High-Resolution Ion Mobility enabled LC-MS for metabolomics applications

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This is an application to the BBSRC ALERT 2022 Mid Range Equipment call. Here we seek support for the acquisition of a Waters Select Series Cyclic Ion Mobility Q-TOF mass spectrometry system. In lay terms we need to buy a new mass spectrometer (MS) which has the ability to separate and measure metabolites not only by their accurate mass, but also of their shape.All parts of biological organisms make, change and use a group of small molecules called metabolites. Together they make up something called the "metabolome". Metabolites do lots of things in cells and also change in response various conditions such as growth, development, infectious disease etc. When we mash up some tissue (this is called homogenising) samples, people can look for them individually (one at a time) if they know what they are and where they are. Looking for them in this way is called "targeted" metabolomics. However, we can also study them with all at once by doing something called "untargeted" metabolomics. At the University of Edinburgh (UoE) we do not have instruments for doing untargeted metabolomics experiments. This new machine we propose to buy, which has a lot of novel features would let us do untargeted metabolomics to see what is in a sample and how much of it is there. This is an incredibly important ability to have. So this instrument will help us to do both targeted and untargeted metabolomics.The new machine will also help us to use a critical piece of equipment which we already have called a DART (Direct Analysis in Real Time). This machine which is dependent on being attached to an MS. The one it's on now won't work for much longer. Importantly, our DART machine is the only one in Scotland and the only one in an academic laboratory. It has broad applications for quick screening at the molecular level in biological (what is where and how much of it is there), clinical (human and veterinary medical - therapies and diseases) and forensic (historic or criminal sample) investigations. This can be in homogenised or intact samples. For example, we have used this instrument to identify contribution of diet to tissue composition (i.e. what is it made of?) and are able to distinguish captive bred from wild lion bones, and are now using it to look at blood to see if we can work out how to tell from these samples if an animal is vulnerable to a disease and things like samples from eggs to see if we can tell if its going to be a male or female. So we need a new MS machine to attach this to. The newer machines are more sensitive, so our DART will still be the only one in Scotland, but it will work faster and be able to tell us more.The new machine will also let us do other things when we detach the DART. For example, the new machine will also let us look at where these metabolites are using intact tissues. This is known as spatial omics combining information on where and how much. Like taking a molecular photograph. This would be interesting for example in the case of something a skin infection. We can take a tissue sample (for example like a piece of skin) and see exactly whereabouts on or in the skin the metabolites are. And that can tell us what is happening in there at the molecular level, and we may be able to work out what controls those aspects of the biology we are interested in like what is the virus doing as it spreads and can we use that information to work out how to stop it.These three things are critical for us: 1. being able to do both untargeted and targeted metabolomics studies, 2. Keeping DART and making it more sensitive, 3. being able to do metabolite imaging. The new piece of equipment will let us do this for our own research and to help other researchers with the same type of interests and questions spanning the range of BBSRC biological research priorities. We can contribute £291,207 and ask for £565,055.75 from the BBSRC.