From the Green Transition to Cardiac Arrhythmia  – how insights from NMR spectroscopy can help

NMR has a wide range of uses in the world of science ranging from structural assessment, chemical reactions to quantification. Reinhard’s group at Aalborg University (AAU) illustrates this diversity, as he works across the spectra of NMR uses, applying NMR in metabolomics, proteins, fungi, and industrial processes.

Reinhard Wimmer took his education as a chemical engineer at the Johannes Kepler University in Linz Austria, where he wrote his PhD in NMR spectroscopy. He then spent two years in Zürich as a post doc doing protein-NMR spectroscopy at ETH Zürich in the group of future Nobel prize laureate Kurt Wüthrich. In 1999, when Aalborg University bought a new NMR-spectrometer, they needed someone who could operate it to its fullest. Reinhard was brought in to fill that position and has stayed there ever since.

Reinhard is now a Professor at AAU and his group is the only one at the university working with NMR spectroscopy. Because of this, he spends a lot of time helping and supporting other research groups determining structures of molecule for all kinds of different research that comes his way. His group might be rather diverse, but all his work has one common denominator, namely the use of NMR spectroscopy.

From plastics . . .

Together with process engineers, Reinhard investigated the chemical processes involved in hydrolysis of PET, a plastic widely used for e.g., drinking bottles. To do this they use a wide range of different 2D NMR spectra for identification of individual products, to make out which signals in the ¹H-NMR spectra that correlate with which substance, allowing their quantification. Put simply, they are using ¹H-NMR to see what species are present in the reaction mixtures and how their concentrations change with reaction conditions.
“PET is made of two building blocks, ethylene glycol and terephthalic acid. What you hope to get from hydrolysis at high temperatures, is a 1:1 mix of the original building blocks, ready to be turned into new PET. However, when you heat the reaction mixture, you lose a lot of valuable building blocks to several side-reactions. We use NMR to describe those side-reactions and to identify reaction conditions where they are kept at a minimum. This will be valuable for minimizing waste of valuable materials, thus enhancing recycling efficiency and supporting a greener future.”

. . . to the heartbeat

One of Reinhard’s ongoing research projects focuses on the calmodulin protein. Calmodulin is a very important messenger within the human body, regulating several different processes. Amongst one of the more important is the ion channels that control the heartbeat in humans and animals alike.

“Every heartbeat starts with an electric impulse and this electric impulse changes the electric potential in the heart, which then opens a cascade of sodium and calcium channels, creating an influx of sodium and calcium to the heart cells, leading to cardiac muscle contraction. These ions are subsequently pumped out of the heart cell again and the muscle relaxes. This is the process of the heartbeat.”

The calmodulin protein is bound to several ion channels and it can close the channels via a feedback mechanism, that ensures that the level of calcium in the cell never gets too high, since it could lead to heart failure. If calmodulin does not work properly, e.g., as a consequence of a mutation, this feedback loop is disturbed, which can cause cardiac arrhythmia that can be potentially lethal. Yet, people with mutations in calmodulin exist, and indeed, many of them suffer from cardiac arrhythmias. Together with collaborators at Aalborg University, Reinhard use NMR spectroscopy to investigate the molecular mechanisms of how calmodulin regulates the ion channel, deciphering how mutations in calmodulin might cause the cardiac phenotypes.

One such mutation has recently reached some notoriety, as it became the central question in an Australian court case on infanticide, where a mother was convicted of having killed her infants despite maintaining her innocence. It later turned out that two of the children carried a mutation in Calmodulin, G113R, that could well have caused cardiac arrest. An inquiry into the convictions was held (https://2022folbigginquiry.dcj.nsw.gov.au/) and it ended with an unconditional pardon to the convicted (https://doi.org/10.1038/d41586-023-01871-8).
Reinhard’s group, together with the groups of Michael Overgaard (AAU) and Hideo Iwaï (Helsinki), investigated structure and dynamics of the G113R variant, discovering that the mutation stabilized Calmodulin in its Ca-free form, but destabilized the Ca-bound form. Thus, the mutation brings imbalance to the finely tuned machinery that regulates the heartbeat.

Collaborators

Besides working with several groups at his own university, Reinhard is also a part of an EU project with twenty-five partners across fourteen different countries, where they use both NMR-metabolomics methods and other analytical methods than NMR to investigate the fermentation processes of seaweed (https://seamark.eu/ ). Seaweed has huge potential as a food resource, but optimization of cultivation and processes are needed, a task the consortium aims to do.

New and current projects

In the future, Reinhard wants to continue working on calmodulin and its role in regulating the heartbeat, continuing the work he has done with his colleague Michael Overgaard, who handles the protein chemistry part of the research.

He is also furthering his interest in metabolomics and developing NMR methods for investigating reactions mixtures to monitor and control chemical reactions, for which there are promising projects in the new bioeconomy, such as seaweed, as well is in more traditional fields of chemical engineering.

Furthermore, he will continue to support groups in need of structural determination at the university of Aalborg, as he finds that these side tasks often evolve into something more. For instance, he has been supporting a group researching natural substances in fungi, which feels a little like making a jigsaw puzzle and is something he really enjoys.

Strength of Danish NMR

“Compared to the size of the country, there are many laboratories and many people doing NMR and a wide range of different groups doing many kinds of NMR. Almost any problem you have regarding anything NMR related, there is a group or an individual who has worked with it before or is interested in working with it now and helping you out.” Reinhard says. “The Danish NMR society is a very diverse one and relatively large compared to the country size.”

Written by: Jonatan Emil Svendsen