The 2003 Nobel Prize in Physiology or Medicine

Paul C Lauterbur and Peter Mansfield
for their discoveries concerning "magnetic resonance imaging"

For centuries the dream of every doctor was to be able to see the internal organs and to follow their functions and structures by non-invasive methods. The dream came true by Roentgen's discovery of X-rays, but the excitement was diminished by the fact that these high energy electromagnetic waves are biologically hazardous.

This year's Nobel Laureates in Physiology or Medicine are awarded for achievements which have fulfilled that dream. The discoveries of Paul Lauterbur and Peter Mansfield have led to the development of magnetic resonance spectroscopy as a useful imaging method, MRI, and the diagnostic method of greatest medical importance. It should be stressed that already four Nobel prizes in fields of physics and chemistry had been awarded for achievements in MR since it was discovered in 1944, and in the same way this year's Laureates are not medical professionals but a chemist and physicist. Paul Lauterbur had stressed it in his Nobel lecture with the indicative title: "All Science is Interdisciplinary - from Magnetic Moments to Molecules to Men".

Magnetic resonance imaging (MRI) has become the main technique in the routine diagnosis of many disease processes throughout the body. It is replacing and sometimes even surpassing X-ray computed tomography (CT). MRI's particular advantage is that it is non-invasive, using non-ionizing radiation, and still has a high soft-tissue resolution and discrimination. Moreover, it provides both morphological and functional information.

To articulate the diagnosis, the prerequisite is to understand the morphology and functions of normal organisms and to be able to determine and interpret the differences which occur in illness. It can be followed on multiple levels and described with different parameters. The most important is that the parameters are measurable and that to the numbers biologically meaningful information could be ascribed. This is why there is a close relationship between basic sciences, physics and chemistry, and medical diagnostics.

MRI is based on NMR spectroscopy which was first used by physicists F. Bloch and E. Purcel in 1944 to detect the magnetic moment of nucleus. Hydrogen nucleus in high intensity stationary magnetic field absorbs the electromagnetic radio waves of well defined frequency, so that it can be the parameter of recognition. The frequency is determined by magnetic field but can differ slightly depending on the chemical environment of the observed nucleus (chemical shift). So the frequency is the parameter with numerous information. In the process of relaxation the excited nucleus radiate the absorbed energy in the same frequency range by the processes characterised with two relaxation times, mainly depending on the dynamic state of the molecules in which are observed nucleus. NMR spectroscopy has a great impact in biochemistry and molecular biology since it enables the investigation of structure and function of biological molecules in solutions since the two main atoms in all living molecules, hydrogen and carbon, have very good magnetic properties. The main problem was how to get rid of the water signal and to follow only the behavior of the molecular hydrogen.

The idea to use NMR spectroscopy in medicine started with measuring the behavior of water molecules in intact tissues. Namely, our tissues have a great percentage of water and a strong enough signal could be expected. Further, there are differences in water content among tissues and organs. In many diseases the pathological process results in changes of the water content. The question was: would the measured parameters differ for tumor tissues and would the difference be of medical importance? The first results have shown that relaxation times are reproducible and different for normal and tumor tissues. Furthermore, the relaxation times differ for different healthy tissues depending on the water content. Hydrogen is also the main component of fat, where it has a different dynamic characteristic, and therefore offers another way of tissue differentiation.

The doctors would like to have picture of inner organs and the questions to be answered were: How to distinguish the spot in the body where the signal is coming from? How to perform MR Imaging? How to construct the image? The answers were given by this year's laureates Paul Lauterbur and Peter Mansfield.

On the 16 March 1973 a short paper by Paul Lauterbur, a Professor of Chemistry at the State University of New York at Stony Brook, was published in Nature entitled "Image formation by induced local interaction; examples employing magnetic resonance". From the title one would not comprehend that it represented the milestone for revolution in imaging. Even the editor did not find anything of sufficiently wide significance for inclusion in Nature. Yet, Lauterbur described a new imaging technique which he termed zeugmatography (zeugmo - yoke or joining together), because he was joining together a weak one-directional gradient magnetic field with the stronger main static magnetic field. This combination would allow the spatial localisation of the signal based on the idea that nuclei absorb and emit radio waves at different frequencies, depending on the strength of the magnetic field in which they are held.

To encode the signals and to produce the image he used a back projection method. This imaging experiment was a step from the single dimension of NMR spectroscopy to the second dimension of spatial orientation and become the foundation of MRI. The main disadvantage was that the recording was time-consuming, and fast processes could not be observed. In his paper he described how successive additions of small gradient magnetic fields to the main magnetic field made it possible to visualise a cross section of tubes with ordinary water surrounded by heavy water. The result was astonishing as no other imaging method can, even today, differentiate between ordinary and heavy water.

In his talk on First Specialized Colloque Ampère in Cracow in 1973.: "Multi-pulse line narrowing experiments: NMR "diffraction" in solids?" Peter Mansfield presented a method for selective imaging of a particular two-dimensional slice of an object. The object was held in a gradient magnetic field and irradiated by radio waves at a particular frequency. To shorten the time of recording he applied the pulses of magnetic field gradients in order to precisely measure the differences in the resonance times and phases of small volume peaces. The algorithms he developed processed signals effectively and transform to an image in just several seconds. This was an essential step for obtaining a practical method for usage in medicine. Mansfield also showed how extremely rapid imaging could be achieved by very fast gradient variations - echo-planar scanning. The technique became useful in clinical practice for observing heartbeat or in brain research, in which mental activity can be tracked by monitoring changes in blood flow.

Prof.dr.sc. Jasminka Brnjas-Kraljevic
University of Zagreb
School of Medicine
Department of Physics and biophysics
Salata 3
10 000 Zagreb
Croatia