Critical mass spectrometry
Interview: Dr Mary Doherty (University of the Highlands and Islands)…
Critical mass spectrometry
Dr Mary Doherty is a Senior Lecturer in Mass Spectrometry, based in the Lipidomics Research Facility at the University of the Highlands and Islands (UHI) in Inverness. Her research focuses on using mass spectrometry to understand fundamental biological and biomedical problems, including diabetes and cardiovascular disease, as well as help develop more sustainable protein production in aquaculture and new materials for medical devices.
When Dr Mary Doherty first graduated 20 years ago with a Degree in Chemistry from the University of Edinburgh, there wasn’t even a word for the science on which she would be focusing only seven years later. In 2002, she was offered a post at the University of Liverpool to specialise in something called “proteomics,” a term coined just five years before to describe the global study of the structures and functions of proteins. And just to make the new job even more pioneering, Doherty and her new colleagues in Liverpool also started using a technology not often used in biology before then – mass spectrometry.
Now a Senior Lecturer in Mass Spectrometry at the University of the Highlands and Islands (UHI), based in Inverness, Doherty has witnessed a spectacular growth in the use of the technology over the last two decades.
In the past, it was primarily used in the petrochemical industry, but Doherty now uses it for everything from analysing new kinds of materials for medical devices to measuring the effects of stress on zebrafish. Her department also carries out research for a wide range of clients, from fish feed manufacturers to leading pharmaceutical companies, combining fundamental research with commercial work.
Doherty has been fascinated with enzymes and proteins since her earliest days as a student, and as her work progressed, she started to focus on “the functional characterisation of electron transport proteins,” to understand more about proteins – how they are made and broken down in cells and generate the energy cells need to grow. One of her specialist subjects is enzyme kinetics – measuring how quickly proteins cause a reaction and how fast they change, so we can understand the properties of individual proteins and use them to develop new products, as well as to improve nutrition or health. For her PhD Thesis, she focused on one special protein, isolated from a marine organism; but when she moved to Liverpool in 2002, she was able to study whole “cohorts” of proteins at once, taking advantage of the latest advances in mass spectrometry and recent breakthroughs in genomics which had led to the sequencing of multiple proteins. “I had dabbled in the use of mass spectrometry in Edinburgh,” says Doherty, “but the Liverpool project was much more advanced, looking at hundreds of proteins at once.”
Before she worked in Liverpool, Doherty studied for her Master's Degree in St Andrews, going back to Edinburgh to get her PhD then moving to New York in 2001, where she continued to focus on enzyme kinetics, after arriving on one of the first flights to cross the Atlantic in the wake of 9/11.
Mass spectrometry in focus
After a year in New York, as a Postdoctoral Research Associate at the Albert Einstein College of Medicine, Doherty spent the next eight years in Liverpool, developing her expertise in mass spectrometry. One ground-breaking project involved feeding chickens with various amino acids (the building blocks of proteins which enable cells to multiply and grow) to study the effects of different diets so researchers could develop better feedstuffs to improve production of poultry and eggs. “Mass spectrometry had a huge impact on what we were able to do,” says Doherty. “It was the enabling technology for our research.”
Since moving to Inverness in 2010, to lead a research programme in proteomics, Doherty’s projects have focused on cell culture, algae and fish, using mass spectrometry to observe what happens in their cells when fed with different proteins, and “understand the mechanisms of protein synthesis and degradation.”
Mass spectrometry enables researchers to analyse what happens in the cells of plants and animals by feeding them with amino acids or other small molecules which have been chemically altered to trace their incorporation into the cells, using a technique called “stable isotope labelling”. For example, by replacing the hydrogen atom in a particular protein with deuterium, you make the atom “heavier” and therefore much more visible and easier to trace using mass spectrometry, and Doherty has used this in her recent work to analyse protein synthesis and degradation – the rate at which proteins are created and die.
“We take small molecules, usually amino acids, and change them into something else,” says Doherty, “then see what happens when we feed them to the fish by analysing the proteins in the individual tissues such as muscle, liver or heart.”
The work at UHI
The team at UHI handle a wide range of projects, including looking at what happens when a new kind of synthetic material (a metal-organic framework) for a healthcare device comes in contact with living tissue such as muscle, to make sure it’s safe. The new material, developed by a team at the University of St Andrews, releases gases such as nitric oxide and hydrogen sulphide, which can be lethal in excessive doses but are also naturally present in the body; so the project helps to measure the effect of different versions of the framework which release each gas at different rates, depending on design.
Another project focuses on zebrafish, analysing the effects of stress on their hearts – ultimately to develop better fish oils, improve aquaculture and improve the health of fish and humans. According to Doherty, the researchers are interested in how stress changes the development of cells and how the proteins are synthesised, focusing on the rate of production rather than the volume. Doherty also reveals why the zebrafish make such good models – their stripes are like barcodes which enable researchers to track the behaviour of each individual as they swim around the tank.
And it’s not just proteins the team are interested in. Since moving to Inverness, Doherty has become increasingly involved in applying the techniques developed in proteomics to understand the roles of different fats, or lipids, in the body. “One fat is not the same as another. They are key components of ell membranes but can also act as signals for the cell, and we are interested, for example, in understanding how specific lipids both cause and resolve inflammation.”
At UHI, says Doherty, researchers are encouraged to engage with industrial partners as well as carry out pure research, and this is a major attraction to her and the rest of the team, helping to make sure they have enough funding and can plan for the future.
In addition to her work as a lecturer and a researcher, Doherty is also the Head of Postgraduate Researcher Development at UHI, monitoring the experience of post-graduate students at different campuses, from Skye and Stornoway to Perth, to ensure “that they all get a place at the table,” covering every department including social sciences and arts as well as science and technology. She is also a Visiting Reader at Robert Gordon University in Aberdeen, and a member of the Young Academy of Scotland's international committee. She has also been active in Scottish Crucible, helping “to develop strategic partnerships across the research spectrum” in Scottish universities, and is responsible for the university's application for accreditation by the Athena SWAN Charter, which encourages and recognises equal treatment for men and women in higher education and research.
Just as mass spectrometry has a critical role to play in biological and biomedical research, collaboration is key to the future success of the Lipidomics Research Facility, set up five years ago with funding of £2 million from the Scottish Funding Council, Highlands and Islands Enterprise and the European Regional Development Fund. The facility is also one of Doherty's proudest achievements, and one of the first specialist centres of its type in the country, attracting researchers from all over the world, including the United States and Europe.
“Our team started with an empty room in what might be perceived as the middle of nowhere,” says Doherty, “and now the centre has a worldwide reputation.”
What is mass spectrometry?
Mass spectrometry (MS) is an analytical chemistry technique which helps identify the amount and type of chemicals present in a sample. Mass spectra are used to determine the elemental or isotopic signature of a sample, the masses of particles and molecules, and to elucidate the chemical structures of molecules such as peptides and other chemical compounds. Mass spectrometry works by ionizing chemical compounds to generate charged molecules and measuring their mass-to-charge ratios. Mass spectrometry is used in a wide range of fields, including new-born screening, drug testing and whisky production, and is now a fundamental tool in biological research.