The analysis of metals is commonly performed on all types of waters and foodstuffs to make sure the water we drink is free from toxic lead and the food we eat does not contain the highly toxic inorganic forms of arsenic. But what about metals in the development of neurodegenerative diseases?
The role and the importance of metals in life sciences is an emerging area of study. Whereas some metals, such as iron, copper or zinc, are acting as important co-factors in proteins (in fact, every 10th protein in a human being contains zinc!), little is known how metals may interact in the development of the diseases of our times, such as cardiovascular or neurodegenerative diseases. Metallomics, an emerging branch of the life sciences, serves to unravel the elusive role of metals in biology with significant implications in human health and disease.
One of the researchers driving the development of Metallomics is Dr. Theodora Stewart, Manager of the London Metallomics Facility, at King´s College London. In this interview, Theodora will explain how she uses laser ablation hyphenated with inductively coupled plasma mass spectrometry (LA-ICP-MS) to generate stunning images of the spatial distribution of metals in thin tissue sections, with up to sub µm resolution.
Q: Could you please introduce yourself?
A: My name is Dr. Theodora Stewart (on publications that is), but most people know me simply as Thea. I moved to London about five years ago after receiving an Early Post-Doc Mobility grant to help build up the London Metallomics Facility. The LMF is a newly created core facility at King´s College London, whose aim is to be a centralized hub for comprehensive multi-institutional integration of state-of-the-art Metallomic analytics and correlative bioimaging. Our objective is to establish direct interaction between leading research groups, commercial partners, and industry, whilst driving educational outreach and public engagement strategies. Over the past three years, I’ve worked to establish an LA-ICP-MS setup and workflow for elemental bioimaging and currently manage the LMF, which finally allowed me to beautifully integrate all the diverse scientific applications and skillsets that I have developed over the past 15 years through lab work and collaborations integrating chemistry, biology and a bit of physics thrown in for fun.
Q: How would you describe Metallomics in your own words?
A: First, I think it is important to recognize that nearly 85% of the periodic table is classified as either metals or metalloids and, although metals may only make up 2.5% of the human body in mass, they support the very foundation of life itself. That realization has been central to the context in which I always describe Metallomics and the reason why I find it to be such a powerful emerging field. In Metallomics, we are trying to understand the role of metal chemistry dynamics in biological processes within the context of a functioning system. This pursuit spans from the atomic to whole-body scales in understanding everything from how a metal is coordinated and bound within a biomolecule to how metal homeostasis is controlled at a systemic level and how that intricate balance is required for human health and, when impacted, effectuates disease. Metals are inextricably woven into the fabric of life and involved in biological processes spanning the genome to metabolome, and I see Metallomics as a master integrator of our current omics fields with the ability to open new horizons of scientific discovery.
Q: What is the main focus of your research?
A: I’ve always been excited by the how part of any scientific question. It is one first essential step to ask a brilliant question and have a hypothesis, but it is how you go about elegantly proving it and unraveling the mystery of a reality that is right in front of you that I feel is the most critical aspect. Step changes and breakthroughs in science are often paired with the evolution of analytical techniques and the use of existing approaches in new and creative ways. My research interests have always been at the interface of biology, chemistry, and physics, with a specific focus on developing analytical techniques and workflows to quantify dynamics of intracellular metal species, their subcellular localization, and to identify key biomolecules involved in their binding and transport with minimal disruption to the system of study. I’ve used elemental mass spectrometry, secondary ion mass spectrometry and synchrotron X-ray spectroscopy-based bioimaging techniques and see the power of taking what I have coined an analytical omics approach to solve scientific questions. Right now my main focus is to develop the most comprehensive analytical toolkit at the LMF for researchers to carry out their work within the context of elemental analyses to underpin the rich and complex field of Metallomics, and a main focal point has been on the development of elemental bioimaging and its integration into other imaging workflows.
Q: What is the benefit of using laser ablation ICP-MS as an imaging technique?
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A: Although this technique is unfortunately destructive, it is currently the best approach for obtaining high-resolution images (down to 1 micron and sometimes even smaller) of elemental isotopes in biological samples. Within the context of understanding the vital roles that trace metals play in biological processes, the combination of cellular resolution and high sensitivity provided by ICP-MS (routinely ppb and often ppt detection limits) is essential. We now know that it is not simply how much of an element is present in a sample, but also where it is localized that imparts its biological function. In addition, LA-ICP-MS is not limited to naturally incorporated elements but can be used in localizing metal-tagged antibodies in tissue sections. In this multiplexing approach, typically up to 40 antibodies can be routinely and simultaneously visualized, far surpassing the number of fluorescence-tagged antibodies typically used in immunohistochemistry approaches.
Q: Why did you decide to go for a triple quadrupole ICP-MS?
A: We are currently using a Thermo Scientific iCAP TQ ICP-MS in our laboratory, together with a Teledyne Cetac Analyte Excite 193 nm excimer laser ablation system. With the triple quad we have an extra mass filter that we can utilize to remove particularly difficult interferences that pop up in ICP-MS. One good example is the determination of titanium in biological samples, where all isotopes suffer from significant polyatomic interferences (caused by, i.e., phosphorous, sulfur or carbon), but, more importantly, some isobaric interferences from calcium, commonly found in biological material. With the ability to remove both polyatomic and isobaric interferences, we have the greatest control to accurately quantify low levels of elements in complex biological samples. This is important because essential metals in small amounts can be critical to biological function and, conversely, certain non-essential metals can cause toxic effects at low levels.
Q: You have recently organized a virtual symposium on Metal Fingerprints in Normal Cell States and Disease. Was there a main takeaway from the presentations on the day?
A: The talks certainly highlighted novel insights into the importance of metal homeostasis in human health and disease along with the analytical approaches used. However, the most prevalent response I received from attendees was how surprised and impressed people were at the wide range of high-level talks in such different scientific fields. This observation is something that has always been the most rewarding aspect of spearheading initiatives in Metallomics: the ability to bring together such disparate scientific communities in finding common ground, expanding personal horizons of thought, and sparking unique scientific collaborations.
Q: What was the reason for you to organize the workshop?
A: We organized this symposium within the context of an internal King’s Together Strategic Award we received to disseminate our findings to a larger scientific community and to illustrate the importance of MetallomicsMetallomics within the context of human health and disease. Our original plan was to have a large face-to-face conference already in 2020, which was obviously not possible at the time. We were unsure if we could proceed and then finally made the decision to turn it into a virtual event. Clearly, we did not know if this concept would work in a virtual meeting but based on the number of attendees and feedback, it was a great success and really illustrated to me that this event will be the first of more to come.
Q: What was your personal highlight of the workshop?
A: The highlight probably came in the last 15 minutes as the vice president and vice principal of Research at King’s College London concluded the symposium following our final keynote Nobel Laureate lecture. He described how exciting and how much potential the field of Metallomics holds and how the LMF is at the forefront of driving the analytics behind this emerging field. After all the hard work and preparation for such a large event, it finally sunk in at what we have accomplished, not just within the context of the grant or the symposium, but over the past three years in building the LMF. The best part? I feel this is just the start of a wild and beautiful ride into opening new expanses of novel scientific discovery and cannot wait to see what the next few years bring.
Thank you, Thea, for taking the time and sharing some insights on the growing importance of Metallomics with us. I am already looking forward to the next Symposium!
For more information on elemental imaging in Metallomics, please have a look at this article authored by Dr. Theodora Stewart. To learn more about our complete ICP-MS instrument portfolio, visit our ICP-MS resource page here. If you have any questions about how to set up a LA-ICP-MS system in your laboratory, or you’d like advice on how to solve your ICP-MS interference challenges, let us know via the comments box below!