Richard Ernst, a self-confessed tool maker, changed the way in which we listen to the magnetic melodies within atoms to such an extent that it became the most powerful tool in chemical analysis.
At the beginning of Richard Ernst’s scientific career, who he worked with mattered more to him than what he worked on. While he was a graduate student at the Swiss Federal Institute of Technology in Zurich, better known by its initials ETH-Z, the only person he wanted to do his PhD thesis with was a physical chemistry professor called Hans Günthard, because he was the only lecturer who had inspired him. Less clear to Ernst, however, was what he should actually work on, so he put the question to Günthard. “Why don’t you work on NMR?” Günthard replied, “It’s an interesting field that has just started.” To which Ernst replied: “I have no idea what that is.”
But Ernst took Günthard’s advice, little suspecting that his breakthroughs would propel what was at the time an intriguing discovery in physics to becoming a widely-used tool in life sciences and medicine.
NMR stands for nuclear magnetic resonance, a phenomenon that exploits the fact that all atomic nuclei that contain odd numbers of protons or neutrons have intrinsic magnetic characteristics. Isaac Rabi received the Nobel Prize in Physics in 1944 for showing how radio waves can detect the magnetic properties of these atoms. The nuclei of these atoms behave like tiny gyroscopes, spinning in random directions and generating their own magnetic fields. These randomly spinning gyroscopes all align when placed in a strong magnetic field, and bombarding them with radio waves at specific frequencies energizes nuclei to such an extent that they can flip, or jump, and the degree to which they jump can be measured.
Felix Bloch and Edward Purcell developed this concept further so that it could be used to reveal the identities of molecules in everyday liquids and solids. When the energized nuclei relax back to their normal state, they fire out radio signals in a manner characteristic of the nuclei’s makeup. Bloch and Purcell’s work created the field of NMR spectroscopy, where the radio signals transmitted from each nucleus register as a series of specific peaks on what is known as an NMR spectrum. This offered an unprecedented insight into the structure of matter. Researchers could now use magnetic fields and radio waves to examine the various atoms and isotopes present in an object, without affecting its form or structure in any perceptible manner.
In his Nobel Banquet address to Bloch and Purcell in 1952, Harald Cramér, member of the Royal Swedish Academy of Sciences, likened the behaviour of nuclei in NMR to a subtle and refined instrument, playing its own faint, magnetic melody, inaudible to human ears. “By your methods,” said Cramér, “this music has been made perceptible, and the characteristic melody of an atom can be used as an identification signal.”
Listening to the music amidst matter would no doubt have struck a chord with Ernst, who had wavered between becoming a chemist or a composer while at school. Ernst started developing NMR spectroscopy equipment under the guidance of Günthard in the late 1950s.
At the time when Ernst was finishing his PhD, though, NMR spectroscopy was still more of an esoteric tool than the method of choice to solve complicated chemical structures. The main Achilles heel of NMR was that radio signals sent out from these magnetic nuclei are feeble, and so it was extremely difficult for an experimental observer to discriminate weak signals from noise. As the sensitivity of NMR was disappointingly low, small amounts of nuclei were almost impossible to detect.
The task of making NMR spectroscopy more sensitive was a project that fitted in with Ernst’s growing realization that he wanted to be a tool-maker. “I wanted to build something that eventually would sell and earn recognition,” Ernst remembers. “It was this engineer-like, constructive endeavour that appealed to me rather than pure science.” The only place to do this, in Ernst’s mind, was in industry, where scientists could work with a clear commercial goal in mind.
After receiving his PhD in the early 1960s he joined the Californian company Varian Associates. There, Ernst was excited by his boss Weston Anderson’s work on a mechanical device called the “wheel of fortune”. Instead of the usual method of bathing a compound in a slowly tuned sweep of radio waves, Anderson was trying to develop a mechanical generator that excited atomic nuclei with more than one radio frequency, which he hoped would save time by plotting several signals in parallel. This approach eventually proved to be unpractical, but Anderson suggested that Ernst work on another possibility for acquiring parallel data.
Rather than subjecting atomic nuclei to different radio frequencies simultaneously, Ernst worked on achieving a similar effect by using a series of short and intense radio pulses. He plotted all the signals together as a function of time after each pulse. A computer converted this complex graph into the conventional NMR pattern, using the same mathematical calculation that is used to identify molecular structures in X-ray crystallography, a formula called the Fourier transformation (FT).
Ernst likened the way in which the new process called Fourier Transform NMR, or FT NMR, identifies nuclei to listening to a piano. “Imagine you want to find out which strings are broken in an old piano, and how time consuming it would be to strike one key after the other,” said Ernst. “FT NMR is like striking all 88 keys at once and immediately identifying which keys are still functioning.”
Combining the signals from the repeated radio pulses improves the signal-to-noise ratio. Now chemists could detect weak signals coming from small amounts of material, or from elements with magnetic nuclei that are rare in nature, and therefore low in abundance, such as 13C and 15N.
Ernst’s contributions to the field of NMR didn’t end there. He returned to Switzerland and became the head of the NMR research group at ETH-Z. In 1971, Ernst’s first graduate student came back from summer school and told him about an interesting presentation by the Belgian scientist Jean Jeener.
Another characteristic about NMR is that the way nuclei respond to radio waves not only depends on its own spin, but also on the spins of adjacent nuclei, as they are close enough together to be coupled by electric and magnetic forces. So each nucleus not only radios back information about itself, it also reports information about its neighbouring atoms.
This phenomenon annoyed physicists trying to use NMR to define the magnetic spins of nuclei, as the different atoms around each magnetic nucleus would shift peaks from their true values. The phenomenon that frustrated physicists, called the “chemical shift”, became a golden opportunity for chemists, as it allowed them to pinpoint the precise location of nuclei within tens and hundreds of molecules in complex organic compounds.
However, a single radio pulse, or a short series of pulses, cannot capture and identify information from this chemical shift. The effects of a single radio pulse disappear before the interactions between nearby nuclei fully play out. Ernst’s student reported how Jeener had proposed a way of capturing more information by using a simple two-pulse sequence – in other words allowing the complex interactions within adjacent nuclei to evolve after the first radio pulse before hitting it with a second pulse.
Jeener never developed his idea further, but using his original concept Ernst’s lab successfully created a method known as two-dimensional NMR spectroscopy. Known better by its abbreviation 2D NMR, this method worked by hitting compounds with radio pulses of varying lengths and intervals, creating a complex table of information that requires two Fourier transformations to convert into a NMR spectrum. This opened up the possibilities of NMR, allowing hopelessly difficult parts of NMR spectra to be analysed, and making it possible to find out which atoms are closely linked to others in a molecule.
Tool of Choice
NMR could now advance to the stage at which it could be used to identify the structure of large biomolecules like proteins, which contain thousands of molecules. Ernst’s colleague Kurt Wüthrich (Nobel Laureate 2002) pioneered the NMR analysis of proteins, and this led to NMR becoming an important alternative to X-ray crystallography. NMR has the advantage that it can assess proteins in their natural state in solution, unlike crystallography, which requires the protein to be in a crystalline form. 2D NMR spectroscopy could also be applied to imaging, and this paved the way to the invention of magnetic resonance imaging for medical diagnosis (Nobel Prize 2003).
Ernst took NMR to new dimensions where it eventually became the most powerful tool in chemical analysis. Ernst is always quick to acknowledge the part others played in the successful development of these methodological advances in NMR. But as every orchestra needs a conductor, finding new ways to listen to the magnetic melodies within atoms requires the guiding hand of a maestro in order to achieve harmonious results.
Ernst, Richard. Nuclear Magnetic Resonance Fourier Transform Spectroscopy. Nobel Lecture, December 9, 1991.
Vega Science Trust: Interview with Richard Ernst. Developer of Modern NMR Technologies (http://www.vega.org.uk).
Purcell, Edward M. Research in nuclear magnetism. Nobel Lecture, December 11, 1952.