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Attentive observer of metabolic processes

Physicist Dr. Jan-Bernd Hövener makes magnetic resonance imaging devices smaller and their magnetic fields weaker in the hope that precisely these properties will help him detect abnormal metabolic processes and tumours. On 9th June 2015, the International Organisation for Medical Physics (IOMP) awarded Hövener the Young Scientist Award in Medical Physics, the organisation’s most important prize for up-and-coming scientists.

The magnets that Dr. Jan-Bernd Hövener is using to study hyperpolarisation are only a fraction of the size of those normally used in MRI devices. © J. Faber/Freiburg University Medical Centre

Jan-Bernd Hövener's research begins on the roof of the Neurocentre of the Freiburg University Medical Centre. In a small shed, the physicist is producing a substance, parahydrogen, that might in future be used to measure an organ's metabolism and to identify tumours at a much earlier stage than currently possible. "Hövener explains: "We need to produce parahydrogen up here on the roof of the building in order to prevent accidents. Up here, any leaking hydrogen immediately dilutes, without the risk of explosions." Hövener, who has worked and studied in Nice (France), Heidelberg (Germany), New York and Pasadena (USA), has been at the Department of Radiology at the Freiburg University Medical Centre since mid-2009, and, since 2014, has been the head of the Emmy Noether research group "Metabolic and Molecular MRI" funded by the German Research Foundation (DFG). Hövener and his group of researchers are investigating a phenomenon known as hyperpolarisation, which could potentially revolutionise clinical imaging.

While he was studying physics, Hövener discovered his enthusiasm for medical physics. "It was important for me that my work led to a concrete application. That was my goal from the very first day. I wanted to come up with something that would benefit each individual and society at large," says Hövener. Although he is only 35 years old, Hövener has already spent ten years optimising magnetic resonance imaging, MRI for short. Hövener has now received the "2014 IUPAP Young Scientist Award in Medical Physics" that is sponsored by the International Union for Pure and Applied Physics (IUPAP) and awarded by the International Organisation for Medical Physics. IUPAP is the world's largest organisation for medical physics and every year it awards a special prize to scientists under 45 for their achievements in the field of medical physics.

Imaging without exposure to radiation

In the early 1970s, it was discovered that magnetic interactions could be used to produce images from inside the body. In 2003, this finding was even honoured with a Nobel Prize. Since then, MRI has become one of the most important and widely used imaging methods in medicine. Using state-of-the-art MRI devices, such as those used at the Freiburg University Medical Centre, short video sequences can be created, blood vessels visualised and the structure and function of the brain imaged. However, unlike X-ray and computed tomography, patients are not exposed to harmful radiation.

The MRI signal is based on the magnetic properties of hydrogen nuclei, which have a so-called nuclear spin and thus align with a magnetic field, similar to compass needles in the Earth's magnetic field. External excitation leads to the deflection of these 'subatomic compass needles'. The 'needles' then send out a weak signal from which the MRI image is calculated. The behaviour of this signal provides information about the tissue structure.

Increasingly stronger magnets

However, in contrast to compass needles used in hiking compasses that always point to the north, even in weak geomagnetic fields, the nuclear spins are very weakly magnetic. This is why stronger MRI magnets are being developed. "The magnets currently used in MRI devices have a magnetic field strength of 1.5 to 3 Tesla. In comparison, magnets that lift cars at a junkyard only have one tenth of this strength," says Hövener.

Even these high-performance magnets align only a fraction of the hydrogen atoms present. "If you gave every person in Freiburg a hiking compass, all 200,000 compass needles would point north. However, the compass needles from an MRI are much weaker. "When we are looking at 200,000 atoms with an MRI device, we only detect signals from two spins, even though the magnetic field is 50,000 times stronger than that of the Earth. We can only see these two spins in an MRI. This fraction, i.e. two signals out of a possible 200,000, is known as thermal polarisation.

Alternative effect amplification by hyperpolarisation

However, scientists have a number of tricks up their sleeves for treating molecules so that more nuclear spins can be aligned and thus made visible with an MRI device. Scientists call this phenomenon hyperpolarisation. However, previous approaches have certain drawbacks. The molecules are only hyperpolarised for a short time, each MRI measurement destroys a portion of the magnetisation, and re-magnetisation of the target molecules is not possible.

In a normal MRI device (left) only the signal of a handful of atoms out of several million can be used (red arrows). Hyperpolarised atoms (right) lead to far better yields. © JB Hövener/Freiburg University Medical Centre

This is where parahydrogen comes into play. As mentioned above, Hövener produces parahydrogen up on the roof of the Neurocentre and takes it in a glass bottle into the basement of the Neurocentre where he and his colleagues carry out their experiments. "We conduct the hyperpolarisation with parahydrogen and a catalyst, which leads to the magnetisation of a large number of target molecules. The polarisation effect therefore remains for as long as a suitable magnetic field is available. Although polarisation is still destroyed by an MRI measurement, it is restored within a few seconds," says Hövener.

Hövener and his colleagues from York (GB) have demonstrated this effect, which Hövener refers to as continuous hyperpolarisation, for pyridine and have published their findings in the renowned journal Nature Communications. Recently, they were also able to describe the effect theoretically. In addition, they have repeated the effect on a biomolecule (nicotinamide), which is involved in many cell metabolism processes, including the respiratory chain. However, the new approach goes well beyond the use of this biomolecule. "We hope that the method will also be applicable to other biomolecules, including amino acids, which are the basic building blocks of proteins," says Hövener.

Smaller and cheaper devices with expanded functionality

The new method could be hugely advantageous for medical applications. "All we need for our measurements is a magnetic field 300 times weaker than that of current MRI devices. These magnetic fields can be generated with a car battery, and the magnet only weighs two kilogrammes, rather than several tonnes. In terms of space, the MRI would therefore be not much bigger than three shoeboxes," says Hövener. In addition to smaller size and hence lower costs, these MRI devices would be able to image molecular processes and so be used for the early detection of tumours. This is because cancer tissue has a significantly altered metabolism and would most likely be detected a lot earlier than with current devices. Also patients who cannot presently undergo MRI due to cardiac pacemakers and surgical screws, could be examined with the new MRIs.

An apparent drawback of the method is that a contrast agent has to be used as a catalyst between parahydrogen and target tissue in order to make visualisation at all possible. However, this apparent disadvantage could also be seen as an advantage as it would only allow the visualisation of tissues and cells with particular properties.

From the test tube to clinical routine

Hövener's continuous hyperpolarisation currently only works in the test tube. Although the physicist does not yet even dare dream of using the new method in clinical routine, his studies are heading in this direction. "Inhalation of hydrogen gas is currently being discussed as a therapeutic measure. If it turned out to be safe, patients would in future be injected with contrast agents that would then be hyperpolarised with parahydrogen. This would help us discern abnormal tissue very effectively," says Hövener.

Hövener's method will probably never replace classical MRI. In cases where large tissue structures need to be examined, where anatomical images are sufficient and where contrast agents cannot be used, normal MRI would remain the method of choice. However, in cases where information about the metabolism or certain cells needs to be acquired, hyperpolarisation could fill an important gap. However, until this happens, Hövener continues to carry out his research up on the roof and in the basement of the University of Freiburg Medical School building.

Literature

Hövener, J.-B. et al. A hyperpolarized equilibrium for magnetic resonance (2013). Nat. Commun, 4:2946. doi: 10.1038/ncomms3946.

http://www.nature.com/ncomms/2013/131216/ncomms3946/full/ncomms3946.html

Hövener, J.-B., Knecht, S., Schwaderlapp, N., Hennig, J. and von Elverfeldt, D. Continuous Re-hyperpolarization of Nuclear Spins Using Parahydrogen: Theory and Experiment (2014). ChemPhysChem, 15:2451–2457. doi: 10.1002/cphc.201402177.

http://onlinelibrary.wiley.com/doi/10.1002/cphc.201402177/abstract

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