"All Science is Interdisciplinary"Nobel Prize for Medicine or Physiology Awarded to MRI PioneersIn 2003, the Nobel Prize in Physiology or Medicine was awarded jointly to Paul C Lauterbur and Peter Mansfield for their discoveries concerning "magnetic resonance imaging". As a biomedical engineer and, if you allow me, a scientist, I was glad and proud that these two excellent researchers and scientists received this prize, generally considered as the most important in the world of science, for their contribution to medical science through their pioneering work that includes a lot of basic science and engineering knowledge. Their efforts resulted in one of the probably most complicated, but also most useful non-invasive devices ever developed for the research of living tissue. Biomedical engineering is an interdisciplinary field of science that increases knowledge in engineering, medicine and biology, and contributes to human health and wellbeing through activities such as research, development and applications, that integrate engineering with biomedical and basic life sciences but also with clinical practice. Therefore, I must mention that, in addition to the Nobel Prize in Medicine, this year is rich with awards to scientists whose field of interest and discoveries are very close to biomedical engineering. The decision of the Royal Swedish Academy of Sciences to award the Nobel Prize in Chemistry in 2003 "for discoveries concerning channels in cell membranes" to Peter Agre "for the discovery of water channels" and to Roderick MacKinnon "for structural and mechanistic studies of ion channels" shows this closeness of research in different scientific fields. Understanding of the spatial structure of the ion (potassium) channel, discovered by MacKinnon, enables the scientists today to "see" the ion flow through channels opened or closed by cellular signals. The action potential of nerve cells is generated whenever a chemical signal transmitted from an adjacent nerve cell opens the channel which again results in an electrical pulse that propagates along the surface of the nerve cell. Please, read more on the Nobel Laureates 2003 in chemistry in the March Issue of the News. The 2003 Nobel Prize in Physics was awarded jointly to Alexei A. Abrikosov, Vitaly L. Ginzburg and Anthony J. Leggett "for pioneering contributions to the theory of superconductors and superfluids". Superconducting material is used, for example, to obtain strong magnetic fields used in magnetic resonance imaging for medical examinations, thus the link to the MRI devices is obvious. Let me come back to the medicine laureates: I especially liked Lauterbur's Nobel Lecture All Science is Interdisciplinary - from Magnetic Moments to Molecules to Men Having listened to it, I could hardly believe that the whole hour of his lecture passed so fast. It does not happen very often that the Nobel Prize for medicine or physiology is awarded to scientists who had been primarily educated in a field other than medicine. P. C. Lauterbur is originally a chemist and P. Mansfield a physicist. But, "that is the natural development of science and engineering," Lauterbur said in his Nobel Lecture held on December 8, 2003 at the Karolinska Institute. He devoted his lecture to fundamental facts about science and commented on how various normally independent disciplines come together in solving a common scientific problem. The discovery of the physical phenomenon of nuclear magnetic resonance made by Felix Bloch and Edward Mills Purcell was awarded a Nobel Prize in Physics in 1952. They demonstrated in 1946 that for every type of atomic nucleus with unpaired protons and / or neutrons which is exposed to a magnetic field, there is a simple relation (a mathematical constant) between the strength of the magnetic field and the frequency of emitted radio waves. Edward Purcell was also investigating the interaction of an NMR machine in his laboratory with biological materials: he put his head into the machine. Felix Bloch was more modest: he was experimenting with his thumb. These events, which became public much later, are an expression of the early recognition of NMR applications in biology, though at the time those experiments happened, the researchers thought the results were too weak and unreliable. It took another quarter of a century to make the step from condensed matter MR applications like spectroscopy and studies of the structure of chemical compounds to medical and biological imaging. Still, Lauterbur thinks that this, rather late step towards imaging in the early 70's was not a matter of undeveloped technology but a matter of previously immature concepts. When he started his experiments, in order to see whether the information from the tissue water was of any use, he noticed that the phenomenon, as well as the measured values, were stable and reproducible for all kinds of different tissue, normal and abnormal, healthy or malignant. So he started thinking of the methods which could present the measurement results in a spatially resolved way, i.e. encoding the NMR signals from non-homogenous and non-uniform magnetic fields. There were three main problems to be considered before starting any experimental work. The first problem was to develop a methodology which could transform one-dimensional signals into a two-dimensional or even three-dimensional image. At the time Lauterbur started his work, computerized tomography was also at a very early stage of development and computational methods used for image reconstruction were not made public at this time. He had to discover the mathematical background on his own. As he said, he used an analogy, since he was familiar with methods used for solving problems of expanding molecular structure, which he found very similar to the problem of MR imaging. Introducing magnetic field gradients enabled obtaining necessary spatial information from the analysis of the emitted radio waves. In order to obtain two-dimensional images, one had to use iterative methods for solving the equations. Signal-to-noise ratio in such a (still hypothetical) machine with the small magnetic field practically available was the second concern in those days. Lauterbur said that he was always proud of the engineering aspect of his education: his calculations showed that one could expect enough signal even with small strengths of the field. Of course, there was the doubt whether it was possible to build magnets powerful and big enough to enable the screening of the whole body of an adult person.
After convincing himself that magnetic resonance imaging of biological tissue is possible, he
dropped most of his other work and concentrated only on this novel method of imaging. He had to
find suitable biological materials for his experiments and therefore he started visiting meat and
vegetable markets more often: a source a biologist could hardly accept for his work. When he
finally finished a series of experiments and obtained, in his opinion, reasonable results,
he sent an article to "Nature", in 1972. It was firstly considered "un-publishable" by the
reviewers. But then, after a discussion with Lauterbur, and a second opinion from another
reviewer, the article was published [Nature 242, 190-1; 1973]. And,
indeed, what does "Nature" write on the Nobel Prize laureates for 2003? At the early stage of research on MRI it was not easy to get support for the investigations and the equipment. The first magnet Lauterbur purchased for his lab, even though it was meant for "whole body" imaging, was much smaller than contracted, but it allowed for the very low frequency of the resulting magnetic field to be treated as direct current which, in turn simplified many of the early experiments and analysis of the results. In the early 80's MRI moved from experimental laboratories to medical and clinical departments in the health care system. Lauterbur said that it: "involved a lot of engineering work in order to make a commercial device that could be sold to a physician and operated in a routine way". It also changed the structure of modern radiology departments in hospitals: because the complexity of the imaging equipment, medical physicists and engineers became standard members of the team. Industrial laboratories took over research and development of different MRI applications in medicine. Due to a large number of engineers and physicists who now worked on solving the practical problems, the time it took for the newly developed devices to reach the market was reduced significantly. The field is still growing and actually nobody knows exactlly how far potential of the technique may lead. MRI is still not an ideal technique, but in Lauterbur's belief it will become just that. Concluding his speech at the Nobel Prize Ceremony, Lauterbur expressed his belief that research in MRI has to stay interdisciplinary: scientists from nature sciences, physicians, primarily radiologists and cardiologists, medical physicists, engineers and biologists, shall all work together, continuing the balance between the clinical and engineering aspects of MRI development. The impact of MRI has been so great because so many people contributed. Peter Mansfield succeeded in showing how detected resonance signals from a precise region of the body, obtained by selective excitement with gradients of the magnetic field can be analysed. He also developed mathematical methods for the accurate and fast transformation of received signals into medical images. Fast imaging methods based on his research enabled practical, clinical applications of MRI since it drastically reduced the time necessary for obtaining the data from the emitted signals. He presented his discoveries in his Nobel Lecture Snap-Shot MRI In his research, Mansfield took quite another direction from Lauterbur. In the same year, 1973, he and A. Grannel published a paper in the Journal of Physics discussing NMR 'diffraction' in solids [Journal of Physics C: Solid State Physics 6, L422-6, 1973]. In 1977 he introduced the echo-planar imaging (EPI) technique based on spin density projections which is a method of active magnetic screening used in practically all modern scanners. The information obtained from the radio waves during the screening was presented in a so called 'k-space map', and by making a Fourier transform of that data, one can get an image of the cross-section of the body. Mansfield developed several methods of producing NMR images. He used "tricks" and "played" with T1 and T2 relaxations in order to pick up the right moment to look into the body and obtain sharp margins of the lesions. He also introduced movies into MRI: a set of rapid images of a slice in a human body was made and afterwards projected one after another so that the heart, fetus or peristaltics for example, could be shown in movement. Mansfield had addressed and solved the problems of scaling up medical imaging experiments to whole-body early in his research. He developed the echo-volumar imaging (EVI) technique, which is much more complicated than EPI. A whole volume, not only a single slice, is scanned at the same time. It was therefore necesary to introduce three gradients all at once. At the time Mansfield was developing EVI, with magnetic field strengths of 0,5T, the total acquisition time was 80ms. Today with magnets up to 3T or 4T, it is reduced to approximately 50 - 60 ms. The latest research in his laboratory is concentrated on active acoustic control. This concept was introduced to ameliorate the problem of acoustic noise from MRI, in particular from high-speed EPI. An acoustic gradient pulse is produced that comprises an oscillating gradient of finite duration. This technique when applied with active acoustic control enables reduction of acoustic noise by 50 dB [Magn Reson Med 50, 931-5, 2003]. Speaking for BBC on October 6, 2003, Prof. Paul Matthews, director of the Centre for Functional MRI at the University of Oxford said: "Professor Mansfield is responsible for many of the major developments that underlie the current use of MRI that has become the single most important medical diagnostic technology. Because of his work, we can now see pictures of the body which give doctors a "snapshot" of the action of the heart. We can also see the action of the brain which allows scientists to see the dynamics of thought." From the 1980s, when the first MRI devices were introduced into clinics, to the present day, approximately 22.000 MRI devices were installed around the world. More than 60 million examinations have been performed in health care in that period. Which are the newest developments in MRI and what is to be expected in the future? Functional MRI (fMRI) is used for the measurement of brain activity by detecting the level of oxygen in different areas of the brain. MR angiography enables diagnostics of the cardiovascular system by producing images of the vessels. Susceptibility weighted imaging (SWI) is also used for imaging of the brain and enables taking pictures of details previously unavailable. Magnetic force resonance microscopy is being developed in order to allow taking images of tissue at the atomic level. Low field MRI provides a possibility to build portable MRI equipment. And, there is certainly much more to come.... The Nobel Prize for the scientists who were the first to discover the major principles of the use of MR in medicine was awarded later than the scientific community had expected. "It could have been given 10 years ago", said George Radda from the University of Oxford for Science [Science 302, 382-3, 2003]. Lauterbur himself said that many people contributed to the development of MRI in the past three decades. Therefore, there is no doubt that the choice of the right people for this award was a "hot potato" for the Nobel Committee. But, as Lauterbur said, "the work has paid off in a deeply personal way". And the 2003 Nobel Prize is most probably not the last one presented to scientists who have dedicated their work to MRI.
Ratko Magjarevic
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