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Fields & Applications Metabolomics & Lipidomics, Proteomics, Translational Science

Metabolomics Originals – With Gary Siuzdak

This year, Scripps Research is celebrating its 100-year anniversary! Their motto? Turning scientific inquiry into innovative treatments that benefit the world. In this series of articles, we aim to shine a spotlight on some of the leading analytical scientists at Scripps – and the crucial role their work plays in delivering on Scripp’s raison d’etre. Here, we speak with Gary Siuzdak, Senior Scientific Director and Professor of Chemistry, Molecular and Computational Biology, who highlights the role analytical scientists play – working closely with biologists – in designing and analyzing experiments that answer fundamental questions about metabolism.

Metabolomics Originals

By Gary Siuzdak

Over the years, my team and I have developed novel analytical tools and computational strategies that have been instrumental in deciphering complex metabolic processes. Our primary focus in this area has been on mass spectrometry-based technologies, beginning in the 1990s when we performed what were then the first LC-MS-based metabolomics experiments in a sleep study. These experiments were in collaboration with Richard Lerner (then Scripps president) and Ben Cravatt (now Scripps professor).

Mass spectrometry is indispensable for the high-throughput and high-resolution analysis of metabolites. This technique allows us to quantitatively analyze the chemical composition of biological samples with an extraordinary level of detail. The data we gather are complex and rich, providing us with snapshots of metabolic dynamics that are integral to understanding disease and health. We use both targeted and untargeted metabolomic approaches to analyze biological samples – the latter allows us to discover novel metabolites and unexpected pathways, while targeted approaches let us quantify known metabolites with precision.

Perhaps our most groundbreaking analytical effort in our laboratory (orginating with the Lerner sleep study) is the creation of our XCMS-METLIN platform, a data processing approach combined with comprehensive database to facilitate metabolomic data analysis. In the sleep study, all data analyses and identifications were originally performed manually, a time consuming process, now XCMS-METLIN allows us to deconvolve these studies more rapidly and ultimately in a simpler and more straightforward format, greatly reducing its complexity. In addition, XCMS-METLIN is being designed to further integrate with other omics data, enabling a more holistic view of biological systems. The completion of this tool represents a significant leap forward in systems biology – establishing a comprehensive database of human metabolites, as well as exogenous molecules with a goal of identifying their ability to modulate disease.

Ongoing metabolomic experiments are all performed, like the original sleep study, with high-resolution mass spectrometry coupled with liquid chromatography (LC-HRMS) – to separate and identify thousands of molecules in a single run with high sensitivity and specificity – as well as advanced tandem mass spectrometry techniques (MS/MS via METLIN) to improve our ability to elucidate the structures of new metabolites.

Looking forward from the original LC-MS-based metabolomics that we performed 30 years ago, our plans in the Scripps Center for Metabolomics have an overarching goal: to significantly advance our understanding of the metabolome and its role in health and disease. We aim to push the boundaries of metabolomics to not only understand disease pathology but also to provide solutions that can be translated into clinical practice.

How It All Started

I decided to combine my background in chemistry and mathematics – culminating in a PhD to focus on mass spectrometry technologies and pioneering work in the then nascent field of metabolomics.

Today, as Professor and Senior Director at the Scripps Center for Metabolomics, my scientific career is still dedicated to advancing the field of metabolomics through the development of mass spectrometry techniques and analysis tools.

Our research has provided insights into various diseases, including cancer, neurodegeneration, inflammation, immunomodulation, neuropathic pain, stem cell differentiation, among many others, and contributed to the discovery of the role that endogenous metabolites play in modulating phenotype and therapeutically treating disease (1). As we celebrate the centennial of Scripps Research, I am honored to have played a part in its history of scientific excellence.

The driving force behind the research

None of our developments or innovative ideas would have been possible without the present and former scientists in my group – they are the driving force behind these discoveries. Their expertise range from biochemistry to analytics to bioinformatics, creating a fertile ground for innovation. They are not only adept at operating sophisticated instrumentation, but also at developing new analytical methodologies and computational tools to better capture and interpret the wealth of data we generate. 

In our projects at Scripps, we work closely with biologists to design experiments that answer fundamental questions about metabolism. Our analytical expertise is what really enables us to move from observing correlations to understanding causations in metabolic pathways. And that’s crucial for our translational goals, as it provides a direct link between metabolic changes and physiological outcomes.

One of my favorite stories, beyond the original sleep study, was work performed by Oscar Yanes fifteen years ago. In short Oscar discovered the plasticity of stem cell lipids were a key attribute of stem cells that enable their differentiation into other cells (2), and he even discovered one endogenous metabolite that drives differentiation, neuroprotectin D1. Along the way, Oscar also created a new way of performing LC-MS thus doubling of sensitivity (3). Pretty cool stuff.

Analytical scientists – not only in our group, but in general – are innovators and thought leaders who push the boundaries of what’s possible in metabolomics research and beyond. 

Gary Siuzdak is Senior Scientific Director and Professor of Chemistry, Molecular, and Computational Biology at Scripps, USA

Headshot - Credit: Supplied by Author | Hero Credit - Images supplied by Scripps Research

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  1. M Rinschen et al., “Identification of bioactive metabolites using activity metabolomics,” Nat Rev Mol Cel Biol, 20, 353–367 (2019). DOI: 10.1038/s41580-019-0108-4.
  2. O Yanes et al., “Metabolic oxidation regulates embryonic stem cell differentiation,” Nat Chem Biol, 6, 411–417 (2010). DOI: 10.1038/nchembio.364. 
  3. O Yanes et al., “Expanding Coverage of the Metabolome for Global Metabolite Profiling,” Anal Chem, 83, 6, 2152–2161 (2011). DOI: 10.1021/ac102981k.
About the Author
Gary Siuzdak

Gary Siuzdak is Professor and Director of the Scripps Center for Metabolomics at Scripps Research, La Jolla, California, USA.

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