrated are the success and impact of non-medical applications of magnetic resonance, in particular the physical roots and high-resolution NMR. This overview and the historic context of the 2003 Nobel Prizes in Medicine shall demonstrate how vital and vibrant NMR has been for several decades. Because high-resolution NMR and in vivo MR apply the same physical effect, I would speculate that many applications still wait to be transferred and that the already extremely successful history of medical MR is just the beginning of an ongoing progress. It is uncertain if this will result in additional Nobel Laureates in the field of MR in the near future; however, the field is so vital and sustaining that it will be a valuable candidate for the coming decades. Chris Boesch, MD, PhD University and Inselspital Bern, Switzerland The next two authors who responded with invited editorial comments are William G. Bradley, MD, PhD, and Jürgen Hennig, PhD, international MRI physicist at Universität Freiburg, Freiburg, Germany. Their comments have been thoughtfully prepared as vehicles to frankly and openly address issues related to the meaning and significance of the Nobel Prize related to fundamental developments in our field. We are appreciative of their willingness to help establish the historic record of the development of MRI during this particular time. It was their opinion that the scientific community has a responsibility to provide the data from which the history of the development of science, related to MRI, may be derived with accuracy and integrity. In that spirit, supporting or opposing views are invited for consideration of publication in JMRI. On October 12, 2003, the Nobel Committee on Physiology and Medicine awarded the Nobel Prize to Paul Lauterbur and Sir Peter Mansfield for MRI. Conspicuously absent from this list was Raymond Damadian. Because the rules allow three individuals to be named for a given prize, the omission of Dr. Damadian was clearly intentional. I believe there are two possible explanations for their omission of Dr. Damadian. The first (and probably less likely) reason is that the focus of this prize was more on imaging than magnetic resonance. Raymond Damadian's initial contribution was the demonstration of T1 prolongation in cancer, not MR imaging per se. Actually, had the Nobel Prize for MRI been awarded 10 years ago, it is doubtful that Sir Peter would have won it. At the time, his main contribution, echo planar imaging (EPI), was a largely experimental technique, because the strong, fast gradients needed to make it clinically useful were only then being beta-tested. Over the last 10 years, the value of EPI—particularly EPI diffusion imaging—has been aptly demonstrated in the setting of acute stroke. Because of EPI perfusion and diffusion imaging, it is likely that MR will replace CT over the next few years as the primary imaging modality used to triage acute stroke patients for thrombolysis. Thus, EPI could have an enormous impact on the management of stroke, which itself has enormous economic impact. This could be one reason that Dr. Mansfield won the award now. A more likely reason that Dr. Damadian did not win the award has to do with his less-than-subtle self-promoting activities over the past 20 years. Because I have known Raymond Damadian for 20 years and consider him a friend, I have always questioned why a brilliant scientist needed to resort to relatively provocative tactics to be appreciated. While I do not condone the self-promoting activities of Dr. Damadian either before or after the prize was announced, it is also difficult for me to understand how the Nobel Committee could not see beyond these idiosyncrasies and base their decision entirely on the science. There is no doubt (in my mind at least) that Dr. Damadian got the ball rolling with his discovery of T1 prolongation in cancer and his construction of the first working human MRI system (for which Sir Godfrey Hounsfeld won the Nobel Prize for CT). Unfortunately, the Nobel Committee apparently could not see the significance of these discoveries and chose to base their decision on politics and social decorum rather than science. William G. Bradley, MD, PhD University of California at San Diego San Diego, California The announcement from the Nobel Assembly at Karolinska Institutet on October 6, 2003 to award the Nobel Prize in Physiology or Medicine for 2003 jointly to Paul C Lauterbur and Peter Mansfield for their discoveries concerning MRI has been received by the MR community with great joy and satisfaction. The award was given to Paul Lauterbur for his discovery of “…the possibility to create a two-dimensional picture by introducing gradients in the magnetic field…” This discovery is described in his paper in Nature, where he demonstrated the first MR image of two smaller test tubes in a NMR sample. Sir Peter Mansfield shares the award for his further development of “… the utilization of gradients in the magnetic field. He showed how the signals could be mathematically analyzed, which made it possible to develop a useful imaging technique. Mansfield also showed how extremely fast imaging could be achievable…” It was already known in the 1950s that the dependency of the resonance frequency of protons on the magnetic field strength can be used to distinguish their localization, if a suitably modified magnetic field were used. Singer described such applications in his papers on flow by NMR. To make the transition from a method for localization of spins to an imaging technique constitutes a quantum leap, one of the rare “Eureka” moments in science. In our current world overflowing with images, it is hard to conceive of the boldness of mind and inspiration it took for Paul Lauterbur to take that big step. NMR spectrometers, at that time, were instruments measuring the resonance signal of protons as a voltage at the output of a highly complex receiver and amplifier apparatus. This voltage could be visualized on an oscilloscope and stored as a hardcopy on paper. Digital signal processing was largely unknown; indeed, the “computers” around the labs at this time could do little more than basic arithmetic. It is difficult to say what should be more admired: the ingenuity of Paul Lauterbur to modify such an apparatus in order to register and collect signals under variable gradients with the aim to convert these signals into an image, or his dedication and inspiration to develop the necessary mathematical methods to finally get the job done. Lauterbur is free to admit that mathematical methods for image reconstruction had been described early this century and have been used by Hounsfield in his work on CT at around the same time. He was, however, unaware of these techniques and had to develop the algorithms for his “MR-Zeugmatography” from scratch, based on his gut feeling, that this must be feasible. Sir Peter Mansfield has been instrumental in the further development of these basic concepts of MRI as we know it today. Most notably, he has invented and introduced EPI, which is the father (or mother?) of all fast imaging techniques. The inherent sensitivity of EPI to imperfections of the magnetic field inhomogeneity; the pathetically low performance of gradient amplifiers of that day in terms of speed, power, and especially reproducibility; and the low signal-to-noise ratio caused by the high receiver bandwidth used to sample the EPI signals made the early EPI images not exactly nice to look at. It took great perseverance and a firm belief in the further technical progress for Sir Peter to keep continuously working at EPI over nearly two decades until MR technology was sufficiently advanced to give us the image quality today. EPI is currently used as the “workhorse” fast imaging sequence in many applications like fMRI, diffusion imaging, perfusion mapping, and many others. In fact, many of the new fields in MR currently under development would be not feasible without EPI. Many scientists felt that the Nobel Prize for magnetic resonance has been long overdue. As a positive side of the apparently long ramifications of the Nobel Committee's decision, one may note that the extremely thorough evaluation progress has finally led to identify the two individuals who are perceived by the MR community as being outstandingly deserving recipients of the award. It is, of course, a fiction to attribute a huge new field of science like MR to two individuals alone. The selection of, at most, three persons to represent a certain field according to the statutes of the Nobel Prize always has something artificial about it and is unfair to those who are not included on the list. This is certainly painful for those omitted. If we are honest, this element of selection is, however, certainly contributing to the appeal and attraction that the award has far into the non-scientific general public. Like any innovation, the invention of MRI took place within the context of a continuous scientific development. Singer, who already has been mentioned, has used inhomogeneous fields to localize protons before. E. Odleblad, T.R. Ligon, R. Damadian, and others had prepared NMR spectra of tissue samples and shown that this may be interesting to look at in man. Last, but not least, it took the efforts, energy, and dedication of highly idealistic clinicians and radiologists like Brian Worthington, Bill Bradley, Graeme Bydder, Alex Margulis, and others to bring MRI into the hospitals. Without the efforts of the Aberdeen group around John Mallard, in particular, who built the first practical human MR scanner, MR might have remained a curiosity in the engineering labs for a long while. Thus, in all gladness and celebration for the highly deserved award for Paul Lauterbur and Peter Mansfield, we should also be grateful to all of the individuals who have shaped and insp