Obtaining a novel type of contrast for Magnetic Resonance Imaging Although water is essential to life on earth, much remains to be learned about its fundamental properties. There are two protons in each water molecule and their magnetic properties can be configured in different ways, now Professor Geoffrey Bodenhausen and his colleagues aim to gain deeper insights into the properties of water. Characterising the fundamental properties of water remains a challenging task. Some of these properties are related to the fact that the hydrogen atoms in water have a nucleus, which itself has a property called spin. “There are two protons in each water molecule, and the two spins talk to each other. It turns out that they can appear in different ways,” says Geoffrey Bodenhausen, Professor of Chemistry at The research group at the Ecole Normale Supérieure in Paris with their equipment for demanding magnetic resonance experiments. In para-water, the two protons are arranged in what can be loosely described as an anti-parallel configuration. “That occurs when one proton is up while the other one is down, or vice-versa,” continues Bodenhausen. “This means that the proton spin is neither on the left side of the molecule nor on the right, but somehow inbetween, somehow de-localised.”
Para-water Para-water accounts for 25 percent of water at room temperature, the remaining 75 percent being ortho-water, in which the proton spins are symmetrical. As the Principal Investigator of the DiluteParaWater ERC project, Bodenhausen aims to look at water in which there is a deviation from this 25-75 balance, also known as a tripletsinglet imbalance (TSI). “The project is about trying to create or amplify this imbalance – to get more para-water than ortho-water beyond this 1:3 ratio, or the other way round,” he outlines. The first step is to prepare water in this particular state, then to isolate it. “We want to isolate this water somehow – in a solid, a liquid, or a matrix of some sort. From there we can then try to study its properties – to see if para-water has different properties from orthowater,” says Bodenhausen. By studying the behaviour of para-water and ortho-water, researchers hope to make progress in understanding the overall mixture. However, preparing para-water itself is a challenging task; parallels can be drawn here with molecular hydrogen gas, which also has two protons. “It’s exactly like water, except that
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his colleagues. “Currently we lose a lot of the imbalance. So the imbalance, instead of being massive, becomes very subtle, on the border of what we can observe,” he explains. A lot of energy in the project has been devoted to optimising the experimental procedures in order to preserve this imbalance in bulk water, which is proving challenging; however, researchers have made more progress in other avenues of investigation. “The concept can be extended to consider para- and orthodrug molecules. Some drugs also have two protons, just like water has two protons. This has become a thriving line of research in its own right,” says Bodenhausen.
Transport phenomena This technique also holds potential as a means of studying transport phenomena within fluids, such as flow and diffusion. While studying these phenomena in water has again proved challenging, Bodenhausen and his co-workers have gained important insights into other molecules with two protons. “We have been able to measure very slow diffusion, in particular the diffusion of very large molecules which – because of their size – is very slow. We have made quite a bit of progress in measuring the diffusion of large objects like large molecular assemblies,” he says. There are several potential avenues of investigation arising out of the project’s work; while fully aware of the wider
If a few para-water molecules could be isolated in dioxane, they would be protected from proton exchange and have a lifetime which we believe to be on the order of 20 seconds.
The research group at the Ecole Normale Supérieure in Paris with equipment for demanding magnetic resonance experiments
there is no oxygen atom in between. From that point of view, hydrogen is analogous to water,” explains Bodenhausen. It is relatively easy to separate ortho-hydrogen from para-hydrogen, and researchers have found that they have very different properties. Yet separating the two forms of water is more difficult. “One of the difficulties is that the protons do not remain attached to the same oxygen atom. Water molecules tend to exchange their protons – so a proton can travel from one oxygen atom to another,” continues Bodenhausen. A pure para-water molecule loses its identity if a proton hops to a neighbouring oxygen atom in this way, which represents a challenge in terms of the project’s overall agenda. The idea of the project is to isolate water molecules by protecting them behind a layer of different molecules. “A solvent we have in mind is called dioxane. This would stick to the water molecule and prevent it from exchanging any protons with other water molecules,” says Bodenhausen. This would help preserve the TSI and turn it into a longlived state (LLS). “The idea is that the water molecules in dioxane would be isolated, there would be few water molecules diluted among a larger number of dioxane molecules. In that
environment they would be protected and have a lifetime which we believe to be on the order of 20 seconds,” explains Bodenhausen. The imbalance between para-water and ortho-water is created by freezing ordinary water protected by diluting it in dioxane at a temperature of around 1 Kelvin, which is about -272° C. Researchers then apply a technique called dynamic nuclear polarisation (DNP) to bring the temperature of the spins down even lower, to about 50 milliKelvin, around 20 times colder than the frozen sample. “We know from our calculations that there is an excess of the triplet state over the singlet state at that temperature – so that we have an excess of the orthowater,” says Bodenhausen. The next question is how to study the imbalance at this very low temperature. “There’s no technique to visualise what we have done at very low temperatures. So we have to extract it from this very low temperature arrangement and transfer it to room temperature,” outlines Bodenhausen. This dissolution part of the procedure has to be performed very quickly, as the lifetime of the imbalance is limited to around 20 seconds. This is a major challenge for Bodenhausen and
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The potential here lies in the idea that a long-lived state can be used to improve the sensitivity of drug screening. Typically, drug screening is performed on a very large scale, and fairly high concentrations of both the drug and the target are required. “The target is typically a molecule in the human body, often a protein. A solution of purified target proteins has to be prepared, and that’s very expensive,” outlines Bodenhausen. The technique developed in the project enables drug researchers to reduce the concentration of their target, so making this kind of experiment much cheaper. “It’s about good sensitivity for small amounts of purified proteins. We can work at much lower concentrations,” says Bodenhausen.
picture, Geoffrey Bodenhausen is keen to also pursue further research into water. “We’re still trying to improve the experimental procedures, as we still want to study water,” he stresses. The transfer of a TSI from an apparatus at very low temperature to a machine that works at room temperature is a key challenge in this respect. The aim is to essentially accelerate this process by transferring a solid pellet instead of a liquid, and so preserve the imbalance between para- and ortho-water more effectively. “We’ve made a lot of progress here, but the method is not yet functional. If we can make it work, that would be the ideal way of proving that we indeed have an imbalance, so that we can study the properties of triplet water, and the role of singlet water,” says Geoffrey Bodenhausen.
DILUTEPARAWATER DILUTEPARAWATER (Long-Lived Nuclear Magnetization in Dilute Para-Water) Project Objectives
The magnetization of hydrogen nuclei in H2O constitutes the basis of most applications of magnetic resonance imaging (MRI.) Only ortho-water, where the two proton spins are in states that are symmetric with respect to permutation, features NMR-allowed transitions. Parawater is analogous to para-hydrogen, where the two proton spins are anti-symmetric with respect to permutation. The objective of this proposal is to render para-H2O accessible to observation. Several strategies will be developed for its preparation and observation in solids, liquids and gas phase.
Project Funding
DILUTEPARAWATER is funded by the European Research Council. Project funding total is € 2,500,000.
Project Team
The research group at the Ecole Normale Supérieure in Paris with their equipment for demanding magnetic resonance experiments.
Contact Details
Project Coordinator, Prof. Geoffrey Bodenhausen Département de chimie Ecole Normale Supérieure 24 rue Lhomond, 75231 Paris cedex 05, France T: +33 1 44 32 34 02 W: http://paris-en-resonance.fr W: https://isic.epfl.ch/faculty-members/ emeritus_professors/bodenhausen/ W: https://cordis.europa.eu/project/ rcn/110296/factsheet/de
Professor Geoffrey Bodenhausen
(a) Carbon-13 NMR signals at 1.2 K in thermal equiibrium (blue) and amplified by DNP (red); (b) Boosting carbon-13 signals by repeated cross-polarization at 1.2 K; (c) Carbon-13 NMR signals after dissolution at 300 K in thermal equiibrium (blue) and amplified by DNP (red); (d) Slow decay of polarization at 300 K.
Geoffrey Bodenhausen is a Professor of Chemistry at ENS in Paris. He specialises in NMR and MRI, and played a pioneering role in the field of 2-dimensional Fourier transform NMR spectroscopy. He is a Fellow of the American Physical Society.
www.euresearcher.com
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